Protocols and Video Articles Authored by Eco J. de Geus (Translated to Turkish)

The Association Between Brain Volume and Intelligence is of Genetic Origin Nature Neuroscience. Feb, 2002 | Pubmed ID: 11818967

Twin-singleton Differences in Brain Structure Using Structural Equation Modelling Brain : a Journal of Neurology. Feb, 2002 | Pubmed ID: 11844738 Twin studies are important to investigate genetic influences on variation in human brain morphology in health and disease. However, the twin method has been criticized for its alleged non-generalizability due to differences in the intrauterine and family environment of twins, compared with singletons. To test whether twin-singleton differences complicate interpretation of genetic contributions on variation in brain volume, brains from 112 pairs of twins and 34 of their siblings with a mean (standard deviation) age of 30.7 (9.6) years were scanned using MRI. The influence of birth order, zygosity and twin-sibling differences on brain volume measures was analysed using maximum-likelihood model fitting. Variances were homogeneous across birth order, zygosity and twin-singleton status. Irrespective of zygosity, intracranial volume was smaller in second-born twins compared with first-born twins and compared with siblings. Grey matter volume was smaller in second-born twins compared with first-born twins. White matter was smaller in twins compared with siblings. Differences in grey and white matter between these groups were no longer significant after correction for intracranial volume. Total brain, and lateral and third ventricle volumes were comparable in twins and singletons. In conclusion, second-born twins have a smaller intracranial volume than their first-born co-twins and siblings. This suggests aberrant early brain development in second-born twins, which is consistent with the suboptimal pre- and perinatal environment related to birth order in twins. Since other brain volume measures were comparable between the groups, twin studies can provide reliable estimates of heritabilities in brain volume measures and these can be generalized to the singleton population.

Diagnostic Strategies for C-reactive Protein BMC Cardiovascular Disorders. May, 2002 | Pubmed ID: 12049676 Serum C-reactive protein (CRP) has been identified in prospective epidemiological research as an independent risk marker for cardiovascular disease. In this paper, short-term biological variation of CRP is documented and a strategy to test the reliability of a single CRP sample is proposed.

Contribution of Tonic Vagal Modulation of Heart Rate, Central Respiratory Drive, Respiratory Depth, and Respiratory Frequency to Respiratory Sinus Arrhythmia During Mental Stress and Physical Exercise Psychophysiology. Jul, 2002 | Pubmed ID: 12212635 This study tested various sources of changes in respiratory sinus arrhythmia (RSA). Twenty-two healthy participants participated in three experimental conditions (mental stress, relaxation, and mild physical exercise) that each consisted of three breathing parts (normal breathing, breathing compressed room air, and breathing compressed 5% CO2-enriched air). Independent contributions to changes in RSA were found for changes in tonic vagal modulation of heart rate, central respiratory drive (i.e., PaCO2), respiratory depth, and respiratory frequency. The relative contributions to changes in RSA differed for mental stress and physical exercise. It is concluded that uncorrected RSA will suffice to index within-subject changes in tonic vagal modulation of heart rate in most situations. However, if the central respiratory drive is expected to change, RSA should ideally be corrected for changes in PaCO2, respiratory depth, and respiratory frequency.

Introducing Genetic Psychophysiology Biological Psychology. Oct, 2002 | Pubmed ID: 12385666 Genetic psychophysiology examines interindividual variation in psychophysiological traits using behavioral genetic and molecular genetic techniques. It aims to delineate the pathways that lead from genomic variation to individual differences in cognitive abilities, affect regulation, and mental and physical health. This editorial provides an introduction to the twin design and gene finding strategies using psychophysiological endophenotypes. It also gives a brief outline of the papers presented in this special issue on genetic psychophysiology. Its main objective, and the objective of the entire special issue, is to interest psychophysiologists in the enormous potential of research in this area and to foster the development of collaborative relationships between psychophysiologists and molecular and behavioral geneticists that are necessary to move research in this area forward.

The Association Between Low Birth Weight and High Levels of Cholesterol is Not Due to an Increased Cholesterol Synthesis or Absorption: Analysis in Twins Pediatric Research. Dec, 2002 | Pubmed ID: 12438663 Low birth weight may be associated with high levels of cholesterol in later life through genetic factors that affect both birth weight and cholesterol metabolism. Alterations in cholesterol synthesis and absorption may play an important role in this association. We examined birth weight and plasma ratios of a precursor of cholesterol, lathosterol (an estimate of cholesterol synthesis), and plant sterols, campesterol and beta-sitosterol (estimates of cholesterol absorption), to cholesterol in 53 dizygotic and 58 monozygotic adolescent twin pairs. After adjustment for current weight, birth weight was not associated with the ratios of lathosterol, campesterol, and beta-sitosterol either in the overall sample [+0.07 micro mol/mmol/kg (95% confidence interval: -0.11 to 0.25), p = 0.5; +0.02 micro mol/mmol/kg (-0.33 to 0.37), p = 0.9; and -0.04 micro mol/mmol/kg (-0.23 to 0.15), p = 0.8, respectively] or in the intrapair analysis in dizygotic twins [+0.27 micro mol/mmol/kg (-0.28 to 0.82), p = 0.3; -0.03 micro mol/mmol/kg (-1.07 to 1.01), p = 1.0; and +0.04 micro mol/mmol/kg (-0.56 to 0.64), p = 0.9, respectively] or in the intrapair analysis in monozygotic twins [+0.54 micro mol/mmol/kg (-0.09 to 1.18), p = 0.09; -0.60 micro mol/mmol/kg (-1.59 to 0.39), p = 0.2; and -0.43 micro mol/mmol/kg (-0.99 to 0.14), p = 0.14, respectively]. Plasma levels of lathosterol, campesterol, and beta-sitosterol, which are indicators of cholesterol synthesis and absorption, thus do not explain the association of low birth weight with high levels of total and LDL cholesterol. As an alternative hypothesis, we suggest that a decrease in cholesterol clearance may play an important role.

Competitiveness and Hemodynamic Reactions to Competition Psychophysiology. Nov, 2002 | Pubmed ID: 12462504 This study examines the effects of competition and competitiveness on hemodynamics. Cardiovascular activity was measured in 27 men at resting baseline and during a car racing game, which comprised a solo race against time and three races against an experimenter. To assess hematocrit, blood was collected at rest and after the final race. Trait competitiveness was assessed by questionnaire. Competition elicited increases in hematocrit, blood pressure, heart rate, and total peripheral resistance, as well as decreases in preejection period and heart rate variability. The final race was rated as more competitive than the solo race. Compared to intrapersonal solo racing, the final interpersonal race was associated with shorter preejection periods and faster heart rates, markers of beta-adrenergic activation. Although trait competitiveness was not associated with beta-adrenergic activation, variations in state competitiveness were.

Event-related Alpha and Theta Responses in a Visuo-spatial Working Memory Task Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. Dec, 2002 | Pubmed ID: 12464325 To explore the reactivity of the theta and alpha rhythms during visuo-spatial working memory.

Stress and Secretory Immunity International Review of Neurobiology. 2002 | Pubmed ID: 12498106

Netherlands Twin Register: a Focus on Longitudinal Research Twin Research : the Official Journal of the International Society for Twin Studies. Oct, 2002 | Pubmed ID: 12537867 In 1986 we began The Netherlands Twin Register (NTR) by recruiting young twins and multiples a few weeks or months after birth. Currently we register around 50% of all newborn multiples in The Netherlands. Their parents receive a questionnaire at registration and afterwards when the children are 2, 3, 5, 7, 10 and 12 years of age. Teachers are asked to rate the behavior of the children at ages 7, 10 and 12 years. Adolescent and young-adult twins were recruited through City Councils in the early 1990s. These twins, their parents and siblings participate in longitudinal survey studies that include items about health, fertility, lifestyle, addiction, personality and psychopathology, religion, socioeconomic status, and educational attainment. The total number of twins and multiples registered with the NTR is currently over 60,000. Subgroups of twins and siblings take part in studies of cognitive development, brain function and neuropsychological indices of attention processes, and molecular genetic studies of classical and behavioral cardiovascular risk factors. DNA samples are currently collected in selected twin families for two large linkage studies, which aim to find QTLs for anxious depression and for nicotine addiction. Sisters who are mothers of DZ twins contribute DNA samples for a linkage study of DZ twinning. Large cohorts of phenotyped family members from the general population are very valuable for genetic epidemiological studies and permit selection of informative families for gene finding studies.

Innate Secretory Immunity in Response to Laboratory Stressors That Evoke Distinct Patterns of Cardiac Autonomic Activity Psychosomatic Medicine. Mar-Apr, 2003 | Pubmed ID: 12651992 Most infections begin at mucosal surfaces. These surfaces are covered by the secretory proteins of the exocrine glands (eg, the salivary, respiratory, and gastrointestinal glands), which provide a first line of innate defense. The release of these secretory proteins is under neuroendocrine control and thus, in theory, sensitive to modulation by psychosocial stress. This was empirically tested by measuring the salivary secretion of cystatin S, lactoferrin, alpha-amylase, the mucins MUC5B and MUC7, and total salivary protein in response to stressors known to evoke distinct patterns of cardiac autonomic activity.

Genetic Correlations Between Brain Volumes and the WAIS-III Dimensions of Verbal Comprehension, Working Memory, Perceptual Organization, and Processing Speed Twin Research : the Official Journal of the International Society for Twin Studies. Apr, 2003 | Pubmed ID: 12723999 We recently showed that the correlation of gray and white matter volume with full scale IQ and the Working Memory dimension are completely mediated by common genetic factors (Posthuma et al., 2002). Here we examine whether the other WAIS III dimensions (Verbal Comprehension, Perceptual Organization, Processing Speed) are also related to gray and white matter volume, and whether any of the dimensions are related to cerebellar volume. Two overlapping samples provided 135 subjects from 60 extended twin families for whom both MRI scans and WAIS III data were available. All three brain volumes are related to Working Memory capacity (r = 0.27). This phenotypic correlation is completely due to a common underlying genetic factor. Processing Speed was genetically related to white matter volume (r(g) = 0.39). Perceptual Organization was both genetically (r(g) = 0.39) and environmentally (r(e) = -0.71) related to cerebellar volume. Verbal Comprehension was not related to any of the three brain volumes. It is concluded that brain volumes are genetically related to intelligence which suggests that genes that influence brain volume may also be important for intelligence. It is also noted however, that the direction of causation (i.e., do genes influence brain volume which in turn influences intelligence, or alternatively, do genes influence intelligence which in turn influences brain volume), or the presence or absence of pleiotropy has not been resolved yet.

Low Birth Weight is Associated with Increased Sympathetic Activity: Dependence on Genetic Factors Circulation. Aug, 2003 | Pubmed ID: 12860905 Low birth weight may be associated with high blood pressure in later life through genetic factors, an association that may be explained by alterations in sympathetic and parasympathetic activity. We examined the association of birth weight with cardiac pre-ejection period and respiratory sinus arrhythmia (indicators of cardiac sympathetic and parasympathetic activity, respectively) and with blood pressure in 53 dizygotic and 61 monozygotic adolescent twin pairs.

Stress As a Determinant of Saliva-mediated Adherence and Coadherence of Oral and Nonoral Microorganisms Psychosomatic Medicine. Jul-Aug, 2003 | Pubmed ID: 12883111 The mucosal secretory proteins, such as the salivary proteins, play a key role in the acquisition and regulation of the mucosal microflora. Most notably, some microorganisms utilize the host's secretory proteins to adhere to the mucosa; a first step in colonization and infection. The secretory proteins also influence colonization by affecting the binding among microorganisms, a process denoted as coadherence. Previously we reported that acute stressors cause specific changes in saliva composition. The present study investigated to what extent these changes influence saliva-mediated microbial adherence and coadherence (ex vivo).

Genetic Correlation of Exercise with Heart Rate and Respiratory Sinus Arrhythmia Medicine and Science in Sports and Exercise. Aug, 2003 | Pubmed ID: 12900680 A twin design was used to test whether the association between exercise behavior and heart rate and the association between exercise behavior and respiratory sinus arrhythmia (RSA) derive from a common genetic factor.

Heritability of Daytime Cortisol Levels in Children Behavior Genetics. Jul, 2003 | Pubmed ID: 14574141 Individual differences in the level of the stress hormone cortisol play a prominent role as an explanatory variable in studies on psychopathology. Relatively few studies have paid attention to individual differences in cortisol levels and the etiology of these differences, in particular their possible genetic basis. All these studies have been in adults. The aim of this study was to estimate genetic and environmental influences on basal cortisol levels in 12-year-old children. To this end, four samples of salivary cortisol were collected on two consecutive days in a sample of 180 twin pairs. Low correlations were found between cortisol levels at different points in time during the day. A significant genetic contribution was found to the variation of basal cortisol levels in the morning and afternoon samples, but not in the evening sample. Heritability did not differ for boys and girls and was highest (60%) for cortisol levels during the sample taken about 45 minutes after awakening. This cortisol awakening response provides a useful endophenotype in the search for genes that may affect hypothalamic-pituitary adrenocortical functioning in children.

Large-scale Ensemble Averaging of Ambulatory Impedance Cardiograms Behavior Research Methods, Instruments, & Computers : a Journal of the Psychonomic Society, Inc. Aug, 2003 | Pubmed ID: 14587556 Impedance cardiography has been used increasingly to measure human physiological responses to emotional and mentally engaging stimuli. The validity of large-scale ensemble averaging of ambulatory impedance cardiograms was evaluated for preejection period (PEP), interbeat interval, and dZ/dt(min) amplitude. We tested whether the average of "classical" 60-sec ensemble averages across periods with fixed activity, posture, physical load, social situation, and location could be accurately estimated from a single large-scale ensemble average spanning these entire periods. Impedance and electrocardiograms were recorded for about 24-h from 21 subjects. Recordings were scored by seven raters, using both methods for each subject. Good agreement (average intraclass correlation coefficient was .91) between both ensemble averaging methods was found for all three cardiac function measures. The results indicate that for unambiguous ambulatory impedance cardiograms, large-scale ensemble averaging is valid, which makes measuring prolonged changes in cardiac sympathetic activity by measuring ambulatory PEP feasible even in large epidemiological samples.

Theory and Practice in Quantitative Genetics Twin Research : the Official Journal of the International Society for Twin Studies. Oct, 2003 | Pubmed ID: 14624720 With the rapid advances in molecular biology, the near completion of the human genome, the development of appropriate statistical genetic methods and the availability of the necessary computing power, the identification of quantitative trait loci has now become a realistic prospect for quantitative geneticists. We briefly describe the theoretical biometrical foundations underlying quantitative genetics. These theoretical underpinnings are translated into mathematical equations that allow the assessment of the contribution of observed (using DNA samples) and unobserved (using known genetic relationships) genetic variation to population variance in quantitative traits. Several statistical models for quantitative genetic analyses are described, such as models for the classical twin design, multivariate and longitudinal genetic analyses, extended twin analyses, and linkage and association analyses. For each, we show how the theoretical biometrical model can be translated into algebraic equations that may be used to generate scripts for statistical genetic software packages, such as Mx, Lisrel, SOLAR, or MERLIN. For using the former program a web-library (available from http://www.psy.vu.nl/mxbib) has been developed of freely available scripts that can be used to conduct all genetic analyses described in this paper.

The Genetics of Coronary Heart Disease: the Contribution of Twin Studies Twin Research : the Official Journal of the International Society for Twin Studies. Oct, 2003 | Pubmed ID: 14624727 Despite the decline in coronary heart disease in many European countries, the disease remains an enormous public health problem. Although we know a great deal about environmental risk factors for coronary heart disease, a heritable component was recognized a long time ago. The earliest and best known examples of how our genetic constitution may determine cardiovascular risk relate to lipoprotein(a), familial hypercholesterolaemia and apolipoprotein E. In the past 20 years a fair number of polymorphisms assessed singly have shown strong associations with the disease but most are subject to poor repeatability. Twins constitute a compelling natural experiment to establish the genetic contribution to coronary heart disease and its risk factors. GenomEUtwin, a recently funded Framework 5 Programme of the European Community, affords the opportunity of comparing the heritability of risk factors in different European Twin Registries. As an illustration we present the heritabilities of systolic and diastolic blood pressure, based on data from over 4000 twin pairs from six different European countries and Australia. Heritabilities for systolic blood pressure are between 52 and 66% and for diastolic blood pressure between 44 and 66%. There is no evidence of sex differences in heritability estimates and very little to no evidence for a significant contribution of shared family environment. A non-twin based prospective case/cohort study of coronary heart disease and stroke (MORGAM) will allow hypotheses relating to cardiovascular disease, generated in the twin cohorts, to be tested prospectively in adult populations. Twin studies have also contributed to our understanding of the life course hypothesis, and GenomEUtwin has the potential to add to this.

Exaggerated Perception of Normal Physiological Responses to Stress and Hypercapnia in Young Women with Numerous Functional Somatic Symptoms Journal of Psychosomatic Research. Dec, 2003 | Pubmed ID: 14642976 This study tested whether functional somatic symptoms are associated with exaggerated increases in self-reported anxiety and somatic complaints in response to stress and CO(2)-enriched air breathing, and whether this association exists in parallel to or in the absence of exaggerated physiological responses.

Overcommitment to Work is Associated with Changes in Cardiac Sympathetic Regulation Psychosomatic Medicine. Sep-Oct, 2004 | Pubmed ID: 15385688 Work stress is associated with an increased risk for cardiovascular disease (CVD). Exaggerated cardiovascular reactivity to work-related stressors or incomplete recovery after work is a proposed mechanism underlying this increase in risk. This study examined the effects of work stress on 24-hour profiles of the pre-ejection period (PEP), a measure of cardiac sympathetic activity, obtained from ambulatory measurement of the impedance cardiogram.

Estimating Non-response Bias in Family Studies: Application to Mental Health and Lifestyle European Journal of Epidemiology. 2004 | Pubmed ID: 15461193 Non-response to mailed surveys reduces the effective sample size and may introduce bias. Non-response has been studied by (1) comparison to available data in population based registers, (2) directly contacting non-respondents by telephone or single-item reply cards, and (3) longitudinal repetition of the survey. The goal of this paper was to propose an additional method to study non-response bias: when the variable of interest has a familial component, data from respondents can be used as proxy for the data from their non-responding family members. This approach was used with data on smoking, alcohol consumption, physical activity, coffee- and tea-use, education, body mass index, religion, burnout, life events, personality and mental health in large number of siblings and DZ twins registered with the Netherlands Twin Register. In addition, for smoking behavior, we also used the second strategy by sending a reply card. Results show that scores of members from less cooperative families or incomplete twin pairs tended to be more unfavorable than the scores from highly cooperative families or complete twin pairs. For example, family members from less cooperative families cycled less often and scored higher on anxious depression and neuroticism. For smoking, both the results of the reply card and the results of the additional method suggested a higher percentage smokers among the non-respondents but this was only significant with reply card method. In general, differences between highly/less cooperative families and complete/incomplete DZ twins were small. Results suggest that, even for studies with moderate response rates, data collected on health, personality and lifestyle are relatively unbiased.

Heritability of Ambulatory Heart Rate Variability Circulation. Nov, 2004 | Pubmed ID: 15492317 Reduced heart rate variability (HRV) is a prognostic factor for cardiac disease and cardiac mortality. Understanding the sources of individual differences in HRV may increase its diagnostic use and provide new angles for preventive therapy. To date, the contribution of genetic and environmental factors to the variance in HRV has not been investigated during prolonged periods of ambulatory monitoring in a naturalistic setting.

Job Strain in Relation to Ambulatory Blood Pressure, Heart Rate, and Heart Rate Variability Among Female Nurses Scandinavian Journal of Work, Environment & Health. Dec, 2004 | Pubmed ID: 15635758 This study examined the effects of exposure to job strain on independent predictors of cardiovascular disease (ambulatory blood pressure, heart rate, and heart rate variability).

On the Role of Working Memory in Response Interference Perceptual and Motor Skills. Dec, 2004 | Pubmed ID: 15648493 A recent study by de Fockert, et al. claimed that working memory and selective attention are interacting cognitive systems. We used a dual task design that closely resembled de Fockert, et al.'s experiment, but using different stimuli. Our subjects first had to store the positions and sequence of a number of blocks. During storage they then had to respond to a few selective attention trials, after which memory was tested. Selective attention was tested using a computerized version of the color Stroop task and the Simon task. We expected to find a monotonic increase of response interference with increasing working memory load, but we found only modest evidence of an influence of working memory on attention. The results shed new light on the nature of and the relation between these cognitive systems.

Heritability of Daytime Ambulatory Blood Pressure in an Extended Twin Design Hypertension. Jan, 2005 | Pubmed ID: 15557390 The present study estimated the genetic influences on ambulatory systolic and diastolic blood pressure, and on hypertensive status derived from ambulatory levels, in a family sample of 535 twins and 257 singleton siblings. This "extended twin design" was used to explicitly test the possibility that results obtained in singleton siblings are different from those obtained in twins. To examine the effects of excluding (medicated) hypertensive subjects, the genetic analyses were first performed under strict exclusion (medication and/or blood pressure >135/85 mm Hg), then without the medicated subjects, and, finally, without any exclusion. For the latter analysis, the untreated blood pressure values in subjects using antihypertensive medication were estimated by augmenting the observed blood pressure by the published efficacy of the specific antihypertensive medication used. No evidence was found for differential means, variances, or covariances of ambulatory blood pressure in singletons compared with twins. This indicates that estimates of heritability of ambulatory blood pressure from twin studies can be generalized to the singleton population. Heritability of hypertension, defined as a mean daytime blood pressure >135/85 mm Hg or antihypertensive medication use, was 61%. Genetic contribution to ambulatory blood pressure was highest when all subjects were included (systolic, 44% to 57%; diastolic, 46% to 63%) and lowest under strict exclusion (systolic, 32% to 50%; diastolic, 31% to 55%). We conclude that exclusion of (medicated) hypertensives removes part of the true genetic variance in ambulatory blood pressure.

A Genetic Analysis of Ambulatory Cardiorespiratory Coupling Psychophysiology. Mar, 2005 | Pubmed ID: 15787857 This study assessed the heritability of ambulatory heart period, respiratory sinus arrhythmia (RSA), and respiration rate and tested the hypothesis that the well-established correlation between these variables is determined by common genetic factors. In 780 healthy twins and siblings, 24-h ambulatory recordings of ECG and thorax impedance were made. Genetic analyses showed considerable heritability for heart period (37%-48%), RSA (40%-55%), and respiration rate (27%-81%) at all daily periods. Significant genetic correlations were found throughout. Common genes explained large portions of the covariance between heart period and RSA and between respiration rate and RSA. During the afternoon and night, the covariance between respiration rate and RSA was completely determined by common genes. This overlap in genes can be exploited to increase the power of linkage studies to detect genetic variation influencing cardiovascular disease risk.

Sports Participation During Adolescence: a Shift from Environmental to Genetic Factors Medicine and Science in Sports and Exercise. Apr, 2005 | Pubmed ID: 15809553 A twin design was used to assess the relative contribution of genetic and environmental influences on the variation in sports participation of Dutch male and female twins between the ages of 13 and 20 yr.

Human Cytokine Response to Ex Vivo Amyloid-beta Stimulation is Mediated by Genetic Factors Twin Research and Human Genetics : the Official Journal of the International Society for Twin Studies. Apr, 2005 | Pubmed ID: 15901476 Through its ability to induce the enhanced release and production of cytokines, amyloid-beta is responsible for the chronic inflammatory response that contributes to Alzheimer's disease (AD). Determining whether the response of monocytes to amyloid-beta stimulation is under genetic control may help understand the basis of why some people are more prone to develop neuronal degeneration than others. In the current study we investigated the heritability of the cytokine (IL-10, IL-6, IL-1beta, IL-1ra, TNF-alpha) production capacity upon ex vivo stimulation with amyloid-beta in whole blood samples of 222 twins and 85 singleton siblings from 139 extended twin families. It was found that individual differences in amyloid-beta induced cytokine production capacity are to a large extent of genetic origin, with heritability estimates ranging from 55% (IL-1beta) to 68% (IL-6). We conclude that genes influencing amyloid-beta-induced cytokine response may provide clues to the progression of AD pathology.

Genetic Components of Functional Connectivity in the Brain: the Heritability of Synchronization Likelihood Human Brain Mapping. Nov, 2005 | Pubmed ID: 15929086 Cognitive functions require the integrated activity of multiple specialized, distributed brain areas. Such functional coupling depends on the existence of anatomical connections between the various brain areas as well as physiological processes whereby the activity in one area influences the activity in another area. Recently, the Synchronization Likelihood (SL) method was developed as a general method to study both linear and nonlinear aspects of coupling. In the present study the genetic architecture of the SL in different frequency bands was investigated. Using a large genetically informative sample of 569 subjects from 282 extended twin families we found that the SL is moderately to highly heritable (41-67%) especially in the alpha frequency (8-13 Hz) range. This index of functional connectivity of the brain has been associated with a number of pathological states of the brain. The significant heritability found here suggests that SL can be used to examine the genetic susceptibility to these conditions.

Familial Influences on Basal Salivary Cortisol in an Adult Population Psychoneuroendocrinology. Oct, 2005 | Pubmed ID: 15949896 To understand the underlying genetic and environmental sources of individual variation in basal cortisol levels, we collected salivary cortisol at awakening and at six fixed time points during the day in adult twins and their singleton siblings. Reported time of awakening was verified with heart rate and body movement recordings. Cortisol data were available for 199 MZ twins, 272 DZ twins and 229 singleton siblings from 309 twin families. No differences in cortisol means and variances were found between twins and singleton siblings. Additionally, the correlations for DZ twins and siblings were not significantly different, indicating generalizability of twin study results to the general population. Genetic model fitting showed heritability for cortisol levels during the awakening period (34% for cortisol level at awakening and 32% for cortisol level at 30 min after awakening) but not for cortisol levels later during the day. The current study shows that, while cortisol levels in the awakening period are influenced by genetic factors, cortisol levels throughout most of the day are not heritable, indicating that future gene finding studies for basal cortisol should focus on the first hour post-awakening.

The Multi-source Interference Task: the Effect of Randomization Journal of Clinical and Experimental Neuropsychology. Aug, 2005 | Pubmed ID: 16019647 Recently a novel interference task was developed, that was aimed at obtaining robust patterns of interference in individual subjects, both behaviorally and neurophysiologically (Bush, Shin, Holmes, Rosen & Vogt, 2003). This multi-source interference task (MSIT) combined elements of spatial and flanker interference, and huge interference effects were obtained in a blocked design. This task could thus in principle be used to assess frontal abnormalities, such as ADHD. In the present study, we further examined the nature of the MSIT. We examined the effect of randomization, and the relative contribution of each type of interference. Using a group of healthy subjects, we found a much smaller interference effect than Bush et al. (2003). In addition, we found that most of the interference could be ascribed to flanker interference, and much less to spatial interference. It seems to be the case that there is a trade-off between obtaining robust and reliable effects, and isolating a specific psychological process.

Response Interference and Working Memory in 12-year-old Children Child Neuropsychology : a Journal on Normal and Abnormal Development in Childhood and Adolescence. Apr, 2005 | Pubmed ID: 16036444 A group of 69 12-year-old children performed three well-known response interference tasks: the Stroop task, the Eriksen flanker task, and the Simon task. Individual differences in accuracy and speed correlated across the tasks. However, there was no correlation between the interference effects on these three tasks. Stroop interference, but not the Simon or flanker effect, was correlated with working memory capacity, as obtained from the WISC-R. These results may help clarify the nature of ADHD, which is characterized by problems with response interference.

Perceptual Speed Does Not Cause Intelligence, and Intelligence Does Not Cause Perceptual Speed Biological Psychology. Sep, 2005 | Pubmed ID: 16038769 There is ongoing debate whether the efficiency of local cognitive processes leads to global cognitive ability or whether global ability feeds the efficiency of basic processes. A prominent example is the well-replicated association between inspection time (IT), a measure of perceptual discrimination speed, and intelligence (IQ), where it is not known whether increased speed is a cause or consequence of high IQ. We investigated the direction of causation between IT and IQ in 2012 genetically related subjects from Australia and The Netherlands. Models in which the reliable variance of each observed variable was specified as a latent trait showed IT correlations of -0.44 and -0.33 with respective Performance and Verbal IQ; heritabilities were 57% (IT), 83% (PIQ) and 77% (VIQ). Directional causation models provided poor fits to the data, with covariation best explained by pleiotropic genes (influencing variation in both IT and IQ). This finding of a common genetic factor provides a better target for identifying genes involved in cognition than genes which are unique to specific traits.

Heritability and Stability of Resting Blood Pressure Twin Research and Human Genetics : the Official Journal of the International Society for Twin Studies. Oct, 2005 | Pubmed ID: 16212839 We examined the contribution of genetic and environmental influences to variation in resting systolic (SBP) and diastolic (DBP) blood pressure in participants from 4 twin studies carried out between 1986 and 2003. A total of 1577 subjects (682 males, 895 females) participated. There were 580 monozygotic twins, 664 dizygotic twins and 333 of their siblings. The 4 studies sampled subjects in different age groups (average age 17, 32, 37, 44 years), allowing for comparison of the relative contribution of genetic and environmental factors across the first part of the life span. Blood pressure was assessed under laboratory conditions in 3 studies and by ambulatory monitoring in 1 study. Univariate analyses of SBP and DBP showed significant heritability of blood pressure in all studies (SBP h(2) 48% to 60%, DBP h(2) 34% to 67%). Overall, there was little evidence for sex differences in blood pressure heritability, and no evidence for differences in heritability due to measurement strategy (laboratory vs. ambulatory). For 431 subjects there were data from 2 or more occasions that allowed us to assess the tracking of blood pressure over time and to estimate the genetic and environmental contributions to blood pressure tracking. Correlations over time across an average period of 7.1 years (tracking) were between .41 and .70. Multivariate genetic analyses showed that blood pressure tracking was entirely explained by the same genetic factors being expressed across time. It was concluded that whole genome scans for resting blood pressure can safely pool data from males and females, laboratory and ambulatory recordings, and different age cohorts.

Familial Clustering of Major Depression and Anxiety Disorders in Australian and Dutch Twins and Siblings Twin Research and Human Genetics : the Official Journal of the International Society for Twin Studies. Dec, 2005 | Pubmed ID: 16354503 The aim of this study was to investigate familial influences and their dependence on sex for panic disorder and/or agoraphobia, social phobia, generalized anxiety disorder and major depression. Data from Australian (N = 2287) and Dutch (N = 1185) twins and siblings who were selected for a linkage study and participated in clinical interviews to obtain lifetime Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) diagnoses were used. In a liability model, tetrachoric correlations were estimated in sibling pairs and sex differences between sibling correlations were tested. For each diagnosis, the sibling correlations could be constrained to be equal across the Australian and Dutch samples. With the exception of panic disorder and/or agoraphobia, all sibling correlations were the same for brother, sister and opposite-sex sibling pairs and were around .20. For panic disorder and/or agoraphobia, the correlation was .23 in brother and sister pairs, but absent in opposite-sex sibling pairs. From these results it can be concluded that upper heritability estimates, based on twice the correlations in the sibling pairs, vary between 36% (major depression) and 50% (social phobia). Furthermore, different genetic risk factors appear to contribute to the vulnerability for panic disorder and/or agoraphobia in men and women. No other sex differences were found.

Validation of the Thoracic Impedance Derived Respiratory Signal Using Multilevel Analysis International Journal of Psychophysiology : Official Journal of the International Organization of Psychophysiology. Feb, 2006 | Pubmed ID: 15893397 The purpose of the current study was to validate the change in thoracic impedance (dZ) derived respiratory signal obtained from four spot electrodes against incidental spirometry. Additionally, a similar validation was performed for a dual respiratory belts signal to compare the relative merit of both methods. Participants were 38 healthy adult subjects (half male, half female). Cross-method comparisons were performed at three (paced) respiration frequencies in sitting, supine and standing postures. Multilevel regression was used to examine the within- and between-subjects structure of the relationship between spirometric volume and the respiratory amplitude signals obtained from either dZ or respiratory belts. Both dZ derived respiratory rate and dual belts derived respiratory rate accurately reflected the pacing frequencies. For both methods, fixed factors indicated acceptable but posture-specific regression on spirometric volume. However, random factors indicated large individual differences, which was supported by variability of gain analyses. It was concluded that both the dZ and dual belts methods can be used for measurement of respiratory rate and within-subjects, posture-specific, changes in respiratory volume. The need for frequent subject-specific and posture-specific calibration combined with relatively large measurement errors may strongly limit the usefulness of both methods to assess absolute tidal volume and minute ventilation in ambulatory designs.

Temporal Stability of Ambulatory Stroke Volume and Cardiac Output Measured by Impedance Cardiography Biological Psychology. Apr, 2006 | Pubmed ID: 16223558 Recently, devices have become available that allow non-invasive measurement of stroke volume and cardiac output through ambulatory thorax impedance recording. If such recordings have adequate temporal stability, they offer great potential to further our understanding of how repeated or chronic cardiovascular activation in response to naturalistic events may contribute to cardiovascular disease. In this study, 24 h ambulatory impedance-derived systolic time intervals, stroke volume and cardiac output were measured in 65 healthy subjects across an average time span of 3 years and 4 months. Stability was computed separately for sleep and daytime recordings. To avoid confounding by differences in posture and physical activity across measurement days, temporal stability was computed using sitting activities only. During the day intraclass correlations were moderate for stroke volume (.29-.46) and cardiac output (.33-.46) and good for systolic time intervals (.55-.81). When test-retest comparison was limited to two comparable days (two work days or two leisure days), correlations for both SV (.42-.46) and CO (.43-.50) improved. CONCLUSION: Moderate long-term temporal stability is found for individual differences in ambulatory stroke volume and cardiac output measured by impedance cardiography.

Genetic Etiology of Stability of Attention Problems in Young Adulthood American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics : the Official Publication of the International Society of Psychiatric Genetics. Jan, 2006 | Pubmed ID: 16287044 Variation in attention problems in children and adolescents from non-clinical samples is highly heritable. It is unknown how attention problems develop later in life and whether the heritability in the general adult population is the same as in children and adolescents. We assessed the heritability and stability of individual differences in attention problems in the general young adult population and explored to what extent the stability can be attributed to genetic or environmental factors. On one or more occasions, young adult twins (age range, 18-30 years, N = 4,245) from the Netherlands Twin Registry filled out the attention problems (AP) subscale of the Young Adult Self-Report [Achenbach, 1997]: in 1991, N = 1,755 (of which 842 complete pairs), in 1995, N = 2,428 (1156 complete pairs) and in 1997, N = 2,344 (958 pairs). There was only a slight decrease in the average level of attention problems during young adulthood. The heritability at each occasion was around 40%. The correlation of attention problems across a period of 6 years was 0.42, and 77% of this correlation could be ascribed to genetic influences. Thus, individual differences in attention problems in young adulthood are heritable, and stability in individual differences over time can largely be ascribed to genetic influences. Genetic correlations across time were high, suggesting that the genes that influence variability in attention problems in late adolescence are largely the same as those that influence variability in early adulthood.

Replicated Linkage for Eye Color on 15q Using Comparative Ratings of Sibling Pairs Behavior Genetics. Jan, 2006 | Pubmed ID: 16341609 : The aim of the study was to perform a genetic linkage analysis for eye color, for comparative data. Similarity in eye color of mono- and dizygotic twins was rated by the twins' mother, their father and/or the twins themselves. For 4,748 twin pairs the similarity in eye color was available on a three point scale ("not at all alike"-"somewhat alike"-"completely alike"), absolute eye color on individuals was not assessed. The probability that twins were alike for eye color was calculated as a weighted average of the different responses of all respondents on several different time points. The mean probability of being alike for eye color was 0.98 for MZ twins (2,167 pairs), whereas the mean probability for DZ twins was 0.46 (2,537 pairs), suggesting very high heritability for eye color. For 294 DZ twin pairs genome-wide marker data were available. The probability of being alike for eye color was regressed on the average amount of IBD sharing. We found a peak LOD-score of 2.9 at chromosome 15q, overlapping with the region recently implicated for absolute ratings of eye color in Australian twins [Zhu, G., Evans, D. M., Duffy, D. L., Montgomery, G. W., Medland, S. E., Gillespie, N. A., Ewen, K. R., Jewell, M., Liew, Y. W., Hayward, N. K., Sturm, R. A., Trent, J. M., and Martin, N. G. (2004). Twin Res. 7:197-210] and containing the OCA2 gene, which is the major candidate gene for eye color [Sturm, R. A. Teasdale, R. D, and Box, N. F. (2001). Gene 277:49-62]. Our results demonstrate that comparative measures on relatives can be used in genetic linkage analysis.

Genetic Influences on Fibrinogen, Tissue Plasminogen Activator-antigen and Von Willebrand Factor in Males and Females Thrombosis and Haemostasis. Mar, 2006 | Pubmed ID: 16525567 Differences in genetic influence on death from CHD between males and females have been reported. Haemostatic factors have consistently been associated with risk for coronary heart disease (CHD), but sex differences in genetic architecture have not been studied. This study in middle-aged twins investigates whether there are sex differences in means and in genetic and/or environmental variance components of haemostatic risk factors for CHD. A total of 93 monozygotic twin pairs (44 male and 49 female) and 116 dizygotic twin pairs (36 male, 40 female and 40 opposite sex) were available for this study. Structural equation modelling was used to estimate the relative influence of genetic and environmental factors on variation in levels of fibrinogen, tissue plasminogen activator (tPA) antigen and von Willebrand factor (vWF). Mean levels of tPA and vWF increased with age. Oral contraceptive pill (OCP) and menopause had significant influences on levels of fibrinogen and tPA. Genetic influences explained 39, 66 and 72% of the variation in levels of fibrinogen, tPA and vWF, respectively. No quantitative or qualitative differences of genetic influences on haemostatic levels were seen between males and females. Haemostatic factors may account for a significant part of the genetic risk for cardiovascular disease. No difference in genetic architecture for levels of fibrinogen, tPA or vWF was observed between males and females.

Genetic Pleiotropy in Depression and Coronary Artery Disease Psychosomatic Medicine. Mar-Apr, 2006 | Pubmed ID: 16554381

Heritability and Stability of Resting Blood Pressure in Australian Twins Twin Research and Human Genetics : the Official Journal of the International Society for Twin Studies. Apr, 2006 | Pubmed ID: 16611489 In Australian twins participating in three different studies (1979-1996), the contribution of genetic and environmental influences to variation in resting systolic (SBP) and diastolic blood pressure (DBP) was studied. The sample consisted of 368 monozygotic and 335 dizygotic twin pairs with measurements for both individuals. Blood pressure measurements in two studies were available for 115 complete twin pairs, and 49 twin pairs had measurements in three studies. This allowed assessment of blood pressure tracking over an average period of 12 years in the age range of 23 to 45 years. Multivariate analyses showed significant heritability (h2) of blood pressure in all studies (SBP h2 = 19%-56%, DBP h2 = 37%-52%). In addition, the analyses showed that the blood pressure tracking was explained by the same set of genetic factors. These results replicate an earlier finding in Dutch twins that also showed stability of the contribution of genetic factors to blood pressure tracking.

Heritability of Indices for Cardiac Contractility in Ambulatory Recordings Journal of Cardiovascular Electrophysiology. Aug, 2006 | Pubmed ID: 16800859 Overactivity of the sympathetic nervous system (SNS) plays a pivotal role in the development of cardiovascular disease. This involvement suggests that the genetic susceptibility to adverse cardiovascular events may derive in part from individual differences in SNS activity.

Physical Activity and Cognitive Function in a Cross-section of Younger and Older Community-dwelling Individuals Health Psychology : Official Journal of the Division of Health Psychology, American Psychological Association. Nov, 2006 | Pubmed ID: 17100496 Previous reports have indicated a small, positive relationship between physical activity and cognition. However, the majority of research has focused on older adults, with few studies examining this relationship during earlier periods of the life span. This study examined the relationship of physical activity to cognition in a cross-section of 241 community-dwelling individuals 15-71 years of age with a task requiring variable amounts of executive control. Data were analyzed with multiple regression, which controlled for age, sex, and IQ. Participants reported their physical activity behavior and were tested for reaction time (RT) and response accuracy on congruent and incongruent conditions of a flanker task, which manipulates interference control. After controlling for confounding variables, an age-related slowing of RT was observed during both congruent and incongruent flanker conditions. However, physical activity was associated with faster RT during these conditions, regardless of age. Response accuracy findings indicated that increased physical activity was associated with better performance only during the incongruent condition for the older cohort. Findings suggest that physical activity may be beneficial to both general and selective aspects of cognition, particularly among older adults.

Genetic Influences on Exercise Participation in 37,051 Twin Pairs from Seven Countries PloS One. 2006 | Pubmed ID: 17183649 A sedentary lifestyle remains a major threat to health in contemporary societies. To get more insight in the relative contribution of genetic and environmental influences on individual differences in exercise participation, twin samples from seven countries participating in the GenomEUtwin project were used.

Accounting for Sequential Trial Effects in the Flanker Task: Conflict Adaptation or Associative Priming? Memory & Cognition. Sep, 2006 | Pubmed ID: 17225507 The conflict-control loop theory proposes that the detection of conflict in information processing triggers an increase in cognitive control, resulting in improved performance on the subsequent trial. This theory seems consistent with the robust finding that conflict susceptibility is reduced following correct trials associated with high conflict: the conflict adaptation effect. However, despite providing favorable conditions for eliciting and detecting conflict-triggered performance adjustments, none of the five experiments reported here provide unequivocal evidence of such adjustments. Instead, the results corroborate and extend earlier findings by demonstrating that the conflict adaptation effect, at least in the flanker task, is only present for a specific subset of trial sequences that is characterized by a response repetition. This pattern of results provides strong evidence that the conflict adaptation effect reflects associative stimulus-response priming instead of conflict-driven adaptations in cognitive control.

Netherlands Twin Register: from Twins to Twin Families Twin Research and Human Genetics : the Official Journal of the International Society for Twin Studies. Dec, 2006 | Pubmed ID: 17254420 In the late 1980s The Netherlands Twin Register (NTR) was established by recruiting young twins and multiples at birth and by approaching adolescent and young adult twins through city councils. The Adult NTR (ANTR) includes twins, their parents, siblings, spouses and their adult offspring. The number of participants in the ANTR who take part in survey and / or laboratory studies is over 22,000 subjects. A special group of participants consists of sisters who are mothers of twins. In the Young NTR (YNTR), data on more than 50,000 young twins have been collected. Currently we are extending the YNTR by including siblings of twins. Participants in YNTR and ANTR have been phenotyped every 2 to 3 years in longitudinal survey studies, since 1986 and 1991 for the YNTR and ANTR, respectively. The resulting large population-based datasets are used for genetic epidemiological studies and also, for example, to advance phenotyping through the development of new syndrome scales based on existing items from other inventories. New research developments further include brain imaging studies in selected and unselected groups, clinical assessment of psychopathology through interviews, and cross-referencing the NTR database to other national databases. A large biobank enterprise is ongoing in the ANTR in which blood and urine samples are collected for genotyping, expression analysis, and metabolomics studies. In this paper we give an update on the YNTR and ANTR phenotyping and on the ongoing ANTR biobank studies.

Intrapair Differences in Hippocampal Volume in Monozygotic Twins Discordant for the Risk for Anxiety and Depression Biological Psychiatry. May, 2007 | Pubmed ID: 17137562 Current biological psychiatric models assume that genetic and environmental risk factors for anxiety and depression act on the same brain structures.

Family Based Association Analyses Between the Serotonin Transporter Gene Polymorphism (5-HTTLPR) and Neuroticism, Anxiety and Depression Behavior Genetics. Mar, 2007 | Pubmed ID: 17216342 We studied the association between the short/long promotor-based length polymorphism of the serotonin transporter gene (5-HTTLPR) and neuroticism, anxiety and depression. Subjects included twins, their siblings and parents from the Netherlands Twin Register (559 parents and 1,245 offspring). Subjects had participated between one and five times in a survey study measuring neuroticism, anxiety and depression. Offspring of these families were also approached to participate in a psychiatric interview diagnosing DSM-IV major depression. Within-family and total association between 5-HTTLPR and these traits were tested. Only three of the 36 tests showed a significant effect of 5-HTTLPR (P

The Ongoing Adaptive Evolution of ASPM and Microcephalin is Not Explained by Increased Intelligence Human Molecular Genetics. Mar, 2007 | Pubmed ID: 17220170 Recent studies have made great strides towards identifying putative genetic events underlying the evolution of the human brain and its emergent cognitive capacities. One of the most intriguing findings is the recurrent identification of adaptive evolution in genes associated with primary microcephaly, a developmental disorder characterized by severe reduction in brain size and intelligence, reminiscent of the early hominid condition. This has led to the hypothesis that the adaptive evolution of these genes has contributed to the emergence of modern human cognition. As with other candidate loci, however, this hypothesis remains speculative due to the current lack of methodologies for characterizing the evolutionary function of these genes in humans. Two primary microcephaly genes, ASPM and Microcephalin, have been implicated not only in the adaptive evolution of the lineage leading to humans, but in ongoing selective sweeps in modern humans as well. The presence of both the putatively adaptive and neutral alleles at these loci provides a unique opportunity for using normal trait variation within humans to test the hypothesis that the recent selective sweeps are driven by an advantage in cognitive abilities. Here, we report a large-scale association study between the adaptive alleles of these genes and normal variation in several measures of IQ. Five independent samples were used, totaling 2393 subjects, including both family-based and population-based datasets. Our overall findings do not support a detectable association between the recent adaptive evolution of either ASPM or Microcephalin and changes in IQ. As we enter the post-genomic era, with the number of candidate loci underlying human evolution growing rapidly, our findings highlight the importance of direct experimental validation in elucidating their evolutionary role in shaping the human phenotype.

Genome-wide Scan for Blood Pressure in Australian and Dutch Subjects Suggests Linkage at 5P, 14Q, and 17P Hypertension. Apr, 2007 | Pubmed ID: 17325240 Large-scale studies estimate the heritability of blood pressure at approximately 50%. We carried out a genome-wide linkage analysis to search for chromosomal loci that might explain this heritability using longitudinal, multiple measures of systolic and diastolic blood pressure obtained in sibling pairs and dizygotic twin pairs from 2 countries (a total of 286 pairs from Australia and 636 pairs from the Netherlands). These pairs and a large number of their parents were genotyped with microsatellite markers. Multivariate linkage analysis of the combined data of both countries, using a variance components approach, showed suggestive linkage for diastolic blood pressure on chromosomes 5p13.1 (logarithm of odds score: 2.48), 14q12 (logarithm of odds score: 2.40) and 17q24.3 (logarithm of odds score: 2.36). The highest logarithm of odds score of 1.21 for systolic blood pressure was observed on chromosome 13q34. These results replicate earlier findings and add to a slowly emerging picture of multiple loci contributing to quantitative blood pressure variation.

Comparison of Time and Frequency Domain Measures of RSA in Ambulatory Recordings Psychophysiology. Mar, 2007 | Pubmed ID: 17343704 The extent to which various measures of ambulatory respiratory sinus arrhythmia (RSA) capture the same information across conditions in different subjects remains unclear. In this study the root mean square of successive differences (RMSSD), peak valley RSA (pvRSA), and high frequency power (HF power) were assessed during ambulatory recording in 84 subjects, of which 64 were retested after about 3 years. We used covariance structure modeling to test the equality of the correlations among three RSA measures over two test days and three conditions (daytime sitting or walking and nighttime sleep) and in groups with low, medium, and high mean heart rate (HR), or low, medium, and high mean respiration rate (RR). Results showed that ambulatory RMSSD, pvRSA, and HF power are highly correlated and that their correlation is stable across time, ambulatory conditions, and a wide range of resting HR and RR values. RMSSD appears to be the most cost-efficient measure of RSA.

Bivariate Genetic Modeling of Cardiovascular Stress Reactivity: Does Stress Uncover Genetic Variance? Psychosomatic Medicine. May, 2007 | Pubmed ID: 17510291 To test the existence of gene-by-stress interaction by assessing cardiovascular stress reactivity in monozygotic and dizygotic twins.

Genetic Contribution to the P3 in Young and Middle-aged Adults Twin Research and Human Genetics : the Official Journal of the International Society for Twin Studies. Apr, 2007 | Pubmed ID: 17564523 Previous studies in young and adolescent twins suggested substantial genetic contributions to the amplitude and latency of the P3 evoked by targets in an oddball paradigm. Here we examined whether these findings can be generalized to adult samples. A total of 651 twins and siblings from 292 families participated in a visual oddball task. In half of the subjects the age centered around 26 (young adult cohort), in the other half the age centered around 49 (middle-aged adult cohort). P3 peak amplitude and latency were scored for 3 midline leads Pz, Cz, and Fz. No cohort differences in heritability were found. P3 amplitude (approximately 50%) and latency (approximately 45%) were moderately heritable for the 3 leads. A single genetic factor influenced latency at all electrodes, suggesting a single P3 timing mechanism. Specific genetic factors influenced amplitude at each lead, suggesting local modulation of the P3 once triggered. Genetic analysis of the full event-related potential waveform showed that P3 heritability barely changes from about 100 ms before to 100 ms after the peak. Age differences are restricted to differences in means and variances, but the proportion of genetic variance as part of the total variance of midline P3 amplitude and latency does not change from young to middle-aged adulthood.

Genome-wide Linkage Scan for Exercise Participation in Dutch Sibling Pairs European Journal of Human Genetics : EJHG. Dec, 2007 | Pubmed ID: 17700629 This study was aimed at identifying the genomic loci linked to exercise participation in males and females. Cross-sectional exercise data of twins and siblings (18-50 years) were used from the Netherlands Twin Registry. The sample consisted of 1432 genotyped sibling pairs from 622 families (1120 sibling pairs were genotyped on all chromosomes). Exercise participation (no/yes, based on a cutoff criterion of four metabolic equivalents and 60 min weekly) was assessed by survey. Genotyping was based on 361 markers and an average marker density of 10.6 cM. Identical by descent status was estimated for a 1 cM grid. A variance components-based sex-limited linkage scan was carried out for exercise participation. The heritability of exercise participation in males was 68.5% and in females 46.3%. The genetic overlap was estimated at 0.32, indicating that partly different genes affect exercise in the two sexes. Suggestive linkage was found in all subjects on chromosome 19p13.3 (LOD=2.18). Although sex differences in linkage effect were not significant, mainly females contributed to the suggestive linkage. The 19p13.3-13.2 region harbors a number of genes related to muscle performance and muscle blood flow, which might affect exercise behavior through exercise ability. Most likely, a large number of genes with each small effects affect exercise participation in males and females. Large collaborative samples are needed to detect these effects.

Heritability of Type-D Personality Psychosomatic Medicine. Sep-Oct, 2007 | Pubmed ID: 17766686 To quantify the influence of genes and environment on individual differences in type-D status, and the type-D subcomponents negative affectivity and social inhibition. Type-D personality independently predicts poor prognosis in patients with cardiovascular disease. However, no previous study has determined the heritability of type-D personality.

Exploring the Functional Role of the CHRM2 Gene in Human Cognition: Results from a Dense Genotyping and Brain Expression Study BMC Medical Genetics. 2007 | Pubmed ID: 17996044 The CHRM2 gene, located on the long arm of chromosome 7 (7q31-35), is involved in neuronal excitability, synaptic plasticity and feedback regulation of acetylcholine release, and has been implicated in higher cognitive processing. The aim of this study is the identification of functional (non)coding variants underlying cognitive phenotypic variation.

Genetic Contributions to Long-range Temporal Correlations in Ongoing Oscillations The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Dec, 2007 | Pubmed ID: 18077700 The amplitude fluctuations of ongoing oscillations in the electroencephalographic (EEG) signal of the human brain show autocorrelations that decay slowly and remain significant at time scales up to tens of seconds. We call these long-range temporal correlations (LRTC). Abnormal LRTC have been observed in several brain pathologies, but it has remained unknown whether genetic factors influence the temporal correlation structure of ongoing oscillations. We recorded the ongoing EEG during eyes-closed rest in 390 monozygotic and dizygotic twins and investigated the temporal structure of ongoing oscillations in the alpha- and beta-frequency bands using detrended fluctuation analysis (DFA). The strength of LRTC was more highly correlated in monozygotic than in dizygotic twins. Statistical analysis attributed up to approximately 60% of the variance in DFA to genetic factors, indicating a high heritability for the temporal structure of amplitude fluctuations in EEG oscillations. Importantly, the DFA and EEG power were uncorrelated. LRTC in ongoing oscillations are robust, heritable, and independent of power, suggesting that LRTC and oscillation power are governed by distinct biophysical mechanisms and serve different functions in the brain. We propose that the DFA method is an important complement to classical spectral analysis in fundamental and clinical research on ongoing oscillations.

Genome-wide Linkage Scan for Athlete Status in 700 British Female DZ Twin Pairs Twin Research and Human Genetics : the Official Journal of the International Society for Twin Studies. Dec, 2007 | Pubmed ID: 18179392 Association studies, comparing elite athletes with sedentary controls, have reported a number of genes that may be related to athlete status. The present study reports the first genome wide linkage scan for athlete status. Subjects were 4488 adult female twins from the TwinsUK Adult Twin Registry (793 monozygotic [MZ] and 1000 dizygotic [DZ] complete twin pairs, and single twins). Athlete status was measured by asking the twins whether they had ever competed in sports and what was the highest level obtained. Twins who had competed at the county or national level were considered elite athletes. Using structural equation modeling in Mx, the heritability of athlete status was estimated at 66%. Seven hundred DZ twin pairs that were successfully genotyped for 1946 markers (736 microsatellites and 1210 SNPs) were included in the linkage analysis. Identical-by-descent probabilities were estimated in Merlin for a 1 cM grid, taking into account the linkage disequilibrium of correlated SNPs. The linkage scan was carried out in Mx using the [Formula: see text]-approach. Suggestive linkages were found on chromosomes 3q22-q24 and 4q31-q34. Both areas converge with findings from previous studies using exercise phenotypes. The peak on 3q22-q24 was found at the SLC9A9 gene. The region 4q31-q34 overlaps with the region for which suggestive linkages were found in two previous linkage studies for physical fitness (FABP2 gene; Bouchard et al., 2000) and physical activity (UCP1 gene; Simonen et al., 2003). Future association studies should further clarify the possible role of these genes in athlete status.

Conditional Accuracy in Response Interference Tasks: Evidence from the Eriksen Flanker Task and the Spatial Conflict Task Advances in Cognitive Psychology / University of Finance and Management in Warsaw. 2007 | Pubmed ID: 20517524 Two well-known response interference tasks are the Eriksen flanker task and the spatial conflict task. The tasks are logically equivalent, and comparable effects of current and previous stimulus type (congruent or incongruent) have been shown with regard to reaction time (RT). Here, we investigated whether interference and sequential trial effects also had comparable effects on accuracy. We specifically tested whether these effects interacted with the speed of responding using conditional accuracy functions (CAFs). The CAFs revealed that in both tasks congruency and sequential trial effects on accuracy are found only in trials with fast responses (< 600 ms). Sequential trial effects on accuracy were weaker for the flanker task than for the spatial conflict task. In very fast trials (< 400 ms) response activation by distracting flankers led to below-chance performance in the flanker task, but response activation by incongruent spatial location did not lead to below-chance performance in the spatial conflict task. The pattern of results hints at subtle differences in processing architecture between the tasks.

Heritability of "small-world" Networks in the Brain: a Graph Theoretical Analysis of Resting-state EEG Functional Connectivity Human Brain Mapping. Dec, 2008 | Pubmed ID: 18064590 Recent studies have shown that resting-state functional networks as studied with fMRI, EEG, and MEG may be so-called small-world networks. We investigated to what extent the characteristic features of small-world networks are genetically determined. To represent functional connectivity between brain areas, we measured resting EEG in 574 twins and their siblings and calculated the synchronization likelihood between each pair of electrodes. We applied a threshold to obtain a binary graph from which we calculated the clustering coefficient C (describing local interconnectedness) and average path length L (describing global interconnectedness) for each individual. Modeling of MZ and DZ twin and sibling resemblance indicated that across various frequency bands 46-89% of the individual differences in C and 37-62% of the individual differences in L are heritable. It is asserted that C, L, and a small-world organization are viable markers of genetic differences in brain organization.

Genome-wide Association of Major Depression: Description of Samples for the GAIN Major Depressive Disorder Study: NTR and NESDA Biobank Projects European Journal of Human Genetics : EJHG. Mar, 2008 | Pubmed ID: 18197199 To identify the genomic regions that confer risk and protection for major depressive disorder (MDD) in humans, large-scale studies are needed. Such studies should collect multiple phenotypes, DNA, and ideally, biological material that allows gene expression analysis, transcriptomic, proteomic, and metabolomic studies. In this paper, we briefly review linkage studies of MDD and then describe the large-scale nationwide biological sample collection in Dutch twin families from the Netherlands Twin Register (NTR) and in participants in the Netherlands Study of Depression and Anxiety (NESDA). Within these studies, 1,862 participants with a diagnosis of MDD and 1,857 controls at low liability for MDD have been selected for genome-wide genotyping by the US Foundation for the National Institutes of Health Genetic Association Information Network. Stage 1 genome-wide association results are scheduled to be accessible before the end of 2007. Genome-wide association results are open-access and can be viewed at the dbGAP web portal (http://www.ncbi.nlm.nih.gov). Approved users can download the genotype and phenotype data, which have been made available as of 9 October 2007.

Catechol O-methyl Transferase and Dopamine D2 Receptor Gene Polymorphisms: Evidence of Positive Heterosis and Gene-gene Interaction on Working Memory Functioning European Journal of Human Genetics : EJHG. Sep, 2008 | Pubmed ID: 18382477 The COMT Val(108/158)Met polymorphism has been extensively studied in relation to individual differences in working memory (WM) performance. The present study tested the association of the COMT Val(108/158)Met polymorphism with WM performance in two independent family-based Dutch samples: 371 children (mean age 12.4 years) and 391 adults (mean age 36.2 years). A significant association was found between the COMT polymorphism and WM scores in the combined adult and young cohorts. The association reflected positive heterosis such that the Met/Met and Val/Val homozygotes did not perform as well as the Met/Val heterozygotes on the WM tasks. A secondary analysis was conducted in which a DRD2-tagging SNP (rs2075654) was tested for an interactive effect with the COMT polymorphism on WM performance. A significant interactive effect of the DRD2 and COMT genes was found such that heterosis was present only in the DRD2 genotype that has been linked to lower receptor density. Our results support previous findings that WM performance needs an optimal level of dopamine signaling within the PFC. This optimum level depends on enzymatic activity controlling dopamine level as well as dopamine receptor sensitivity, both of which may differ as a function of age and genotype. We conclude that the effects of a single polymorphism in a dopaminergic gene on a well-defined cognitive trait may easily remain hidden if the interaction with age and other genes in the pathway are not taken into account.

Amygdala Responses to Emotional Faces in Twins Discordant or Concordant for the Risk for Anxiety and Depression NeuroImage. Jun, 2008 | Pubmed ID: 18396414 Functional brain imaging studies have shown deviant amygdala responses to emotional stimuli in subjects suffering from anxiety and depressive disorder, but both hyperactivity and hypoactivity compared to healthy controls have been reported. To account for these discrepant findings, we hypothesize that genetic and environmental risk factors differently impact on amygdala functioning.

Testing Replication of a 5-SNP Set for General Cognitive Ability in Six Population Samples European Journal of Human Genetics : EJHG. Nov, 2008 | Pubmed ID: 18493267 A 5-single nucleotide polymorphism (SNP) set has been associated with general cognitive ability in 5000 7-year-old children from the Twins Early Development Study (TEDS). Four of these SNPs were identified through a 10 K microarray analysis and one was identified through a targeted analysis of brain-expressed genes. The present study tested this association with general cognitive ability in six population samples of varying size and age from Australia, the UK (Scotland and England) and the Netherlands. Results from the largest sample (N=1310) approached significance (P=0.06) in the direction of the original finding, but results from the other samples (N=205-758) were mixed. A meta-analysis of the results--allowing for effect size heterogeneity between samples--yielded a non-significant correlation (r=-0.01, P=0.57), indicating that this SNP set was not associated with general cognitive ability in the populations studied.

Genome-wide Linkage Analysis of Multiple Measures of Neuroticism of 2 Large Cohorts from Australia and the Netherlands Archives of General Psychiatry. Jun, 2008 | Pubmed ID: 18519823 People meeting diagnostic criteria for anxiety or depressive disorders tend to score high on the personality scale of neuroticism. Studying this personality dimension can give insights into the etiology of these important psychiatric disorders.

Gene-environment Interaction in Adults' IQ Scores: Measures of Past and Present Environment Behavior Genetics. Jul, 2008 | Pubmed ID: 18535898 Gene-environment interaction was studied in a sample of young (mean age 26 years, N = 385) and older (mean age 49 years, N = 370) adult males and females. Full scale IQ scores (FSIQ) were analyzed using biometric models in which additive genetic (A), common environmental (C), and unique environmental (E) effects were allowed to depend on environmental measures. Moderators under study were parental and partner educational level, as well as urbanization level and mean real estate price of the participants' residential area. Mean effects were observed for parental education, partner education and urbanization level. On average, FSIQ scores were roughly 5 points higher in participants with highly educated parents, compared to participants whose parents were less well educated. In older participants, IQ scores were about 2 points higher when their partners were highly educated. In younger males, higher urbanization levels were associated with slightly higher FSIQ scores. Our analyses also showed increased common environmental variation in older males whose parents were more highly educated, and increased unique environmental effects in older males living in more affluent areas. Contrary to studies in children, however, the variance attributable to additive genetic effects was stable across all levels of the moderators under study. Most results were replicated for VIQ and PIQ.

Testing Causality in the Association Between Regular Exercise and Symptoms of Anxiety and Depression Archives of General Psychiatry. Aug, 2008 | Pubmed ID: 18678794 In the population at large, regular exercise is associated with reduced anxious and depressive symptoms. Results of experimental studies in clinical populations suggest a causal effect of exercise on anxiety and depression, but it is unclear whether such a causal effect also drives the population association. We cannot exclude the major contribution of a third underlying factor influencing exercise behavior and symptoms of anxiety and depression.

Comparing Low Frequency Heart Rate Variability and Preejection Period: Two Sides of a Different Coin Psychophysiology. Nov, 2008 | Pubmed ID: 18823417 It has been hypothesized that the ratio of heart rate variability in the low- (LF) and high- (HF) frequency bands may capture variation in cardiac sympathetic control. Here we tested the temporal stability of the LF/HF ratio in 24-h ambulatory recordings and compared this ratio to the preejection period (PEP), an established measure of cardiac sympathetic control. Good temporal stability was found across a period of 3.3 years (.46

Sleep During a Regular Week Night: a Twin-sibling Study Twin Research and Human Genetics : the Official Journal of the International Society for Twin Studies. Oct, 2008 | Pubmed ID: 18828737 Previous genetic investigations of variation in normal sleep have focused on measures that describe sleep over longer periods of time. We undertook a study with the aim of evaluating whether heritability can be found in single-night sleep traits. A classical twin study design of monozygotic and dizygotic twins, enriched with siblings of twins was employed. The study included adult twin pairs and their siblings (N = 813 subjects from 342 families). A subsample of 66 individuals participated twice. For a single night, bedtime, awakening time and subjective sleep quality were assessed using a diary. The diary also assessed smoking, alcohol and coffee consumption, and the subjective evaluation of stress. Resemblance between family members was used to estimate the heritability of bedtime, awakening time, sleep problems and sleep quality as a function of sex. Most sleep measures showed familial clustering, but results differed for men and women. Heritability for bedtime and sleep problems was seen in women; and for awakening time in men. We conclude that heritability can be demonstrated for bedtime and subjective evaluation of even a single night of sleep. The contribution of the genetic make-up is sex specific. In women variance in awakening time is so affected by environmental circumstances, that the genetic contribution to the variance becomes negligible. In contrast, for males, variance in the evening bedtime is so affected by environmental circumstances, that the genetic contribution to the variance becomes negligible.

The Heritability of HbA1c and Fasting Blood Glucose in Different Measurement Settings Twin Research and Human Genetics : the Official Journal of the International Society for Twin Studies. Dec, 2008 | Pubmed ID: 19016616 In an extended twin study we estimated the heritability of fasting HbA1c and blood glucose levels. Blood glucose was assessed in different settings (at home and in the clinic). We tested whether the genetic factors influencing fasting blood glucose levels overlapped with those influencing HbA1c and whether the same genetic factors were expressed across different settings. Fasting blood glucose was measured at home and during two visits to the clinic in 77 healthy families with same-sex twins and siblings, aged 20 to 45 years. HbA1c was measured during the first clinic visit. A 4-variate genetic structural equation model was used that estimated the heritability of each trait and the genetic correlations among traits. Heritability explained 75% of the variance in HbA1c. The heritability of fasting blood glucose was estimated at 66% at home and lower in the clinic (57% and 38%). Fasting blood glucose levels were significantly correlated across settings (0.34 < r < 0.54), mostly due to a common set of genes that explained between 53% and 95% of these correlations. Correlations between HbA1c and fasting blood glucoses were low (0.11 < r < 0.23) and genetic factors influencing HbA1c and fasting glucose were uncorrelated. These results suggest that in healthy adults the genes influencing HbA1c and fasting blood glucose reflect different aspects of the glucose metabolism. As a consequence these two glycemic parameters can not be used interchangeably in diagnostic procedures or in studies attempting to find genes for diabetes. Both contribute unique (genetic) information.

Association Between Major Depressive Disorder and Heart Rate Variability in the Netherlands Study of Depression and Anxiety (NESDA) Archives of General Psychiatry. Dec, 2008 | Pubmed ID: 19047522 It has been hypothesized that depression is associated with lower heart rate variability and decreased cardiac vagal control. This may play an important role in the risk of cardiovascular disease among depressed individuals.

Suggestive Linkage on Chromosome 2, 8, and 17 for Lifetime Major Depression American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics : the Official Publication of the International Society of Psychiatric Genetics. Apr, 2009 | Pubmed ID: 18615541 It is well established that major depressive disorder (MDD) is partly heritable. We present a genome-wide linkage study aiming to find regions on the genome that influence the vulnerability for MDD. Our sample consists of 110 Australian and 23 Dutch pedigrees with two or more siblings affected with MDD (total N = 278). Linkage analysis was carried out in MERLIN. Three regions showed suggestive linkage signals. The highest LOD-score of 2.1 was found on chromosome 17 at 52.6 cM along with LOD scores of 1.9 and 1.7 on chromosome 8 at 2.7 cM and chromosome 2 at 90.6 cM, respectively. The result on chromosome 8 seems most promising as two previous studies also found linkage in this region, once suggestive and once significant. The linkage peak on chromosome 17 harbors the serotonin transporter gene. In the Australian and Dutch sample, the serotonin transporter length polymorphism did not show evidence for association, thus other genes in this region or other polymorphisms in the serotonin transporter gene might be associated with MDD. Further replication is needed to establish the relevance of our linkage finding on chromosome 2.

Strong Resemblance in the Amplitude of Oscillatory Brain Activity in Monozygotic Twins is Not Caused by "trivial" Similarities in the Composition of the Skull Human Brain Mapping. Jul, 2009 | Pubmed ID: 18819108 Previous twin studies have shown strong heritability of electroencephalogram amplitude characteristics, such as power spectra. However, it has been suggested that these high heritabilities may reflect "trivial" twin resemblance in intervening tissues such as the skull. Here we demonstrate strong monozygotic twin correlation (0.79 < r < 0.88) of eyes-closed resting-state magnetoencephalogram power, which is insensitive to intervening tissues. These results confirm that brain activity itself is highly heritable.

A Functional Polymorphism Under Positive Evolutionary Selection in ADRB2 is Associated with Human Intelligence with Opposite Effects in the Young and the Elderly Behavior Genetics. Jan, 2009 | Pubmed ID: 18855131 Comparative genomics offers a novel approach to unravel the genetic basis of complex traits. We performed a two stage analysis where genes ascertained for enhanced protein evolution in primates are subsequently searched for the presence of non-synonymous coding SNPs in the current human population at amino acid sites that differ between humans and chimpanzee. Positively selected genes among primates are generally presumed to determine phenotypic differences between humans and chimpanzee, such as the enhanced cognitive ability of our species. Amino acid substitutions segregating in humans at positively selected amino acid sites are expected to affect phenotypic differences among humans. Therefore we conducted an association study in two family based cohorts and one population based cohort between cognitive ability and the most likely candidate gene among the five that harbored more than one such polymorphism. The derived, human-specific allele of the beta-2 adrenergic receptor Arg16Gly polymorphism was found to be the increaser allele for performance IQ in the young, family based cohort but the decreaser allele for two different measures of cognition in the large Scottish cohort of unrelated individuals. The polymorphism is known to affect signaling activity and modulation of beta-2 adrenergic signaling has been shown to adjust memory consolidation, a trait related to cognition. The opposite effect of the polymorphism on cognition in the two age classes observed in the different cohorts resembles the effect of ADRB2 on hypertension, which also has been reported to be age dependent. This result illustrates the relevance of comparative genomics to detect genes that are involved in human behavior.

Variants in MTNR1B Influence Fasting Glucose Levels Nature Genetics. Jan, 2009 | Pubmed ID: 19060907 To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 x 10(-50)) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 x 10(-15)). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 x 10(-7)) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 x 10(-57)) and GCK (rs4607517, P = 1.0 x 10(-25)) loci.

Loci Influencing Lipid Levels and Coronary Heart Disease Risk in 16 European Population Cohorts Nature Genetics. Jan, 2009 | Pubmed ID: 19060911 Recent genome-wide association (GWA) studies of lipids have been conducted in samples ascertained for other phenotypes, particularly diabetes. Here we report the first GWA analysis of loci affecting total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides sampled randomly from 16 population-based cohorts and genotyped using mainly the Illumina HumanHap300-Duo platform. Our study included a total of 17,797-22,562 persons, aged 18-104 years and from geographic regions spanning from the Nordic countries to Southern Europe. We established 22 loci associated with serum lipid levels at a genome-wide significance level (P < 5 x 10(-8)), including 16 loci that were identified by previous GWA studies. The six newly identified loci in our cohort samples are ABCG5 (TC, P = 1.5 x 10(-11); LDL, P = 2.6 x 10(-10)), TMEM57 (TC, P = 5.4 x 10(-10)), CTCF-PRMT8 region (HDL, P = 8.3 x 10(-16)), DNAH11 (LDL, P = 6.1 x 10(-9)), FADS3-FADS2 (TC, P = 1.5 x 10(-10); LDL, P = 4.4 x 10(-13)) and MADD-FOLH1 region (HDL, P = 6 x 10(-11)). For three loci, effect sizes differed significantly by sex. Genetic risk scores based on lipid loci explain up to 4.8% of variation in lipids and were also associated with increased intima media thickness (P = 0.001) and coronary heart disease incidence (P = 0.04). The genetic risk score improves the screening of high-risk groups of dyslipidemia over classical risk factors.

What's in a Name? Psychosomatic Medicine and Biobehavioral Medicine Psychosomatic Medicine. Jan, 2009 | Pubmed ID: 19124618

Phenotypic and Genetic Correlations Between Evoked EEG/ERP Measures During the Response Anticipation Period of a Delayed Response Task Psychophysiology. Mar, 2009 | Pubmed ID: 19170951 We investigated the relationship between three electrophysiological indices of response anticipation in a spatial delayed response task with a low and high memory load manipulation: a slow cortical potential (SCP), theta desynchronization, and upper alpha synchronization. Individual differences in these three measures were examined in 531 adult twins and siblings. Heritability of the SCP at occipital-parietal leads varied from 30% to 43%. Heritability of upper alpha synchronization (35% to 65%) and theta desynchronization (31% to 50%) was significant at all leads. Theta desynchronization and upper alpha synchronization were significantly correlated (r approximately 43%), but SCP was not correlated with either. The effect of working memory load on all three measures was not heritable. Response anticipation reliably evokes an SCP, upper alpha synchronization and theta desynchronization, but variation in these measures reflects different (genetic) sources.

Depression is Associated with Decreased Blood Pressure, but Antidepressant Use Increases the Risk for Hypertension Hypertension. Apr, 2009 | Pubmed ID: 19237679 The present study compared blood pressure levels between subjects with clinical anxiety and depressive disorders with healthy controls. Cross-sectional data were obtained in a large cohort study, the Netherlands Study of Depression and Anxiety (N=2981). Participants were classified as controls (N=590) or currently or remittedly depressed or anxious subjects (N=2028), of which 1384 were not and 644 were using antidepressants. Regression analyses calculated the contributions of anxiety and depressive disorders and antidepressant use to diastolic and systolic blood pressures, after controlling for multiple covariates. Heart rate and heart rate variability measures were subsequently added to test whether effects of anxiety/depression or medication were mediated by vagal control over the heart. Higher mean diastolic blood pressure was found among the current anxious subjects (beta=0.932; P=0.03), although anxiety was not significantly related to hypertension risk. Remitted and current depressed subjects had a lower mean systolic blood pressure (beta=-1.74, P=0.04 and beta=-2.35, P=0.004, respectively) and were significantly less likely to have isolated systolic hypertension than controls. Users of tricyclic antidepressants had higher mean systolic and diastolic blood pressures and were more likely to have hypertension stage 1 (odds ratio: 1.90; 95% CI: 0.94 to 3.84; P=0.07) and stage 2 (odds ratio: 3.19; 95% CI: 1.35 to 7.59; P=0.008). Users of noradrenergic and serotonergic working antidepressants were more likely to have hypertension stage 1. This study shows that depressive disorder is associated with low systolic blood pressure and less hypertension, whereas the use of certain antidepressants is associated with both high diastolic and systolic blood pressures and hypertension.

Genome-wide Association Study of Smoking Initiation and Current Smoking American Journal of Human Genetics. Mar, 2009 | Pubmed ID: 19268276 For the identification of genes associated with smoking initiation and current smoking, genome-wide association analyses were carried out in 3497 subjects. Significant genes that replicated in three independent samples (n = 405, 5810, and 1648) were visualized into a biologically meaningful network showing cellular location and direct interaction of their proteins. Several interesting groups of proteins stood out, including glutamate receptors (e.g., GRIN2B, GRIN2A, GRIK2, GRM8), proteins involved in tyrosine kinase receptor signaling (e.g., NTRK2, GRB14), transporters (e.g., SLC1A2, SLC9A9) and cell-adhesion molecules (e.g., CDH23). We conclude that a network-based genome-wide association approach can identify genes influencing smoking behavior.

Attention Problems, Inhibitory Control, and Intelligence Index Overlapping Genetic Factors: a Study in 9-, 12-, and 18-year-old Twins Neuropsychology. May, 2009 | Pubmed ID: 19413451 It is assumed that attention problems (AP) are related to impaired executive functioning. We investigated the association between AP and inhibitory control and tested to what extent the association was due to genetic factors shared with IQ. Data were available from 3 independent samples of 9-, 12-, and 18-year-old twins and their siblings (1,209 participants). AP were assessed with checklists completed by multiple informants. Inhibitory control was measured with the Stroop Color Word Task (Stroop, 1935), and IQ with the Wechsler Intelligence Scale for Children (Wechsler et al., 2002) or Wechsler Adult Intelligence Scale (Wechsler, 1997). AP and inhibitory control were only correlated in the 12-year-old cohort (r = .18), but appeared non-significant after controlling for IQ. Significant correlations existed between AP and IQ in 9- and 12-year olds (r = -.26/-.34). Inhibitory control and IQ were correlated in all cohorts (r = -.16, -.24 and -.35, respectively). Genetic factors that influenced IQ also influenced inhibitory control. We conclude that the association between AP and inhibitory control as reported in the literature may largely derive from genetic factors that are shared with IQ.

Association Between Anxiety Disorders and Heart Rate Variability in The Netherlands Study of Depression and Anxiety (NESDA) Psychosomatic Medicine. Jun, 2009 | Pubmed ID: 19414616 To determine whether patients with different types of anxiety disorder (panic disorder, social phobia, generalized anxiety disorder) have higher heart rate and lower heart rate variability compared with healthy controls in a sample that was sufficiently powered to examine the confounding effects of lifestyle and antidepressants.

A Genome-wide Association Study of Northwestern Europeans Involves the C-type Natriuretic Peptide Signaling Pathway in the Etiology of Human Height Variation Human Molecular Genetics. Sep, 2009 | Pubmed ID: 19570815 Northwestern Europeans are among the tallest of human populations. The increase in body height in these people appears to have reached a plateau, suggesting the ubiquitous presence of an optimal environment in which genetic factors may have exerted a particularly strong influence on human growth. Therefore, we performed a genome-wide association study (GWAS) of body height using 2.2 million markers in 10 074 individuals from three Dutch and one German population-based cohorts. Upon genotyping, the 12 most significantly height-associated single nucleotide polymorphisms (SNPs) from this GWAS in 6912 additional individuals of Dutch and Swedish origin, a genetic variant (rs6717918) on chromosome 2q37.1 was found to be associated with height at a genome-wide significance level (P(combined) = 3.4 x 10(-9)). Notably, a second SNP (rs6718438) located approximately 450 bp away and in strong LD (r(2) = 0.77) with rs6717918 was previously found to be suggestive of a height association in 29 820 individuals of mainly northwestern European ancestry, and the over-expression of a nearby natriuretic peptide precursor type C (NPPC) gene, has been associated with overgrowth and skeletal anomalies. We also found a SNP (rs10472828) located on 5p14 near the natriuretic peptide receptor 3 (NPR3) gene, encoding a receptor of the NPPC ligand, to be associated with body height (P(combined) = 2.1 x 10(-7)). Taken together, these results suggest that variation in the C-type natriuretic peptide signaling pathway, involving the NPPC and NPR3 genes, plays an important role in determining human body height.

Genome-wide Association Study of Exercise Behavior in Dutch and American Adults Medicine and Science in Sports and Exercise. Oct, 2009 | Pubmed ID: 19727025 The objective of this study was to identify genetic variants that are associated with adult leisure time exercise behavior using genome-wide association (GWA) in two independent samples.

A General Enhancement of Autonomic and Cortisol Responses During Social Evaluative Threat Psychosomatic Medicine. Oct, 2009 | Pubmed ID: 19779143 To examine the Social Self Preservation Theory, which predicts that stressors involving social evaluative threat (SET) characteristically activate the hypothalamic-pituitary-adrenal (HPA) axis. The idea that distinct psychosocial factors may underlie specific patterns of neuroendocrine stress responses has been a topic of recurrent debate.

Common Variants in TMPRSS6 Are Associated with Iron Status and Erythrocyte Volume Nature Genetics. Nov, 2009 | Pubmed ID: 19820699 We report a genome-wide association study to iron status. We identify an association of SNPs in TPMRSS6 to serum iron (rs855791, combined P = 1.5 x 10(-20)), transferrin saturation (combined P = 2.2 x 10(-23)) and erythrocyte mean cell volume (MCV, combined P = 1.1 x 10(-10)). We also find suggestive evidence of association with blood hemoglobin levels (combined P = 5.3 x 10(-7)). These findings demonstrate the involvement of TMPRSS6 in control of iron homeostasis and in normal erythropoiesis.

Sequence Variants in Three Loci Influence Monocyte Counts and Erythrocyte Volume American Journal of Human Genetics. Nov, 2009 | Pubmed ID: 19853236 Blood cells participate in vital physiological processes, and their numbers are tightly regulated so that homeostasis is maintained. Disruption of key regulatory mechanisms underlies many blood-related Mendelian diseases but also contributes to more common disorders, including atherosclerosis. We searched for quantitative trait loci (QTL) for hematology traits through a whole-genome association study, because these could provide new insights into both hemopoeitic and disease mechanisms. We tested 1.8 million variants for association with 13 hematology traits measured in 6015 individuals from the Australian and Dutch populations. These traits included hemoglobin composition, platelet counts, and red blood cell and white blood cell indices. We identified three regions of strong association that, to our knowledge, have not been previously reported in the literature. The first was located in an intergenic region of chromosome 9q31 near LPAR1, explaining 1.5% of the variation in monocyte counts (best SNP rs7023923, p=8.9x10(-14)). The second locus was located on chromosome 6p21 and associated with mean cell erythrocyte volume (rs12661667, p=1.2x10(-9), 0.7% variance explained) in a region that spanned five genes, including CCND3, a member of the D-cyclin gene family that is involved in hematopoietic stem cell expansion. The third region was also associated with erythrocyte volume and was located in an intergenic region on chromosome 6q24 (rs592423, p=5.3x10(-9), 0.6% variance explained). All three loci replicated in an independent panel of 1543 individuals (p values=0.001, 9.9x10(-5), and 7x10(-5), respectively). The identification of these QTL provides new opportunities for furthering our understanding of the mechanisms regulating hemopoietic cell fate.

An Association Between Epac-1 Gene Variants and Anxiety and Depression in Two Independent Samples American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics : the Official Publication of the International Society of Psychiatric Genetics. Jan, 2010 | Pubmed ID: 19475578 Deficiency in signal transduction might play a role in the development of anxiety and depression, as suggested by a study on the involvement of the PKA-independent Epac pathway. We investigated the association between Epac-1 gene variants, also known as RapGEF-3, and measures of anxiety and depression in a Dutch twin-family sample. Replication was sought in a USA sample consisting of unrelated individuals. Genotype and phenotype data were available for 910 Dutch and 684 USA individuals. Longitudinal self-report measures of neuroticism, anxiety and depression and genetic factor scores (GFS-NL), based on these measures, were analyzed in the Dutch sample. In the USA sample, neuroticism and Genetic Factor Scores (GFS-USA), based on neuroticism and diagnoses of anxiety disorders and depression, were analyzed. Three intronic SNPs were genotyped. Analyses were performed in QTDT. Genotype and haplotype frequencies differed significantly between the samples. In the Dutch sample, rs2072115 showed a significant dominant effect for anxiety and depression. Subjects with haplotype G-C-C (ordered rs2072115-rs757281-2074533) had significantly lower anxiety, neuroticism and GFS-NL scores. In the USA sample, a significant additive effect of rs2074533 on GFS-USA was found. Subjects with haplotypes G-C-C and A-C-T had significantly higher and lower GFS-USA scores, respectively. Both samples showed an association between Epac-1 gene variants and anxiety and depression, but for different variants or in opposite directions. The divergent results could be due to differences in linkage disequilibrium between the investigated SNPs and a functional polymorphism in the Dutch and USA sample.

Combined Risk Allele Score of Eight Type 2 Diabetes Genes is Associated with Reduced First-phase Glucose-stimulated Insulin Secretion During Hyperglycemic Clamps Diabetes. Jan, 2010 | Pubmed ID: 19808892 At least 20 type 2 diabetes loci have now been identified, and several of these are associated with altered beta-cell function. In this study, we have investigated the combined effects of eight known beta-cell loci on insulin secretion stimulated by three different secretagogues during hyperglycemic clamps.

Gene Variants in the Novel Type 2 Diabetes Loci CDC123/CAMK1D, THADA, ADAMTS9, BCL11A, and MTNR1B Affect Different Aspects of Pancreatic Beta-cell Function Diabetes. Jan, 2010 | Pubmed ID: 19833888 Recently, results from a meta-analysis of genome-wide association studies have yielded a number of novel type 2 diabetes loci. However, conflicting results have been published regarding their effects on insulin secretion and insulin sensitivity. In this study we used hyperglycemic clamps with three different stimuli to test associations between these novel loci and various measures of beta-cell function.

New Genetic Loci Implicated in Fasting Glucose Homeostasis and Their Impact on Type 2 Diabetes Risk Nature Genetics. Feb, 2010 | Pubmed ID: 20081858 Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

Individual Differences in Processing Speed and Working Memory Speed As Assessed with the Sternberg Memory Scanning Task Behavior Genetics. May, 2010 | Pubmed ID: 20091112 The Sternberg Memory Scanning (SMS) task provides a measure of processing speed (PS) and working memory retrieval speed (WMS). In this task, participants are presented with sets of stimuli that vary in size. After a delay, one item is presented, and participants indicate whether or not the item was part of the set. Performance is assessed by speed and accuracy for both the positive (item is part of the set) and the negative trials (items is not part of the set). To examine the causes of variation in PS and WMS, 623 adult twins and their siblings completed the SMS task. A non-linear growth curve (nLGC) model best described the increase in reaction time with increasing set size. Genetic analyses showed that WMS (modeled as the Slope in the nLGC model) has a relatively small variance which is not due to genetic variation while PS (modeled as the Intercept in the nLGC model) showed large individual differences, part of which could be attributed to additive genetic factors. Heritability was 38% for positive and 32% for negative trials. Additional multivariate analyses showed that the genetic effects on PS for positive and negative trials were completely shared. We conclude that genetic influences on working memory performance are more likely to act upon basic processing speed and (pre)motoric processes than on the speed with which an item is retrieved from short term memory.

The Association of Mitochondrial Content with Prevalent and Incident Type 2 Diabetes The Journal of Clinical Endocrinology and Metabolism. Apr, 2010 | Pubmed ID: 20150578 It has been shown that mitochondrial DNA (mtDNA) content is associated with type 2 diabetes (T2D) and related traits. However, empirical data, often based on small samples, did not confirm this observation in all studies. Therefore, the role of mtDNA content in T2D remains elusive.

A Genomewide Association Study of Nicotine and Alcohol Dependence in Australian and Dutch Populations Twin Research and Human Genetics : the Official Journal of the International Society for Twin Studies. Feb, 2010 | Pubmed ID: 20158304 Persistent tobacco use and excessive alcohol consumption are major public health concerns worldwide. Both alcohol and nicotine dependence (AD, ND) are genetically influenced complex disorders that exhibit a high degree of comorbidity. To identify gene variants contributing to one or both of these addictions, we first conducted a pooling-based genomewide association study (GWAS) in an Australian population, using Illumina Infinium 1M arrays. Allele frequency differences were compared between pooled DNA from case and control groups for: (1) AD, 1224 cases and 1162 controls; (2) ND, 1273 cases and 1113 controls; and (3) comorbid AD and ND, 599 cases and 488 controls. Secondly, we carried out a GWAS in independent samples from the Netherlands for AD and for ND. Thirdly, we performed a meta-analysis of the 10,000 most significant AD- and ND-related SNPs from the Australian and Dutch samples. In the Australian GWAS, one SNP achieved genomewide significance (p < 5 x 10(-8)) for ND (rs964170 in ARHGAP10 on chromosome 4, p = 4.43 x 10(-8)) and three others for comorbid AD/ND (rs7530302 near MARK1 on chromosome 1 (p = 1.90 x 10(-9)), rs1784300 near DDX6 on chromosome 11 (p = 2.60 x 10(-9)) and rs12882384 in KIAA1409 on chromosome 14 (p = 4.86 x 10(-8))). None of the SNPs achieved genomewide significance in the Australian/Dutch meta-analysis, but a gene network diagram based on the top-results revealed overrepresentation of genes coding for ion-channels and cell adhesion molecules. Further studies will be required before the detailed causes of comorbidity between AD and ND are understood.

Increased Sympathetic and Decreased Parasympathetic Activity Rather Than Changes in Hypothalamic-pituitary-adrenal Axis Activity is Associated with Metabolic Abnormalities The Journal of Clinical Endocrinology and Metabolism. May, 2010 | Pubmed ID: 20237163 Stress is suggested to lead to metabolic dysregulations as clustered in the metabolic syndrome, but the underlying biological mechanisms are not yet well understood.

Variants in ADCY5 and Near CCNL1 Are Associated with Fetal Growth and Birth Weight Nature Genetics. May, 2010 | Pubmed ID: 20372150 To identify genetic variants associated with birth weight, we meta-analyzed six genome-wide association (GWA) studies (n = 10,623 Europeans from pregnancy/birth cohorts) and followed up two lead signals in 13 replication studies (n = 27,591). rs900400 near LEKR1 and CCNL1 (P = 2 x 10(-35)) and rs9883204 in ADCY5 (P = 7 x 10(-15)) were robustly associated with birth weight. Correlated SNPs in ADCY5 were recently implicated in regulation of glucose levels and susceptibility to type 2 diabetes, providing evidence that the well-described association between lower birth weight and subsequent type 2 diabetes has a genetic component, distinct from the proposed role of programming by maternal nutrition. Using data from both SNPs, we found that the 9% of Europeans carrying four birth weight-lowering alleles were, on average, 113 g (95% CI 89-137 g) lighter at birth than the 24% with zero or one alleles (P(trend) = 7 x 10(-30)). The impact on birth weight is similar to that of a mother smoking 4-5 cigarettes per day in the third trimester of pregnancy.

Heritability and Genome-wide Linkage Scan of Subjective Happiness Twin Research and Human Genetics : the Official Journal of the International Society for Twin Studies. Apr, 2010 | Pubmed ID: 20397744 Causes of individual differences in happiness, as assessed with the Subjective Happiness Scale, are investigated in a large of sample twins and siblings from the Netherlands Twin Register. Over 12,000 twins and siblings, average age 24.7 years (range 12 to 88), took part in the study. A genetic model with an age by sex design was fitted to the data with structural equation modeling in Mx. The heritability of happiness was estimated at 22% for males and 41% in females. No effect of age was observed. To identify the genomic regions contributing to this heritability, a genome-wide linkage study for happiness was conducted in sibling pairs. A subsample of 1157 offspring from 441 families was genotyped with an average of 371 micro-satellite markers per individual. Phenotype and genotype data were analyzed in MERLIN with multipoint variance component linkage analysis and age and sex as covariates. A linkage signal (logarithm of odds score 2.73, empirical p value 0.095) was obtained at the end of the long arm of chromosome 19 for marker D19S254 at 110 cM. A second suggestive linkage peak was found at the short arm of chromosome 1 (LOD of 2.37) at 153 cM, marker D1S534 (empirical p value of .209). These two regions of interest are not overlapping with the regions found for contrasting phenotypes (such as depression, which is negatively associated with happiness). Further linkage and future association studies are warranted.

Genetic Influence Demonstrated for MEG-recorded Somatosensory Evoked Responses Psychophysiology. Nov, 2010 | Pubmed ID: 20409017 We tested for a genetic influence on magnetoencephalogram (MEG)-recorded somatosensory evoked fields (SEFs) in 20 monozygotic (MZ) and 14 dizygotic (DZ) twin pairs. Previous electroencephalogram (EEG) studies that demonstrated a genetic contribution to evoked responses generally focused on characteristics of representative brain potentials. Here we demonstrate significantly smaller amplitude differences within MZ compared to DZ twin pairs for the complete SEF time series (across left and right hand SEFs: 0.37 vs. 0.60 pT(2) and 0.28 vs. 0.39 pT(2) for primary [SI] and secondary [SII] sensory cortex activation) and higher MZ than DZ wave shape correlations (.71 vs. .44 and .52 vs. .35 for SI and SII activation). Our findings indicate a genetic influence on MEG-recorded evoked brain activity and also confirm our recent conclusion (van 't Ent, van Soelen, Stam, De Geus, & Boomsma, 2009) that higher MZ resemblance for EEG amplitudes is not trivially reflecting greater MZ concordance in intervening biological tissues.

The Netherlands Twin Register Biobank: a Resource for Genetic Epidemiological Studies Twin Research and Human Genetics : the Official Journal of the International Society for Twin Studies. Jun, 2010 | Pubmed ID: 20477721 In 2004 the Netherlands Twin Register (NTR) started a large scale biological sample collection in twin families to create a resource for genetic studies on health, lifestyle and personality. Between January 2004 and July 2008, adult participants from NTR research projects were invited into the study. During a home visit between 7:00 and 10:00 am, fasting blood and morning urine samples were collected. Fertile women were bled on day 2-4 of the menstrual cycle, or in their pill-free week. Biological samples were collected for DNA isolation, gene expression studies, creation of cell lines and for biomarker assessment. At the time of blood sampling, additional phenotypic information concerning health, medication use, body composition and smoking was collected. Of the participants contacted, 69% participated. Blood and urine samples were collected in 9,530 participants (63% female, average age 44.4 (SD 15.5) years) from 3,477 families. Lipid profile, glucose, insulin, HbA1c, haematology, CRP, fibrinogen, liver enzymes and creatinine have been assessed. Longitudinal survey data on health, personality and lifestyle are currently available for 90% of all participants. Genome-wide SNP data are available for 3,524 participants, with additional genotyping ongoing. The NTR biobank, combined with the extensive phenotypic information available within the NTR, provides a valuable resource for the study of genetic determinants of individual differences in mental and physical health. It offers opportunities for DNA-based and gene expression studies as well as for future metabolomic and proteomic projects.

Genetic Epidemiology of Attention Deficit Hyperactivity Disorder (ADHD Index) in Adults PloS One. 2010 | Pubmed ID: 20485550 In contrast to the large number of studies in children, there is little information on the contribution of genetic factors to Attention Deficit Hyperactivity Disorder (ADHD) in adults.

The Anatomical and Functional Relationship Between the P3 and Autonomic Components of the Orienting Response Psychophysiology. Jun, 2010 | Pubmed ID: 20557480 Abstract Many psychophysiologists have noted the striking similarities between the antecedent conditions for the P3 component of the event-related potential and the orienting response: both are typically elicited by salient, unexpected, novel, task-relevant, and other motivationally significant stimuli. Although the close coupling of the P3 and orienting response has been well documented, the neural basis and functional role of this relationship is still poorly understood. Here we propose that the simultaneous occurrence of the P3 and autonomic components of the orienting response reflects the co-activation of the locus coeruleus-norepinephrine system and the peripheral sympathetic nervous system by their common major afferent: the rostral ventrolateral medulla, a key sympathoexcitatory region. A comparison of the functional significance of the locus coeruleus-norepinephrine system and the peripheral sympathetic nervous system suggests that the P3 and orienting response reflect complementary cognitive and physical contributions to the mobilization for action following motivationally significant stimuli.

Genome-wide Association Analysis Identifies Multiple Loci Related to Resting Heart Rate Human Molecular Genetics. Oct, 2010 | Pubmed ID: 20639392 Higher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38,991 subjects of European ancestry, estimating the association between age-, sex- and body mass-adjusted RR interval (inverse heart rate) and approximately 2.5 million markers. Results with P < 5 Ã— 10(-8) were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain approximately 0.7% of RR interval variance. A multivariant regression model including 20 variants with P < 10(-5) increased the explained variance to 1.6%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care.

Genetic Influences on Individual Differences in Exercise Behavior During Adolescence International Journal of Pediatrics. 2010 | Pubmed ID: 20672022 The aim of this study was to investigate the degree to which genetic and environmental influences affect variation in adolescent exercise behavior. Data on regular leisure time exercise activities were analyzed in 8,355 adolescent twins, from three-age cohorts (13-14, 15-16, and 17-19 years). Exercise behavior was assessed with survey items about type of regular leisure time exercise, frequency, and duration of the activities. Participants were classified as sedentary, regular exercisers, or vigorous exercisers. The prevalence of moderate exercise behavior declined from age 13 to 19 years with a parallel increase in prevalence of sedentary behavior, whereas the prevalence of vigorous exercise behavior remained constant across age cohorts. Variation in exercise behavior was analyzed with genetic structural equation modeling employing a liability threshold model. Variation was largely accounted for by genetic factors (72% to 85% of the variance was explained by genetic factors), whereas shared environmental factors only accounted for a substantial part of the variation in girls aged 13-14 years (46%). We hypothesize that genetic effects on exercise ability may explain the high heritability of exercise behavior in this phase of life.

Biological, Clinical and Population Relevance of 95 Loci for Blood Lipids Nature. Aug, 2010 | Pubmed ID: 20686565 Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

Heritability of Head Size in Dutch and Australian Twin Families at Ages 0-50 Years Twin Research and Human Genetics : the Official Journal of the International Society for Twin Studies. Aug, 2010 | Pubmed ID: 20707707 We assessed the heritability of head circumference, an approximation of brain size, in twin-sib families of different ages. Data from the youngest participants were collected a few weeks after birth and from the oldest participants around age 50 years. In nearly all age groups the largest part of the variation in head circumference was explained by genetic differences. Heritability estimates were 90% in young infants (4 to 5 months), 85-88% in early childhood, 83-87% in adolescence, 75% in young and mid adulthood. In infants younger than 3 months, heritability was very low or absent. Quantitative sex differences in heritability were observed in 15- and 18-year-olds, but there was no evidence for qualitative sex differences, that is, the same genes were expressed in both males and females. Longitudinal analysis of the data between 5, 7, and 18 years of age showed high genetic stability (.78 > R(G) > .98). These results indicate that head circumference is a highly heritable biometric trait and a valid target for future GWA studies.

Physiological Reactivity to Phobic Stimuli in People with Fear of Flying Journal of Psychosomatic Research. Sep, 2010 | Pubmed ID: 20708454 The nature of the relationship between physiological and subjective responses in phobic subjects remains unclear. Phobics have been thought to be characterized by a heightened physiological response (physiological perspective) or by a heightened perception of a normal physiological response (psychological perspective).

Migraine Symptomatology and Major Depressive Disorder Cephalalgia : an International Journal of Headache. Sep, 2010 | Pubmed ID: 20713558 Migraine and major depressive disorder (MDD) frequently co-occur, but it is unclear whether depression is associated with a specific subtype of migraine. The objective of this study was to investigate whether migraine is qualitatively different in MDD patients (N = 1816) and non-depressed controls (N = 3428).

Brain Activation During Cognitive Planning in Twins Discordant or Concordant for Obsessive-compulsive Symptoms Brain : a Journal of Neurology. Oct, 2010 | Pubmed ID: 20823085 Neuroimaging studies have indicated abnormalities in cortico-striatal-thalamo-cortical circuits in patients with obsessive-compulsive disorder compared with controls. However, there are inconsistencies between studies regarding the exact set of brain structures involved and the direction of anatomical and functional changes. These inconsistencies may reflect the differential impact of environmental and genetic risk factors for obsessive-compulsive disorder on different parts of the brain. To distinguish between functional brain changes underlying environmentally and genetically mediated obsessive-compulsive disorder, we compared task performance and brain activation during a Tower of London planning paradigm in monozygotic twins discordant (n=38) or concordant (n=100) for obsessive-compulsive symptoms. Twins who score high on obsessive-compulsive symptoms can be considered at high risk for obsessive-compulsive disorder. We found that subjects at high risk for obsessive-compulsive disorder did not differ from the low-risk subjects behaviourally, but we obtained evidence that the high-risk subjects differed from the low-risk subjects in the patterns of brain activation accompanying task execution. These regions can be separated into those that were affected by mainly environmental risk (dorsolateral prefrontal cortex and lingual cortex), genetic risk (frontopolar cortex, inferior frontal cortex, globus pallidus and caudate nucleus) and regions affected by both environmental and genetic risk factors (cingulate cortex, premotor cortex and parts of the parietal cortex). Our results suggest that neurobiological changes related to obsessive-compulsive symptoms induced by environmental factors involve primarily the dorsolateral prefrontal cortex, whereas neurobiological changes induced by genetic factors involve orbitofrontal-basal ganglia structures. Regions showing similar changes in high-risk twins from discordant and concordant pairs may be part of compensatory networks that keep planning performance intact, in spite of cortico-striatal-thalamo-cortical deficits.

The Impact of Genetic Variation in the G6PC2 Gene on Insulin Secretion Depends on Glycemia The Journal of Clinical Endocrinology and Metabolism. Dec, 2010 | Pubmed ID: 20826583 Single-nucleotide polymorphisms (SNPs) within the G6PC2 locus are associated with fasting glucose and insulin secretion. These SNPs are not associated with type 2 diabetes risk.

Longitudinal Evidence for Unfavorable Effects of Antidepressants on Heart Rate Variability Biological Psychiatry. Nov, 2010 | Pubmed ID: 20843507 It was previously shown that antidepressants are associated with diminished vagal control over the heart. Longitudinal studies are needed to test the causality of this association further.

Common Variants at 10 Genomic Loci Influence Hemoglobin Aâ‚(C) Levels Via Glycemic and Nonglycemic Pathways Diabetes. Dec, 2010 | Pubmed ID: 20858683 Glycated hemoglobin (HbAâ‚(c)), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbAâ‚(c). We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbAâ‚(c) levels.

Genome-wide Association Study (GWAS)-identified Disease Risk Alleles Do Not Compromise Human Longevity Proceedings of the National Academy of Sciences of the United States of America. Oct, 2010 | Pubmed ID: 20921414 A set of currently known alleles increasing the risk for coronary artery disease, cancer, and type 2 diabetes as identified by genome-wide association studies was tested for compatibility with human longevity. Here, we show that nonagenarian siblings from long-lived families and singletons older than 85 y of age from the general population carry the same number of disease risk alleles as young controls. Longevity in this study population is not compromised by the cumulative effect of this set of risk alleles for common disease.

Thirty New Loci for Age at Menarche Identified by a Meta-analysis of Genome-wide Association Studies Nature Genetics. Dec, 2010 | Pubmed ID: 21102462 To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 Ã— 10â»â¶â°) and 9q31.2 (P = 2.2 Ã— 10â»Â³Â³), we identified 30 new menarche loci (all P < 5 Ã— 10â»â¸) and found suggestive evidence for a further 10 loci (P < 1.9 Ã— 10â»â¶). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.

The Serotonin Transporter Gene Length Polymorphism (5-HTTLPR) and Life Events: No Evidence for an Interaction Effect on Neuroticism and Anxious Depressive Symptoms Twin Research and Human Genetics : the Official Journal of the International Society for Twin Studies. Dec, 2010 | Pubmed ID: 21142930 The finding of a significant gene by environment interaction effect on depression of the serotonin transporter length polymorphism (5-HTTLPR) and the Number of experienced Life Events (NLE) was not replicated in two large meta-analyses (Munafo et al., 2009; Risch et al., 2009). These meta-analyses have been criticized on the grounds that large studies that get most weight in meta-analyses have the poorest measurement quality of life events and, as a consequence, do not find an effect. Another issue is the time frame across which the NLE are measured. Proximal life events appear to be better predictors of depression than more distal events. We present the results of analyses of the 5-HTTLPR Ã— NLE effect on anxious depression and neuroticism scores in a sample of 1,155 twins and their parents and siblings from 438 families. The interaction effect was tested separately for NLE experienced across the life span and NLE experienced in the past year. There was a significant main effect of NLE on anxious depression and neuroticism, especially when these were experienced in the past year. No interaction with 5-HTTLPR was found for NLE either experienced across the life span or across the past year. Our results support the two recent meta-analyses. Given recent insights from genome wide association studies, it seems more useful to focus on the joint effect of several genes, that are, for example, part of the same biological pathway, in interaction with the environment, than on one candidate gene.

Network Analysis of Resting State EEG in the Developing Young Brain: Structure Comes with Maturation Human Brain Mapping. Mar, 2011 | Pubmed ID: 20589941 During childhood, brain structure and function changes substantially. Recently, graph theory has been introduced to model connectivity in the brain. Small-world networks, such as the brain, combine optimal properties of both ordered and random networks, i.e., high clustering and short path lengths. We used graph theoretical concepts to examine changes in functional brain networks during normal development in young children. Resting-state eyes-closed electroencephalography (EEG) was recorded (14 channels) from 227 children twice at 5 and 7 years of age. Synchronization likelihood (SL) was calculated in three different frequency bands and between each pair of electrodes to obtain SL-weighted graphs. Mean normalized clustering index, average path length and weight dispersion were calculated to characterize network organization. Repeated measures analysis of variance tested for time and gender effects. For all frequency bands mean SL decreased from 5 to 7 years. Clustering coefficient increased in the alpha band. Path length increased in all frequency bands. Mean normalized weight dispersion decreased in beta band. Girls showed higher synchronization for all frequency bands and a higher mean clustering in alpha and beta bands. The overall decrease in functional connectivity (SL) might reflect pruning of unused synapses and preservation of strong connections resulting in more cost-effective networks. Accordingly, we found increases in average clustering and path length and decreased weight dispersion indicating that normal brain maturation is characterized by a shift from random to more organized small-world functional networks. This developmental process is influenced by gender differences early in development.

To Include or Not to Include? A Response to the Meta-analysis of Heart Rate Variability and Depression Biological Psychiatry. Feb, 2011 | Pubmed ID: 20926065

Nine-year Stability of Type D Personality: Contributions of Genes and Environment Psychosomatic Medicine. Jan, 2011 | Pubmed ID: 20947779 To assess longitudinal changes in genetic and environmental influences on Type D personality and its subcomponents negative affectivity (NA) and social inhibition (SI) over a 9-year period. Most personality constructs have good retest reliability over long periods, with stability attributed to genes, and changes to environmental factors. Type D personality is stable across an 18-month period and is influenced by genetic factors. However, there is no knowledge on long-term stability, and the contributions of genes and environment to that stability.

Exercise Participation in Adolescents and Their Parents: Evidence for Genetic and Generation Specific Environmental Effects Behavior Genetics. Mar, 2011 | Pubmed ID: 21086156 Individual differences in adolescent exercise behavior are to a large extent explained by shared environmental factors. The aim of this study was to explore to what extent this shared environment represents effects of cultural transmission of parents to their offspring, generation specific environmental effects or assortative mating. Survey data on leisure-time exercise behavior were available from 3,525 adolescent twins and their siblings (13-18Â years) and 3,138 parents from 1,736 families registered at the Netherlands Twin Registry. Data were also available from 5,471 adult twins, their siblings and spouses similar in age to the parents. Exercise participation (No/Yes, using a cut-off criterion of 4 metabolic equivalents and 60Â min weekly) was based on questions on type, frequency and duration of exercise. A model to analyze dichotomous data from twins, siblings and parents including differences in variance decomposition across sex and generation was developed. Data from adult twins and their spouses were used to investigate the causes of assortative mating (correlation between spousesÂ =Â 0.41, due to phenotypic assortment). The heritability of exercise in the adult generation was estimated at 42%. The shared environment for exercise behavior in adolescents mainly represents generation specific shared environmental influences that seem somewhat more important in explaining familial clustering in girls than in boys (52 versus 41%). A small effect of vertical cultural transmission was found for boys only (3%). The remaining familial clustering for exercise behavior was explained by additive genetic factors (42% in boys and 36% in girls). Future studies on adolescent exercise behavior should focus on identification of the generation specific environmental factors.

ADHD in Dutch Adults: Heritability and Linkage Study American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics : the Official Publication of the International Society of Psychiatric Genetics. Apr, 2011 | Pubmed ID: 21294247 Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental phenotype that persists into adulthood. This study investigated the heritability of inattentive and hyperactive symptoms and of total ADHD symptomatology load (ADHD index) in adults and performed linkage scans for these dimensions. Data on sibling pairs and their family members from the Netherlands Twin Register with genotype and phenotype data for inattention, hyperactivity and ADHD index (âˆ¼750 sib-pairs) were analyzed. Phenotypes were assessed with the short self-report form of the Conners' Adult ADHD Rating Scales (CAARS). Heritabilities were estimated in SOLAR under polygenic models. Genome-wide linkage scans were performed using variance components (VC) in MERLIN and MINX and model-based linkage analysis was carried out in MENDEL with empirical evaluation of the results via simulations. Heritability estimates for inattention, hyperactivity and ADHD index were 35%, 23%, and 31%, respectively. Chromosomes 18q21.31-18q21.32 (VC LODâ€‰=â€‰4.58, p(emp) â€‰=â€‰0.0026) and 2p25.1 (LODâ€‰=â€‰3.58, p(emp) â€‰=â€‰0.0372) provided significant evidence for linkage for inattention and the ADHD index, respectively. The QTL on chromosome 2p25.1 also showed suggestive linkage for hyperactivity. Two additional suggestive QTLs for hyperactivity and the ADHD index shared the same location on chromosome 3p24.3-3p24.1. Finally, a suggestive QTL on 8p23.3-8p23.2 for hyperactivity was also found. Heritability of inattention, hyperactivity and total ADHD symptoms is lower in adults than in children. Chromosomes 18q and 2p are likely to harbor genes that influence several aspects of adult ADHD.

Î±-Amylase As a Reliable and Convenient Measure of Sympathetic Activity: Don't Start Salivating Just Yet! Psychoneuroendocrinology. May, 2011 | Pubmed ID: 21295411 Recent years have seen a growing interest in salivary Î±-amylase (sAA) as a non-invasive marker for sympathetic nervous system (SNS) activity. Saliva offers many advantages as a biomarker fluid and sAA is one of its most plentiful components. sAA is a digestive enzyme that breaks down starch, which provides a simple means of quantification by measuring its enzymatic activity. This commentary will address a number of common misconceptions and methodological issues that surround the use of sAA as a marker of SNS activity and limit its utility in biobehavioral research. The usefulness of sAA as an SNS marker is undermined by the fact that the parasympathetic nerves also play a significant role in sAA release. Local parasympathetic nerves regulate sAA activity via: (1) Î±-amylase release from glands that are solely or mainly parasympathetically innervated; (2) via synergistic sympathetic-parasympathetic effects on protein secretion (known as 'augmented secretion'); and (3) via effects on salivary flow rate. Regarding methodology, we discuss why it is problematic: (1) to ignore the contribution of salivary flow rate; (2) to use absorbent materials for saliva collection, and; (3) to stimulate saliva secretion by chewing. While these methodological problems can be addressed by using standardized and timed collection of unstimulated saliva, the physiological regulation of sAA secretion presents less resolvable issues. We conclude that at present there is insufficient support for the use and interpretation of sAA activity as a valid and reliable measure of SNS activity.

Meta-analysis of Genome-wide Association Studies in >80 000 Subjects Identifies Multiple Loci for C-reactive Protein Levels Circulation. Feb, 2011 | Pubmed ID: 21300955 C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels.

Variance Components Models for Physical Activity with Age As Modifier: a Comparative Twin Study in Seven Countries Twin Research and Human Genetics : the Official Journal of the International Society for Twin Studies. Feb, 2011 | Pubmed ID: 21314253 Physical activity is influenced by genetic factors whose expression may change with age. We employed an extension to the classical twin model that allows a modifier variable, age, to interact with the effects of the latent genetic and environmental factors. The model was applied to self-reported data from twins aged 19 to 50 from seven countries that collaborated in the GenomEUtwin project: Australia, Denmark, Finland, Norway, Netherlands, Sweden and United Kingdom. Results confirmed the importance of genetic influences on physical activity in all countries and showed an age-related decrease in heritability for 4 countries. In the other three countries age did not interact with heritability but those samples were smaller or had a more restricted age range. Effects of shared environment were absent, except in older Swedish participants. The study confirms the importance of taking age effects into account when exploring the genetic and environmental contribution to physical activity. It also suggests that the power of genome-wide association studies to identify the genetic variants contributing to physical activity may be larger in young adult cohorts.

Heavy Alcohol Use, Rather Than Alcohol Dependence, is Associated with Dysregulation of the Hypothalamic-pituitary-adrenal Axis and the Autonomic Nervous System Drug and Alcohol Dependence. Jul, 2011 | Pubmed ID: 21330066 Heavy alcohol use as well as alcohol dependence (AD) have been associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA)-axis and the autonomic nervous system (ANS). However, the relative contribution of alcohol use and AD is unclear.

Genome-wide Association Study Identifies a Single Major Locus Contributing to Survival into Old Age; the APOE Locus Revisited Aging Cell. Aug, 2011 | Pubmed ID: 21418511 By studying the loci that contribute to human longevity, we aim to identify mechanisms that contribute to healthy aging. To identify such loci, we performed a genome-wide association study (GWAS) comparing 403 unrelated nonagenarians from long-living families included in the Leiden Longevity Study (LLS) and 1670 younger population controls. The strongest candidate SNPs from this GWAS have been analyzed in a meta-analysis of nonagenarian cases from the Rotterdam Study, Leiden 85-plus study, and Danish 1905 cohort. Only one of the 62 prioritized SNPs from the GWAS analysis (P

Genetic Architecture of Circulating Lipid Levels European Journal of Human Genetics : EJHG. Jul, 2011 | Pubmed ID: 21448234 Serum concentrations of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs) and total cholesterol (TC) are important heritable risk factors for cardiovascular disease. Although genome-wide association studies (GWASs) of circulating lipid levels have identified numerous loci, a substantial portion of the heritability of these traits remains unexplained. Evidence of unexplained genetic variance can be detected by combining multiple independent markers into additive genetic risk scores. Such polygenic scores, constructed using results from the ENGAGE Consortium GWAS on serum lipids, were applied to predict lipid levels in an independent population-based study, the Rotterdam Study-II (RS-II). We additionally tested for evidence of a shared genetic basis for different lipid phenotypes. Finally, the polygenic score approach was used to identify an alternative genome-wide significance threshold before pathway analysis and those results were compared with those based on the classical genome-wide significance threshold. Our study provides evidence suggesting that many loci influencing circulating lipid levels remain undiscovered. Cross-prediction models suggested a small overlap between the polygenic backgrounds involved in determining LDL-C, HDL-C and TG levels. Pathway analysis utilizing the best polygenic score for TC uncovered extra information compared with using only genome-wide significant loci. These results suggest that the genetic architecture of circulating lipids involves a number of undiscovered variants with very small effects, and that increasing GWAS sample sizes will enable the identification of novel variants that regulate lipid levels.

Meta-analysis of Genome-wide Association for Migraine in Six Population-based European Cohorts European Journal of Human Genetics : EJHG. Aug, 2011 | Pubmed ID: 21448238 Migraine is a common neurological disorder with a genetically complex background. This paper describes a meta-analysis of genome-wide association (GWA) studies on migraine, performed by the Dutch-Icelandic migraine genetics (DICE) consortium, which brings together six population-based European migraine cohorts with a total sample size of 10,980 individuals (2446 cases and 8534 controls). A total of 32 SNPs showed marginal evidence for association at a P-value

Genome-wide Association and Genetic Functional Studies Identify Autism Susceptibility Candidate 2 Gene (AUTS2) in the Regulation of Alcohol Consumption Proceedings of the National Academy of Sciences of the United States of America. Apr, 2011 | Pubmed ID: 21471458 Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of âˆ¼2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. SNP rs6943555 in autism susceptibility candidate 2 gene (AUTS2) was associated with alcohol consumption at genome-wide significance (P = 4 Ã— 10(-8) to P = 4 Ã— 10(-9)). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples (P = 0.026) and significant (P < 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Down-regulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila (P < 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior.

White Matter Differences in Monozygotic Twins Discordant or Concordant for Obsessive-compulsive Symptoms: a Combined Diffusion Tensor Imaging/voxel-based Morphometry Study Biological Psychiatry. Nov, 2011 | Pubmed ID: 21549354 Neuroimaging studies of obsessive-compulsive disorder (OCD) patients point to deficits in cortico-striato-thalamo-cortical circuits that might include changes in white matter. The contribution of environmental and genetic factors to the various OCD-related changes in brain structures remains to be established.

A 3p26-3p25 Genetic Linkage Finding for DSM-IV Major Depression in Heavy Smoking Families The American Journal of Psychiatry. Aug, 2011 | Pubmed ID: 21572167 The authors tested for genetic linkage of DSM-IV-diagnosed major depressive disorder in families that were ascertained for cigarette smoking.

LPAR1 and ITGA4 Regulate Peripheral Blood Monocyte Counts Human Mutation. Aug, 2011 | Pubmed ID: 21598361 We recently mapped a quantitative trait locus for monocyte counts to chromosome 9q31 (rs7023923). Here we extend this work by showing with two independent approaches that rs7023923 regulates the expression levels of the nearby LPAR1 gene (P

Underestimation of Cardiac Vagal Control in Regular Exercisers by 24-hour Heart Rate Variability Recordings International Journal of Psychophysiology : Official Journal of the International Organization of Psychophysiology. Sep, 2011 | Pubmed ID: 21723331 To examine whether ceiling effects at long inter beat intervals (IBIs)cause an underestimation of cardiac vagal control in regular exercisers by time and frequency-domain measures of respiratory sinus arrhythmia (RSA).

Identification of IL6R and Chromosome 11q13.5 As Risk Loci for Asthma Lancet. Sep, 2011 | Pubmed ID: 21907864 We aimed to identify novel genetic variants affecting asthma risk, since these might provide novel insights into molecular mechanisms underlying the disease.

Genome-wide Association Study Identifies Six New Loci Influencing Pulse Pressure and Mean Arterial Pressure Nature Genetics. Oct, 2011 | Pubmed ID: 21909110 Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 Ã— 10(-8) to P = 2.3 Ã— 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.

Scale-free Modulation of Resting-state Neuronal Oscillations Reflects Prolonged Brain Maturation in Humans The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Sep, 2011 | Pubmed ID: 21917796 Human neuronal circuits undergo life-long functional reorganization with profound effects on cognition and behavior. Well documented prolonged development of anatomical brain structures includes white and gray matter changes that continue into the third decade of life. We investigated resting-state EEG oscillations in 1433 subjects from 5 to 71 years. Neuronal oscillations exhibit scale-free amplitude modulation as reflected in power-law decay of autocorrelations--also known as long-range temporal correlations (LRTC)--which was assessed by detrended fluctuation analysis. We observed pronounced increases in LRTC from childhood to adolescence, during adolescence, and even into early adulthood (âˆ¼25 years of age) after which the temporal structure stabilized. A principal component analysis of the spatial distribution of LRTC revealed increasingly uniform scores across the scalp. Together, these findings indicate that the scale-free modulation of resting-state oscillations reflects brain maturation, and suggests that scaling analysis may prove useful as a biomarker of pathophysiology in neurodevelopmental disorders such as attention deficit hyperactivity disorder and schizophrenia.

Genome-wide Association Study Identifies Loci Influencing Concentrations of Liver Enzymes in Plasma Nature Genetics. Nov, 2011 | Pubmed ID: 22001757 Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10(-8) to P = 10(-190)). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function.

A Genome-wide Screen for Interactions Reveals a New Locus on 4p15 Modifying the Effect of Waist-to-hip Ratio on Total Cholesterol PLoS Genetics. Oct, 2011 | Pubmed ID: 22028671 Recent genome-wide association (GWA) studies described 95 loci controlling serum lipid levels. These common variants explain âˆ¼25% of the heritability of the phenotypes. To date, no unbiased screen for gene-environment interactions for circulating lipids has been reported. We screened for variants that modify the relationship between known epidemiological risk factors and circulating lipid levels in a meta-analysis of genome-wide association (GWA) data from 18 population-based cohorts with European ancestry (maximum Nâ€Š=â€Š32,225). We collected 8 further cohorts (Nâ€Š=â€Š17,102) for replication, and rs6448771 on 4p15 demonstrated genome-wide significant interaction with waist-to-hip-ratio (WHR) on total cholesterol (TC) with a combined P-value of 4.79Ã—10(-9). There were two potential candidate genes in the region, PCDH7 and CCKAR, with differential expression levels for rs6448771 genotypes in adipose tissue. The effect of WHR on TC was strongest for individuals carrying two copies of G allele, for whom a one standard deviation (sd) difference in WHR corresponds to 0.19 sd difference in TC concentration, while for A allele homozygous the difference was 0.12 sd. Our findings may open up possibilities for targeted intervention strategies for people characterized by specific genomic profiles. However, more refined measures of both body-fat distribution and metabolic measures are needed to understand how their joint dynamics are modified by the newly found locus.

New Gene Functions in Megakaryopoiesis and Platelet Formation Nature. Dec, 2011 | Pubmed ID: 22139419 Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.

Heritability of Problem Drinking and the Genetic Overlap with Personality in a General Population Sample Frontiers in Genetics. 2011 | Pubmed ID: 22303371 This study examined the heritability of problem drinking and investigated the phenotypic and genetic relationships between problem drinking and personality. In a sample of 5,870 twins and siblings and 4,420 additional family members from the Netherlands Twin Register. Data on problem drinking (assessed with the AUDIT and CAGE; 12 items) and personality [NEO Five-Factor Inventory (FFI); 60 items] were collected in 2009/2010 by surveys. Confirmatory factor analysis on the AUDIT and CAGE items showed that the items clustered on two separate but highly correlated (râ€‰=â€‰0.74) underlying factors. A higher-order factor was extracted that reflected those aspects of problem drinking that are common to the AUDIT and CAGE, which showed a heritability of 40%. The correlations between problem drinking and the five dimensions of personality were small but significant, ranging from 0.06 for Extraversion to -0.12 for Conscientiousness. All personality dimensions (with broad-sense heritabilities between 32 and 55%, and some evidence for non-additive genetic influences) were genetically correlated with problem drinking. The genetic correlations were small to modest (between |0.12| and |0.41|). Future studies with longitudinal data and DNA polymorphisms are needed to determine the biological mechanisms that underlie the genetic link between problem drinking and personality.

Loci Affecting Gamma-glutamyl Transferase in Adults and Adolescents Show Age Ã— SNP Interaction and Cardiometabolic Disease Associations Human Molecular Genetics. Jan, 2012 | Pubmed ID: 22010049 Serum gamma-glutamyl transferase (GGT) activity is a marker of liver disease which is also prospectively associated with the risk of all-cause mortality, cardiovascular disease, type 2 diabetes and cancers. We have discovered novel loci affecting GGT in a genome-wide association study (rs1497406 in an intergenic region of chromosome 1, P = 3.9 Ã— 10(-8); rs944002 in C14orf73 on chromosome 14, P = 4.7 Ã— 10(-13); rs340005 in RORA on chromosome 15, P = 2.4 Ã— 10(-8)), and a highly significant heterogeneity between adult and adolescent results at the GGT1 locus on chromosome 22 (maximum P(HET) = 5.6 Ã— 10(-12) at rs6519520). Pathway analysis of significant and suggestive single-nucleotide polymorphism associations showed significant overlap between genes affecting GGT and those affecting common metabolic and inflammatory diseases, and identified the hepatic nuclear factor (HNF) family as controllers of a network of genes affecting GGT. Our results reinforce the disease associations of GGT and demonstrate that control by the GGT1 locus varies with age.

A Genome-wide Association Search for Type 2 Diabetes Genes in African Americans PloS One. 2012 | Pubmed ID: 22238593 African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (nâ€Š=â€Š550 independent loci) were genotyped in a replication cohort and 122 SNPs (nâ€Š=â€Š98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P

Facilitated Defensive Coping, Silent Ischaemia and ECG Left-ventricular Hypertrophy: the SABPA Study Journal of Hypertension. Mar, 2012 | Pubmed ID: 22245987 Defensive active coping responses (being-in-control, acceptance of the stressor as reality) have been associated with vascular hyper-responsiveness in urban Africans. However, the association between active coping responses, blood pressure (BP), and ECG-derived left-ventricular hypertrophy (LVH) responses is unknown.

Meta-analyses Identify 13 Loci Associated with Age at Menopause and Highlight DNA Repair and Immune Pathways Nature Genetics. Mar, 2012 | Pubmed ID: 22267201 To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 Ã— 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-ÎºB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

Regular Exercise, Subjective Wellbeing, and Internalizing Problems in Adolescence: Causality or Genetic Pleiotropy? Frontiers in Genetics. 2012 | Pubmed ID: 22303410 This study tests in a genetically informative design whether exercise behavior causally influences subjective wellbeing (SWB) and internalizing problems (INT). If exercise causally influences SWB and INT, genetic and environmental factors influencing exercise behavior will also influence SWB and INT. Furthermore, within genetically identical (MZ) twin pairs, the twin who exercises more should also show higher levels of SWB and lower levels of INT, than the co-twin who exercises less, because genetic confounding is excluded. Data on these phenotypes were available in a sample of 6317 adolescent twins and 1180 non-twin-siblings. Most participants had longitudinal data with 2-year follow-up. Exercise behavior was cross-sectionally and longitudinally associated with fewer internalizing problems and increased SWB (correlations ranged from 0.12 to 0.16). Cross-sectional and longitudinal associations were mainly accounted for by genetic factors, whereas the contribution of environmental factors was negligible. Within MZ twin pairs, the twin who exercised more did not show fewer internalizing problems and increased SWB. This was found cross-sectionally and longitudinally. We conclude that exercise behavior is associated with fewer internalizing problems and higher levels of SWB. The association largely reflects the effects of common genetic factors on these traits.

Genetic and Environmental Influences on Individual Differences in Sedentary Behavior During Adolescence: a Twin-family Study Archives of Pediatrics & Adolescent Medicine. Jun, 2012 | Pubmed ID: 22312167 To investigate the degree to which genetic and environmental influences affect individual differences in sedentary behavior throughout adolescence.

Common Variants in the Type 2 Diabetes KCNQ1 Gene Are Associated with Impairments in Insulin Secretion During Hyperglycaemic Glucose Clamp PloS One. 2012 | Pubmed ID: 22403629 Genome-wide association studies in Japanese populations recently identified common variants in the KCNQ1 gene to be associated with type 2 diabetes. We examined the association of these variants within KCNQ1 with type 2 diabetes in a Dutch population, investigated their effects on insulin secretion and metabolic traits and on the risk of developing complications in type 2 diabetes patients.

Dysregulation of the Autonomic Nervous System and Its Association with the Presence and Intensity of Chronic Widespread Pain Arthritis Care & Research. Aug, 2012 | Pubmed ID: 22422576 To test the hypotheses that dysregulation of the autonomic nervous system (ANS) is associated with the presence of chronic widespread pain (CWP), and that dysregulation of the ANS is associated with higher pain intensity in CWP.

Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits: a Multi-ethnic Meta-analysis of 45,891 Individuals PLoS Genetics. Mar, 2012 | Pubmed ID: 22479202 Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (Pâ€Š=â€Š4.5Ã—10(-8)-1.2Ã—10(-43)). Using a novel method to combine data across ethnicities (Nâ€Š=â€Š4,232 African Americans, Nâ€Š=â€Š1,776 Asians, and Nâ€Š=â€Š29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p

De Novo and Inherited CNVs in MZ Twin Pairs Selected for Discordance and Concordance on Attention Problems European Journal of Human Genetics : EJHG. Oct, 2012 | Pubmed ID: 22490988 Copy number variations (CNVs) have been reported to be causal suspects in a variety of psychopathologic traits. We investigate whether de novo and/or inherited CNVs contribute to the risk for Attention Problems (APs) in children. Based on longitudinal phenotyping, 50 concordant and discordant monozygotic (MZ) twin pairs were selected from a sample of âˆ¼3200 MZ pairs. Two types of de novo CNVs were investigated: (1) CNVs shared by both MZ twins, but not inherited (pre-twinning de novo CNVs), which were detected by comparing copy number (CN) calls between parents and twins and (2) CNVs not shared by co-twins (post-twinning de novo CNVs), which were investigated by comparing the CN calls within MZ pairs. The association between the overall CNV burden and AP was also investigated for CNVs genome-wide, CNVs within genes and CNVs outside of genes. Two de novo CNVs were identified and validated using quantitative PCR: a pre-twinning de novo duplication in a concordant-unaffected twin pair and a post-twinning deletion in the higher scoring twin from a concordant-affected pair. For the overall CNV burden analyses, affected individuals had significantly larger CNVs that overlapped with genes than unaffected individuals (P=0.008). This study suggests that the presence of larger CNVs may increase the risk for AP, because they are more likely to affect genes, and confirms that MZ twins are not always genetically identical.

Identification of Common Variants Associated with Human Hippocampal and Intracranial Volumes Nature Genetics. 2012 | Pubmed ID: 22504417 Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 Ã— 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 Ã— 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 Ã— 10(-7)).

Estimating the Genetic Variance of Major Depressive Disorder Due to All Single Nucleotide Polymorphisms Biological Psychiatry. Oct, 2012 | Pubmed ID: 22520966 Genome-wide association studies of psychiatric disorders have been criticized for their lack of explaining a considerable proportion of the heritability established in twin and family studies. Genome-wide association studies of major depressive disorder in particular have so far been unsuccessful in detecting genome-wide significant single nucleotide polymorphisms (SNPs). Using two recently proposed methods designed to estimate the heritability of a phenotype that is attributable to genome-wide SNPs, we show that SNPs on current platforms contain substantial information concerning the additive genetic variance of major depressive disorder. To assess the consistency of these two methods, we analyzed four other complex phenotypes from different domains. The pattern of results is consistent with estimates of heritability obtained in twin studies carried out in the same population.

The Relationship Between Impulsive Choice and Impulsive Action: a Cross-species Translational Study PloS One. 2012 | Pubmed ID: 22574225 Maladaptive impulsivity is a core symptom in various psychiatric disorders. However, there is only limited evidence available on whether different measures of impulsivity represent largely unrelated aspects or a unitary construct. In a cross-species translational study, thirty rats were trained in impulsive choice (delayed reward task) and impulsive action (five-choice serial reaction time task) paradigms. The correlation between those measures was assessed during baseline performance and after pharmacological manipulations with the psychostimulant amphetamine and the norepinephrine reuptake inhibitor atomoxetine. In parallel, to validate the animal data, 101 human subjects performed analogous measures of impulsive choice (delay discounting task, DDT) and impulsive action (immediate and delayed memory task, IMT/DMT). Moreover, all subjects completed the Stop Signal Task (SST, as an additional measure of impulsive action) and filled out the Barratt impulsiveness scale (BIS-11). Correlations between DDT and IMT/DMT were determined and a principal component analysis was performed on all human measures of impulsivity. In both rats and humans measures of impulsive choice and impulsive action did not correlate. In rats the within-subject pharmacological effects of amphetamine and atomoxetine did not correlate between tasks, suggesting distinct underlying neural correlates. Furthermore, in humans, principal component analysis identified three independent factors: (1) self-reported impulsivity (BIS-11); (2) impulsive action (IMT/DMT and SST); (3) impulsive choice (DDT). This is the first study directly comparing aspects of impulsivity using a cross-species translational approach. The present data reveal the non-unitary nature of impulsivity on a behavioral and pharmacological level. Collectively, this warrants a stronger focus on the relative contribution of distinct forms of impulsivity in psychopathology.

The Brain Matures with Stronger Functional Connectivity and Decreased Randomness of Its Network PloS One. 2012 | Pubmed ID: 22615837 We investigated the development of the brain's functional connectivity throughout the life span (ages 5 through 71 years) by measuring EEG activity in a large population-based sample. Connectivity was established with Synchronization Likelihood. Relative randomness of the connectivity patterns was established with Watts and Strogatz' (1998) graph parameters C (local clustering) and L (global path length) for alpha (~10 Hz), beta (~20 Hz), and theta (~4 Hz) oscillation networks. From childhood to adolescence large increases in connectivity in alpha, theta and beta frequency bands were found that continued at a slower pace into adulthood (peaking at ~50 yrs). Connectivity changes were accompanied by increases in L and C reflecting decreases in network randomness or increased order (peak levels reached at ~18 yrs). Older age (55+) was associated with weakened connectivity. Semi-automatically segmented T1 weighted MRI images of 104 young adults revealed that connectivity was significantly correlated to cerebral white matter volume (alpha oscillations: r = 33, p

Effect of Shared Environmental Factors on Exercise Behavior from Age 7 to 12 Years Medicine and Science in Sports and Exercise. Oct, 2012 | Pubmed ID: 22617397 The aim of this study was to investigate the relative influence of genetic and environmental factors on children's leisure time exercise behavior through the classic twin design.

A Fine-mapping Study of 7 Top Scoring Genes from a GWAS for Major Depressive Disorder PloS One. 2012 | Pubmed ID: 22649524 Major depressive disorder (MDD) is a psychiatric disorder that is characterized--amongst others--by persistent depressed mood, loss of interest and pleasure and psychomotor retardation. Environmental circumstances have proven to influence the aetiology of the disease, but MDD also has an estimated 40% heritability, probably with a polygenic background. In 2009, a genome wide association study (GWAS) was performed on the Dutch GAIN-MDD cohort. A non-synonymous coding single nucleotide polymorphism (SNP) rs2522833 in the PCLO gene became only nominally significant after post-hoc analysis with an Australian cohort which used similar ascertainment. The absence of genome-wide significance may be caused by low SNP coverage of genes. To increase SNP coverage to 100% for common variants (m.a.f.>0.1, r(2)>0.8), we selected seven genes from the GAIN-MDD GWAS: PCLO, GZMK, ANPEP, AFAP1L1, ST3GAL6, FGF14 and PTK2B. We genotyped 349 SNPs and obtained the lowest P-value for rs2715147 in PCLO at Pâ€Š=â€Š6.8E-7. We imputed, filling in missing genotypes, after which rs2715147 and rs2715148 showed the lowest P-value at Pâ€Š=â€Š1.2E-6. When we created a haplotype of these SNPs together with the non-synonymous coding SNP rs2522833, the P-value decreased to Pâ€Š=â€Š9.9E-7 but was not genome wide significant. Although our study did not identify a more strongly associated variant, the results for PCLO suggest that the causal variant is in high LD with rs2715147, rs2715148 and rs2522833.

Effects of Antidepressants, but Not Psychopathology, on Cardiac Sympathetic Control: a Longitudinal Study Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. Oct, 2012 | Pubmed ID: 22763618 Increased sympathetic activity has been hypothesized to have a role in the elevated somatic disease risk in persons with depressive or anxiety disorders. However, it remains unclear whether increased sympathetic activity reflects a direct effect of anxiety or depression or an indirect effect of antidepressant medication. The aim of this study was to test longitudinally whether cardiac sympathetic control, measured by pre-ejection period (PEP), was increased by depression/anxiety status and by antidepressant use. Cross-sectional and longitudinal data were from a depression and anxiety cohort: the Netherlands Study of Depression and Anxiety (NESDA). Baseline data of 2838 NESDA subjects (mean age 41.7 years, 66.7% female) and 2-year follow-up data of 2226 subjects were available for analyses. Included were subjects with and without depressive/anxiety disorders, using or not using different antidepressants at baseline or follow-up. The PEP was measured non-invasively by 1.5â€‰h of ambulatory impedance cardiography. Cross-sectional analyses compared PEP across psychopathology and antidepressant groups. Longitudinal analyses compared 2-year changes in PEP in relation to changes in psychopathology and antidepressant use. Cross-sectional analyses showed that antidepressant-naÃ¯ve depressive/anxious subjects had comparable PEP as controls, whereas subjects using tricyclic (TCA) or combined serotonergic/noradrenergic antidepressants (SNRI) had significantly shorter PEP compared with controls. In contrast, subjects using selective serotonin re-uptake inhibitors (SSRIs) had longer PEP than controls. Longitudinal results confirmed these findings: compared with 2-year change in PEP in continuous non-users (+2â€‰ms), subjects who started TCA or SNRI treatment showed significantly shortened PEP (-11â€‰ms, p=0.005 and p

Twin Specific Risk Factors in Primary School Achievements Twin Research and Human Genetics : the Official Journal of the International Society for Twin Studies. Feb, 2012 | Pubmed ID: 22784460 The main aim of this study was to examine twin specific risk factors that influence educational achievement in primary school. We included prenatal factors that are not unique to twins, except for zygosity, but show a higher prevalence in twins than in singletons. In addition, educational achievement was compared between twins and their nontwin siblings in a within-family design. Data were obtained from parents and teachers of approximately 10,000 twins and their nontwin siblings registered with the Netherlands Twin Register. Teachers rated the proficiency of the children on arithmetic, language, reading, and physical education, and reported a national educational achievement test score (CITO). Structural equation modeling showed that gestational age, birth weight, and sex were significant predictors of educational achievement, even after correction for socioeconomic status. Mode of delivery and zygosity did not have an effect, while parental age only influenced arithmetic. Mode of conception, incubator time, and birth complications negatively affected achievement in physical education. The comparison of educational achievement of twins and singletons showed significantly lower ratings on arithmetic, reading, and language in twins, compared to their older siblings, but not compared to their younger siblings. Low gestational age and low birth weight were the most important risk factors for lower educational achievement of twins in primary school. It seems that the differences observed between twins and their nontwin siblings in educational achievement can largely be explained by birth order within the family.

Brain Activation During Response Interference in Twins Discordant or Concordant for Obsessive Compulsive Symptoms Twin Research and Human Genetics : the Official Journal of the International Society for Twin Studies. Jun, 2012 | Pubmed ID: 22856371 One of the core behavioral features associated with obsessive compulsive symptomatology is the inability to inhibit thoughts and/or behaviors. Neuroimaging studies have indicated abnormalities in frontostriatal and dorsolateral prefrontal - anterior cingulate circuits during inhibitory control in patients with obsessive compulsive disorder compared with controls. In the present study, task performance and brain activation during Stroop color-word and Flanker interference were compared within monozygotic twin pairs discordant for obsessive compulsive symptoms and between groups of pairs scoring very low or very high on obsessive compulsive symptoms, in order to examine the differential impact of non-shared environmental versus genetic risk factors for obsessive compulsive symptomatology on inhibitory control related functional brain activation. Although performance was intact, brain activation during inhibition of distracting information differed between obsessive compulsive symptom high-scoring compared to low-scoring subjects. Regions affected in the discordant group (e.g., temporal and anterior cingulate gyrus) were partly different from those observed to be affected in the concordant groups (e.g., parietal gyrus and thalamus). A robust increase in dorsolateral prefrontal activity during response interference was observed in both the high-scoring twins of the discordant sample and the high-scoring twins of the concordant sample, marking this structure as a possible key region for disturbances in inhibitory control in obsessive compulsive disorder.

Individual Differences in EEG Spectral Power Reflect Genetic Variance in Gray and White Matter Volumes Twin Research and Human Genetics : the Official Journal of the International Society for Twin Studies. Jun, 2012 | Pubmed ID: 22856372 The human electroencephalogram (EEG) consists of oscillations that reflect the summation of postsynaptic potentials at the dendritic tree of cortical neurons. The strength of the oscillations (EEG power) is a highly genetic trait that has been related to individual differences in many phenotypes, including intelligence and liability for psychopathology. Here, we investigated whether brain anatomy underlies these EEG power differences by correlating it to gray and white matter volumes (GMV, WMV), and additionally investigated whether this association can be attributed to genes or environmental factors. EEG was measured in a sample of 405 young adult twins and their siblings, and power in the theta (~4 Hz), alpha (~10 Hz), and beta (~20 Hz) frequency bands determined. A subset of 121 subjects were also scanned in a 1.5 T MRI scanner, and gray and white matter volumes defined as the total of cortical and subcortical volumes, excluding cerebellum. Both MRI-based volumes and EEG power spectra were highly heritable. GMV and WMV correlated .25 to .29 with EEG power for the slower oscillations (theta, alpha). Moreover, these phenotypic correlations largely reflected genetic covariation, irrespective of oscillation frequency and volume type. Genetic correlations (.31 < rA < .43) revealed that only moderate proportions of the heritable variance overlapped between MRI volumes and EEG power. The results suggest that MRI volumes and EEG power share genetic sources of variation, which may reflect such processes as myelination, synaptic density, and dendritic outgrowth.

Large-scale Association Analyses Identify New Loci Influencing Glycemic Traits and Provide Insight into the Underlying Biological Pathways Nature Genetics. Aug, 2012 | Pubmed ID: 22885924 Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.

FTO Genotype is Associated with Phenotypic Variability of Body Mass Index Nature. Sep, 2012 | Pubmed ID: 22982992 There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using âˆ¼170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of âˆ¼0.5â€‰kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.

Twins, Tissue, and Time: an Assessment of SNPs and CNVs Twin Research and Human Genetics : the Official Journal of the International Society for Twin Studies. Dec, 2012 | Pubmed ID: 23021707 With the desire to assess genetic variation across the lifespan in large-scale collaborative projects, one question is whether inference of copy number (CN) is sensitive to the source of material for deoxyribonucleic acid (DNA) analysis (e.g., blood and buccal) and another question is whether CN is stable as individual sage. Here, we address these questions by applying Affymetrix 6.0 single nucleotide polymorphism (SNP)micro-arrays to 1,472 DNA samples from 710 individuals from the Netherlands Twin Register, including twin and non-twin individuals (372 with buccal and blood derived DNA and 388 with longitudinal data).Similar concordance for CN and genotype inference between samples from the same individual [or from the monozygotic (MZ) co-twins] was found for blood and buccal tissues. There was a small but statistically significant decrease in across-tissue concordance compared with concordance of samples from the same tissue type. No temporal effect was seen on CN variation from the 388 individuals sampled at two time points ranging from 1 to 12 years apart. The majority of our individuals were sampled at age younger than 20 years. Genotype concordance was very high (~ > 99%) between co-twins from 43 MZ pairs. For75 dizygotic (DZ) pairs, ~was ~65%. CN estimates were highly consistent between co-twins from MZ pairs for both deletions (f?2 ~ 90%) and duplications (~ ~ 86%). For DZ, these were similar for within-individual comparisons, but naturally lower between co-twins (~ ~ 50-60%). These results suggest that DNA from buccal samples perform as well as DNA from blood samples on the current generation of micro-array technologies.

A Genome-wide Association Study of Monozygotic Twin-pairs Suggests a Locus Related to Variability of Serum High-density Lipoprotein Cholesterol Twin Research and Human Genetics : the Official Journal of the International Society for Twin Studies. Dec, 2012 | Pubmed ID: 23031429 Genome-wide association analysis on monozygotic twin-pairs offers a route to discovery of gene environment interactions through testing for variability loci associated with sensitivity to individual environment/lifestyle. We present a genome-wide scan of loci associated with intra-pair differences in serum lipid and apolipoprotein levels. We report data for 1,720 monozygotic female twin-pairs from GenomEUtwin project with 2.5 million SNPs, imputed or genotyped, and measured serum lipid fractions for both twins. We found one locus associated with intra-pair differences in high-density lipoprotein cholesterol, rs2483058 in an intron of SRGAP2, where twins carrying the C allele are more sensitive to environmental factors(P=3.98 x 10-8). We followed up the association in further genotyped monozygotic twins (N= 1,261),which showed a moderate association for the variant (P= 0.200, same direction of an effect). In addition,we report a new association on the level of apolipoprotein A-ll (P= 4.03 x 1 o-8).

Growing Trees in Child Brains: Graph Theoretical Analysis of EEG Derived Minimum Spanning Tree in 5 and 7 Year Old Children Reflects Brain Maturation Brain Connectivity. Oct, 2012 | Pubmed ID: 23106635 The child brain is a small-world network which is hypothesized to change towards more ordered configurations with development. In graph theoretical studies, comparing network topologies under different conditions remains a critical point. Constructing a minimum spanning tree (MST) might present a solution since it does not require setting a threshold and uses a fixed number of nodes and edges. In this study, the MST method is introduced to examine developmental changes in functional brain network topology in young children. Resting-state electroencephalography (EEG) was recorded from 227 children twice at 5 and 7 years of age. Synchronization likelihood (SL) weighted matrices were calculated in three different frequency bands from which "minimum spanning trees" were constructed, which represent constructs of the most important routes for information flow in a network. From these trees, several parameters were calculated to characterize developmental change in network organization. MST diameter and eccentricity significantly increased, while leaf number and hierarchy significantly decreased in the alpha band with development. Boys showed significant higher leaf number, betweenness, degree and hierarchy and significant lower SL, diameter and eccentricity than girls in theta band. The developmental changes indicate a shift towards more decentralized line-like trees, which supports the previously hypothesized increase towards regularity of brain networks with development. Additionally, girls showed more line-like decentralized configurations, which is consistent with the view that girls are ahead of boys in brain development. MST provides an elegant method sensitive to capture subtle developmental changes in network organization without the bias of network comparison.

New Loci Associated with Birth Weight Identify Genetic Links Between Intrauterine Growth and Adult Height and Metabolism Nature Genetics. Dec, 2012 | Pubmed ID: 23202124 Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.

Seventy-five Genetic Loci Influencing the Human Red Blood Cell Nature. Dec, 2012 | Pubmed ID: 23222517 Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at Pâ€‰

Sex Differences in Genetic Architecture of Complex Phenotypes? PloS One. 2012 | Pubmed ID: 23272036 We examined sex differences in familial resemblance for a broad range of behavioral, psychiatric and health related phenotypes (122 complex traits) in children and adults. There is a renewed interest in the importance of genotype by sex interaction in, for example, genome-wide association (GWA) studies of complex phenotypes. If different genes play a role across sex, GWA studies should consider the effect of genetic variants separately in men and women, which affects statistical power. Twin and family studies offer an opportunity to compare resemblance between opposite-sex family members to the resemblance between same-sex relatives, thereby presenting a test of quantitative and qualitative sex differences in the genetic architecture of complex traits. We analyzed data on lifestyle, personality, psychiatric disorder, health, growth, development and metabolic traits in dizygotic (DZ) same-sex and opposite-sex twins, as these siblings are perfectly matched for age and prenatal exposures. Sample size varied from slightly over 300 subjects for measures of brain function such as EEG power to over 30,000 subjects for childhood psychopathology and birth weight. For most phenotypes, sample sizes were large, with an average sample size of 9027 individuals. By testing whether the resemblance in DZ opposite-sex pairs is the same as in DZ same-sex pairs, we obtain evidence for genetic qualitative sex-differences in the genetic architecture of complex traits for 4% of phenotypes. We conclude that for most traits that were examined, the current evidence is that same the genes are operating in men and women.

A Mega-analysis of Genome-wide Association Studies for Major Depressive Disorder Molecular Psychiatry. Apr, 2013 | Pubmed ID: 22472876 Prior genome-wide association studies (GWAS) of major depressive disorder (MDD) have met with limited success. We sought to increase statistical power to detect disease loci by conducting a GWAS mega-analysis for MDD. In the MDD discovery phase, we analyzed more than 1.2 million autosomal and X chromosome single-nucleotide polymorphisms (SNPs) in 18â€‰759 independent and unrelated subjects of recent European ancestry (9240 MDD cases and 9519 controls). In the MDD replication phase, we evaluated 554 SNPs in independent samples (6783 MDD cases and 50â€‰695 controls). We also conducted a cross-disorder meta-analysis using 819 autosomal SNPs with P

The Impact of Stress Systems and Lifestyle on Dyslipidemia and Obesity in Anxiety and Depression Psychoneuroendocrinology. Feb, 2013 | Pubmed ID: 22717171 Dyslipidemia and obesity have been observed in persons with severe anxiety or depression, and in tricyclic antidepressant (TCA) users. This likely contributes to the higher risk of cardiovascular disease (CVD) in anxiety and depressive disorders. We aimed to elucidate whether biological stress systems or lifestyle factors underlie these associations. If so, they may be useful targets for CVD prevention and intervention.

Strong Effects of Environmental Factors on Prevalence and Course of Major Depressive Disorder Are Not Moderated by 5-HTTLPR Polymorphisms in a Large Dutch Sample Journal of Affective Disorders. Mar, 2013 | Pubmed ID: 23021380 There is ongoing interest in the possible interaction of the serotonin-transporter-linked polymorphic region (5-HTTLPR) with environmental factors in determining Major Depressive Disorder (MDD). The current study contributes to this research area by comprehensively examining the interaction-effects and direct-effects of 5-HTTLPR and five environmental factors on MDD prevalence and course in a well-characterized longitudinal sample.

Estimated Preejection Period (PEP) Based on the Detection of the R-wave and DZ/dt-min Peaks Does Not Adequately Reflect the Actual PEP Across a Wide Range of Laboratory and Ambulatory Conditions International Journal of Psychophysiology : Official Journal of the International Organization of Psychophysiology. Jan, 2013 | Pubmed ID: 23142412 The current study evaluates the validity of the PEP computed from a fixed value for the Q-wave onset to R-wave peak (QR) interval and an R-wave peak to B-point (RB) interval that is estimated from the R-peak to dZ/dt-min peak (ISTI) interval. Ninety-one subjects participated in a 90min laboratory experiment in which a variety of often employed physical and mental stressors were presented and 31 further subjects participated in a structured 2hour ambulatory recording in which they partook in natural activities that induced large variation in posture and physical activity. PEP, QR interval, and ISTI were scored and rigorously checked by interactive inspection. Across the very diverse laboratory and ambulatory conditions the QR interval could be approximated by a fixed interval of 40ms but 95% confidence intervals were large (25.5 to 54.5ms). Multilevel analysis showed that 79% to 81% of the within and between-subject variation in the RB interval could be predicted by the ISTI with a simple linear regression equation. However, the optimal intercept and slope values in this equation varied significantly across subjects and study setting. Bland Altman plots revealed a large discrepancy between the estimated PEP using the R-wave peak and dZ/dt-min peak and the actual PEP based on the Q-wave onset and B-point. We conclude that the PEP estimated from a fixed QR interval and the ISTI could be a useful addition to the psychophysiologist's toolbox, but that it cannot replace the actual PEP to index cardiac sympathetic control.

The Young Netherlands Twin Register (YNTR): Longitudinal Twin and Family Studies in Over 70,000 Children Twin Research and Human Genetics : the Official Journal of the International Society for Twin Studies. Feb, 2013 | Pubmed ID: 23186620 The Netherlands Twin Register (NTR) began in 1987 with data collection in twins and their families, including families with newborn twins and triplets. Twenty-five years later, the NTR has collected at least one survey for 70,784 children, born after 1985. For the majority of twins, longitudinal data collection has been done by age-specific surveys. Shortly after giving birth, mothers receive a first survey with items on pregnancy and birth. At age 2, a survey on growth and achievement of milestones is sent. At ages 3, 7, 9/10, and 12 parents and teachers receive a series of surveys that are targeted at the development of emotional and behavior problems. From age 14 years onward, adolescent twins and their siblings report on their behavior problems, health, and lifestyle. When the twins are 18 years and older, parents are also invited to take part in survey studies. In sub-groups of different ages, in-depth phenotyping was done for IQ, electroencephalography , MRI, growth, hormones, neuropsychological assessments, and cardiovascular measures. DNA and biological samples have also been collected and large numbers of twin pairs and parents have been genotyped for zygosity by either micro-satellites or sets of short nucleotide polymorphisms and repeat polymorphisms in candidate genes. Subject recruitment and data collection is still ongoing and the longitudinal database is growing. Data collection by record linkage in the Netherlands is beginning and we expect these combined longitudinal data to provide increased insights into the genetic etiology of development of mental and physical health in children and adolescents.

Anxiety Sensitivity Moderates the Relationship of Changes in Physiological Arousal with Flight Anxiety During InÂ vivo Exposure Therapy Behaviour Research and Therapy. Feb, 2013 | Pubmed ID: 23262117 Physiological sensations and discomfort constitute the major symptoms reported by aviophobics. Anxiety sensitivity (AS) seems to moderate the relationship between self-reported somatic sensations and flight anxiety, and AS has been identified as a vulnerability factor for flight phobia. In this study we examined whether AS moderates the effects of somatic sensations and autonomic nervous system reactivity on flight anxiety induced by real flight. In fifty aviophobics participating in Cognitive Behaviour Group Therapy (CBGT), flight anxiety, somatic sensations and autonomic nervous system reactivity were assessed during a guided return flight. Results indicate that physiological reactivity interacted with AS. Changes in heart rate and parasympathetic activity were more strongly associated with changes in reported flight anxiety for high AS participants, and less for participants low on AS. Results did not indicate a moderating effect of AS on the relationship between self-reported somatic sensations and flight anxiety. Our results suggest that therapy for flight phobia might benefit from addressing the physical effect of anxiety, by means of cognitive restructuring and exposure to interoceptive stimuli, particularly in aviophobics high in AS.

The Adult Netherlands Twin Register: Twenty-five Years of Survey and Biological Data Collection Twin Research and Human Genetics : the Official Journal of the International Society for Twin Studies. Feb, 2013 | Pubmed ID: 23298648 Over the past 25 years, the Adult Netherlands Twin Register (ANTR) has collected a wealth of information on physical and mental health, lifestyle, and personality in adolescents and adults. This article provides an overview of the sources of information available, the main research findings, and an outlook for the future. Between 1991 and 2012, longitudinal surveys were completed by twins, their parents, siblings, spouses, and offspring. Data are available for 33,957 participants, with most individuals having completed two or more surveys. Smaller projects provided in-depth phenotyping, including measurements of the autonomic nervous system, neurocognitive function, and brain imaging. For 46% of the ANTR participants, DNA samples are available and whole genome scans have been obtained in more than 11,000 individuals. These data have resulted in numerous studies on heritability, gene x environment interactions, and causality, as well as gene finding studies. In the future, these studies will continue with collection of additional phenotypes, such as metabolomic and telomere length data, and detailed genetic information provided by DNA and RNA sequencing. Record linkage to national registers will allow the study of morbidity and mortality, thus providing insight into the development of health, lifestyle, and behavior across the lifespan.

Meta-analysis of Telomere Length in 19â€‰713 Subjects Reveals High Heritability, Stronger Maternal Inheritance and a Paternal Age Effect European Journal of Human Genetics : EJHG. Jan, 2013 | Pubmed ID: 23321625 Telomere length (TL) has been associated with aging and mortality, but individual differences are also influenced by genetic factors, with previous studies reporting heritability estimates ranging from 34 to 82%. Here we investigate the heritability, mode of inheritance and the influence of parental age at birth on TL in six large, independent cohort studies with a total of 19â€‰713 participants. The meta-analysis estimate of TL heritability was 0.70 (95% CI 0.64-0.76) and is based on a pattern of results that is highly similar for twins and other family members. We observed a stronger mother-offspring (r=0.42; P-value=3.60 Ã— 10(-61)) than father-offspring correlation (r=0.33; P-value=7.01 Ã— 10(-5)), and a significant positive association with paternal age at offspring birth (Î²=0.005; P-value=7.01 Ã— 10(-5)). Interestingly, a significant and quite substantial correlation in TL between spouses (r=0.25; P-value=2.82 Ã— 10(-30)) was seen, which appeared stronger in older spouse pairs (mean age â‰¥55 years; r=0.31; P-value=4.27 Ã— 10(-23)) than in younger pairs (mean age

Population Structure, Migration, and Diversifying Selection in the Netherlands European Journal of Human Genetics : EJHG. Mar, 2013 | Pubmed ID: 23531865 Genetic variation in a population can be summarized through principal component analysis (PCA) on genome-wide data. PCs derived from such analyses are valuable for genetic association studies, where they can correct for population stratification. We investigated how to capture the genetic population structure in a well-characterized sample from the Netherlands and in a worldwide data set and examined whether (1) removing long-range linkage disequilibrium (LD) regions and LD-based SNP pruning significantly improves correlations between PCs and geography and (2) whether genetic differentiation may have been influenced by migration and/or selection. In the Netherlands, three PCs showed significant correlations with geography, distinguishing between: (1) North and South; (2) East and West; and (3) the middle-band and the rest of the country. The third PC only emerged with minimized LD, which also significantly increased correlations with geography for the other two PCs. In addition to geography, the Dutch North-South PC showed correlations with genome-wide homozygosity (r=0.245), which may reflect a serial-founder effect due to northwards migration, and also with height (â™‚: r=0.142, â™€: r=0.153). The divergence between subpopulations identified by PCs is partly driven by selection pressures. The first three PCs showed significant signals for diversifying selection (545 SNPs - the majority within 184 genes). The strongest signal was observed between North and South for the functional SNP in HERC2 that determines human blue/brown eye color. Thus, this study demonstrates how to increase ancestry signals in a relatively homogeneous population and how those signals can reveal evolutionary history.European Journal of Human Genetics advance online publication, 27 March 2013; doi:10.1038/ejhg.2013.48.

The Genetic Architecture of Liver Enzyme Levels: GGT, ALT and AST Behavior Genetics. Apr, 2013 | Pubmed ID: 23580007 High levels of liver enzymes GGT, ALT and AST are predictive of disease and all-cause mortality and can reflect liver injury, fatty liver and/or oxidative stress. Variation in GGT, ALT and AST levels is heritable. Moderation of the heritability of these liver enzymes by age and sex has not often been explored, and it is not clear to what extent non-additive genetic and shared environmental factors may play a role. To examine the genetic architecture of GGT, ALT and AST, plasma levels were assessed in a large sample of twins, their siblings, parents and spouses (NÂ =Â 8,371; age range 18-90). For GGT and ALT, but not for AST, genetic structural equation modeling showed evidence for quantitative sex differences in the genetic architecture. There was no evidence for qualitative sex differences, i.e. the same genes were expressed in males and females. Both additive and non-additive genetic factors were important for GGT in females (total heritability h(2) 60Â %) and AST in both sexes (total h(2) 43Â %). The heritability of GGT in males and ALT for both sexes was due to additive effects only (GGT males 30Â %; ALT males 40Â %, females 22Â %). Evidence emerged for shared environmental factors influencing GGT in the male offspring generation (variance explained 28Â %). Thus, the same genes influence liver enzyme levels across sex and age, but their relative contribution to the variation in GGT and ALT differs in males and females and for GGT across age. Given adequate sample sizes these results suggest that genome-wide association studies may result in the detection of new susceptibility loci for liver enzyme levels when pooling results over sex and age.

Identification of Heart Rate-associated Loci and Their Effects on Cardiac Conduction and Rhythm Disorders Nature Genetics. Apr, 2013 | Pubmed ID: 23583979 Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

The Molecular Genetic Architecture of Self-employment PloS One. 2013 | Pubmed ID: 23593239 Economic variables such as income, education, and occupation are known to affect mortality and morbidity, such as cardiovascular disease, and have also been shown to be partly heritable. However, very little is known about which genes influence economic variables, although these genes may have both a direct and an indirect effect on health. We report results from the first large-scale collaboration that studies the molecular genetic architecture of an economic variable-entrepreneurship-that was operationalized using self-employment, a widely-available proxy. Our results suggest that common SNPs when considered jointly explain about half of the narrow-sense heritability of self-employment estimated in twin data (Ïƒg (2)/ÏƒP (2)â€Š=â€Š25%, h (2)â€Š=â€Š55%). However, a meta-analysis of genome-wide association studies across sixteen studies comprising 50,627 participants did not identify genome-wide significant SNPs. 58 SNPs with p

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