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Find video protocols related to scientific articles indexed in Pubmed.
Ambulatory measurement of the ECG T-wave amplitude.
Psychophysiology
PUBLISHED: 08-13-2014
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Ambulatory recording of the preejection period (PEP) can be used to measure changes in cardiac sympathetic nervous system (SNS) activity under naturalistic conditions. Here, we test the ECG T-wave amplitude (TWA) as an alternative measure, using 24-h ambulatory monitoring of PEP and TWA in a sample of 564 healthy adults. The TWA showed a decrease in response to mental stress and a monotonic decrease from nighttime sleep to daytime sitting and more physically active behaviors. Within-participant changes in TWA were correlated with changes in the PEP across the standardized stressors (r?=?.42) and the unstandardized naturalistic conditions (mean r?=?.35). Partialling out changes in heart rate and vagal effects attenuated these correlations, but they remained significant. Ambulatory TWA cannot replace PEP, but simultaneous recording of TWA and PEP provides a more comprehensive picture of changes in cardiac SNS activity in real-life settings.
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Genetics of regular exercise and sedentary behaviors.
Twin Res Hum Genet
PUBLISHED: 07-19-2014
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Studies on the determinants of physical activity have traditionally focused on social factors and environmental barriers, but recent research has shown the additional importance of biological factors, including genetic variation. Here we review the major tenets of this research to arrive at three major conclusions: First, individual differences in physical activity traits are significantly influenced by genetic factors, but genetic contribution varies strongly over age, with heritability of leisure time exercise behavior ranging from 27% to 84% and heritability of sedentary behaviors ranging from 9% to 48%. Second, candidate gene approaches based on animal or human QTLs or on biological relevance (e.g., dopaminergic or cannabinoid activity in the brain, or exercise performance influencing muscle physiology) have not yet yielded the necessary evidence to specify the genetic mechanisms underlying the heritability of physical activity traits. Third, there is significant genetic modulation of the beneficial effects of daily physical activity patterns on strength and endurance improvements and on health-related parameters like body mass index. Further increases in our understanding of the genetic determinants of sedentary and exercise behaviors as well as the genetic modulation of their effects on fitness and health will be key to meaningful future intervention on these behaviors.
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DNA Modification Study of Major Depressive Disorder: Beyond Locus-by-Locus Comparisons.
Biol. Psychiatry
PUBLISHED: 07-01-2014
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Major depressive disorder (MDD) exhibits numerous clinical and molecular features that are consistent with putative epigenetic misregulation. Despite growing interest in epigenetic studies of psychiatric diseases, the methodologies guiding such studies have not been well defined.
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Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.
John R B Perry, Felix Day, Cathy E Elks, Patrick Sulem, Deborah J Thompson, Teresa Ferreira, Chunyan He, Daniel I Chasman, Tonu Esko, Gudmar Thorleifsson, Eva Albrecht, Wei Q Ang, Tanguy Corre, Diana L Cousminer, Bjarke Feenstra, Nora Franceschini, Andrea Ganna, Andrew D Johnson, Sanela Kjellqvist, Kathryn L Lunetta, George McMahon, Ilja M Nolte, Lavinia Paternoster, Eleonora Porcu, Albert V Smith, Lisette Stolk, Alexander Teumer, Natalia Tšernikova, Emmi Tikkanen, Sheila Ulivi, Erin K Wagner, Najaf Amin, Laura J Bierut, Enda M Byrne, Jouke-Jan Hottenga, Daniel L Koller, Massimo Mangino, Tune H Pers, Laura M Yerges-Armstrong, Jing Hua Zhao, Irene L Andrulis, Hoda Anton-Culver, Femke Atsma, Stefania Bandinelli, Matthias W Beckmann, Javier Benitez, Carl Blomqvist, Stig E Bojesen, Manjeet K Bolla, Bernardo Bonanni, Hiltrud Brauch, Hermann Brenner, Julie E Buring, Jenny Chang-Claude, Stephen Chanock, Jinhui Chen, Georgia Chenevix-Trench, J Margriet Collée, Fergus J Couch, David Couper, Andrea D Coviello, Angela Cox, Kamila Czene, Adamo Pio D'adamo, George Davey Smith, Immaculata De Vivo, Ellen W Demerath, Joe Dennis, Peter Devilee, Aida K Dieffenbach, Alison M Dunning, Gudny Eiriksdottir, Johan G Eriksson, Peter A Fasching, Luigi Ferrucci, Dieter Flesch-Janys, Henrik Flyger, Tatiana Foroud, Lude Franke, Melissa E Garcia, Montserrat Garcia-Closas, Frank Geller, Eco E J de Geus, Graham G Giles, Daniel F Gudbjartsson, Vilmundur Gudnason, Pascal Guénel, Suiqun Guo, Per Hall, Ute Hamann, Robin Haring, Catharina A Hartman, Andrew C Heath, Albert Hofman, Maartje J Hooning, John L Hopper, Frank B Hu, David J Hunter, David Karasik, Douglas P Kiel, Julia A Knight, Veli-Matti Kosma, Zoltan Kutalik, Sandra Lai, Diether Lambrechts, Annika Lindblom, Reedik Mägi, Patrik K Magnusson, Arto Mannermaa, Nicholas G Martin, Gisli Masson, Patrick F McArdle, Wendy L McArdle, Mads Melbye, Kyriaki Michailidou, Evelin Mihailov, Lili Milani, Roger L Milne, Heli Nevanlinna, Patrick Neven, Ellen A Nohr, Albertine J Oldehinkel, Ben A Oostra, Aarno Palotie, Munro Peacock, Nancy L Pedersen, Paolo Peterlongo, Julian Peto, Paul D P Pharoah, Dirkje S Postma, Anneli Pouta, Katri Pylkäs, Paolo Radice, Susan Ring, Fernando Rivadeneira, Antonietta Robino, Lynda M Rose, Anja Rudolph, Veikko Salomaa, Serena Sanna, David Schlessinger, Marjanka K Schmidt, Mellissa C Southey, Ulla Sovio, Meir J Stampfer, Doris Stöckl, Anna M Storniolo, Nicholas J Timpson, Jonathan Tyrer, Jenny A Visser, Peter Vollenweider, Henry Völzke, Gérard Waeber, Melanie Waldenberger, Henri Wallaschofski, Qin Wang, Gonneke Willemsen, Robert Winqvist, Bruce H R Wolffenbuttel, Margaret J Wright, , Dorret I Boomsma, Michael J Econs, Kay-Tee Khaw, Ruth J F Loos, Mark I McCarthy, Grant W Montgomery, John P Rice, Elizabeth A Streeten, Unnur Thorsteinsdottir, Cornelia M van Duijn, Behrooz Z Alizadeh, Sven Bergmann, Eric Boerwinkle, Heather A Boyd, Laura Crisponi, Paolo Gasparini, Christian Gieger, Tamara B Harris, Erik Ingelsson, Marjo-Riitta Järvelin, Peter Kraft, Debbie Lawlor, Andres Metspalu, Craig E Pennell, Paul M Ridker, Harold Snieder, Thorkild I A Sørensen, Tim D Spector, David P Strachan, André G Uitterlinden, Nicholas J Wareham, Elisabeth Widén, Marek Zygmunt, Anna Murray, Douglas F Easton, Kari Stefansson, Joanne M Murabito, Ken K Ong.
Nature
PUBLISHED: 05-30-2014
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Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P?
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The contribution of the functional IL6R polymorphism rs2228145, eQTLs and other genome-wide SNPs to the heritability of plasma sIL-6R levels.
Behav. Genet.
PUBLISHED: 04-03-2014
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The non-synonymous SNP rs2228145 in the IL6R gene on chromosome 1q21.3 is associated with a wide range of common diseases, including asthma, rheumatoid arthritis, type 1 diabetes and coronary heart disease. We examined the contribution of this functional IL6R gene polymorphism rs2228145 versus other genome-wide SNPs to the variance of sIL-6R levels in blood plasma in a large population-based sample (N ~5,000), and conducted an expression QTL analysis to identify SNPs associated with IL6R gene expression. Based on data from 2,360 twin families, the broad heritability of sIL-6R was estimated at 72 and 51% of the total variance was explained by the functional SNP rs2228145. Converging findings from GWAS, linkage, and GCTA analyses indicate that additional variance of sIL-6R levels can be explained by other variants in the IL6R region, including variants at the 3'-end of IL6R tagged by rs60760897 that are associated with IL6R RNA expression.
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Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age.
Joris Deelen, Marian Beekman, Hae-Won Uh, Linda Broer, Kristin L Ayers, Qihua Tan, Yoichiro Kamatani, Anna M Bennet, Riin Tamm, Stella Trompet, Daníel F Guðbjartsson, Friederike Flachsbart, Giuseppina Rose, Alexander Viktorin, Krista Fischer, Marianne Nygaard, Heather J Cordell, Paolina Crocco, Erik B van den Akker, Stefan Böhringer, Quinta Helmer, Christopher P Nelson, Gary I Saunders, Maris Alver, Karen Andersen-Ranberg, Marie E Breen, Ruud van der Breggen, Amke Caliebe, Miriam Capri, Elisa Cevenini, Joanna C Collerton, Serena Dato, Karen Davies, Ian Ford, Jutta Gampe, Paolo Garagnani, Eco J C de Geus, Jennifer Harrow, Diana van Heemst, Bastiaan T Heijmans, Femke-Anouska Heinsen, Jouke-Jan Hottenga, Albert Hofman, Bernard Jeune, Palmi V Jonsson, Mark Lathrop, Doris Lechner, Carmen Martin-Ruiz, Susan E McNerlan, Evelin Mihailov, Alberto Montesanto, Simon P Mooijaart, Anne Murphy, Ellen A Nohr, Lavinia Paternoster, Iris Postmus, Fernando Rivadeneira, Owen A Ross, Stefano Salvioli, Naveed Sattar, Stefan Schreiber, Hreinn Stefansson, David J Stott, Henning Tiemeier, André G Uitterlinden, Rudi G J Westendorp, Gonneke Willemsen, Nilesh J Samani, Pilar Galán, Thorkild I A Sørensen, Dorret I Boomsma, J Wouter Jukema, Irene Maeve Rea, Giuseppe Passarino, Anton J M de Craen, Kaare Christensen, Almut Nebel, Kari Stefansson, Andres Metspalu, Patrik Magnusson, Hélène Blanché, Lene Christiansen, Thomas B L Kirkwood, Cornelia M van Duijn, Claudio Franceschi, Jeanine J Houwing-Duistermaat, P Eline Slagboom.
Hum. Mol. Genet.
PUBLISHED: 03-31-2014
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The genetic contribution to the variation in human lifespan is ? 25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (? 85 years) and 16 121 younger controls (<65 years) followed by replication in an additional set of 13 060 long-lived individuals and 61 156 controls. In addition, we performed a subset analysis in cases aged ? 90 years. We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR = 1.10, P = 1.74 × 10(-8)). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR = 0.72, P = 3.40 × 10(-36)), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n = 34 103), the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR = 0.95, P = 0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure. We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.
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Harmonization of Neuroticism and Extraversion phenotypes across inventories and cohorts in the Genetics of Personality Consortium: an application of Item Response Theory.
Behav. Genet.
PUBLISHED: 03-20-2014
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Mega- or meta-analytic studies (e.g. genome-wide association studies) are increasingly used in behavior genetics. An issue in such studies is that phenotypes are often measured by different instruments across study cohorts, requiring harmonization of measures so that more powerful fixed effect meta-analyses can be employed. Within the Genetics of Personality Consortium, we demonstrate for two clinically relevant personality traits, Neuroticism and Extraversion, how Item-Response Theory (IRT) can be applied to map item data from different inventories to the same underlying constructs. Personality item data were analyzed in >160,000 individuals from 23 cohorts across Europe, USA and Australia in which Neuroticism and Extraversion were assessed by nine different personality inventories. Results showed that harmonization was very successful for most personality inventories and moderately successful for some. Neuroticism and Extraversion inventories were largely measurement invariant across cohorts, in particular when comparing cohorts from countries where the same language is spoken. The IRT-based scores for Neuroticism and Extraversion were heritable (48 and 49 %, respectively, based on a meta-analysis of six twin cohorts, total N = 29,496 and 29,501 twin pairs, respectively) with a significant part of the heritability due to non-additive genetic factors. For Extraversion, these genetic factors qualitatively differ across sexes. We showed that our IRT method can lead to a large increase in sample size and therefore statistical power. The IRT approach may be applied to any mega- or meta-analytic study in which item-based behavioral measures need to be harmonized.
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Heritability of cardiac vagal control in 24-h heart rate variability recordings: influence of ceiling effects at low heart rates.
Psychophysiology
PUBLISHED: 03-17-2014
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This study estimated the heritability of 24-h heart rate variability (HRV) measures, while considering ceiling effects on HRV at low heart rates during the night. HRV was indexed by the standard deviation of all valid interbeat intervals (SDNN), the root mean square of differences between valid, successive interbeat intervals (RMSSD), and peak-valley respiratory sinus arrhythmia (pvRSA). Sleep and waking levels of cardiac vagal control were assessed in 1,003 twins and 285 of their non-twin siblings. Comparable heritability estimates were found for SDNN (46%-53%), RMSSD (49%-54%), and pvRSA (48%-57%) during the day and night. A nighttime ceiling effect was revealed in 10.7% of participants by a quadratic relationship between mean pvRSA and the interbeat interval. Excluding these participants did not change the heritability estimates. The genetic factors influencing ambulatory pvRSA, RMSSD, and SDNN largely overlap. These results suggest that gene-finding studies may pool the different cardiac vagal indices and that exclusion of participants with low heart rates is not required.
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Polygenic scores associated with educational attainment in adults predict educational achievement and ADHD symptoms in children.
Am. J. Med. Genet. B Neuropsychiatr. Genet.
PUBLISHED: 03-15-2014
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The American Psychiatric Association estimates that 3 to 7 per cent of all school aged children are diagnosed with attention deficit hyperactivity disorder (ADHD). Even after correcting for general cognitive ability, numerous studies report a negative association between ADHD and educational achievement. With polygenic scores we examined whether genetic variants that have a positive influence on educational attainment have a protective effect against ADHD. The effect sizes from a large GWA meta-analysis of educational attainment in adults were used to calculate polygenic scores in an independent sample of 12-year-old children from the Netherlands Twin Register. Linear mixed models showed that the polygenic scores significantly predicted educational achievement, school performance, ADHD symptoms and attention problems in children. These results confirm the genetic overlap between ADHD and educational achievement, indicating that one way to gain insight into genetic variants responsible for variation in ADHD is to include data on educational achievement, which are available at a larger scale.
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Heritability and genomics of gene expression in peripheral blood.
Nat. Genet.
PUBLISHED: 03-14-2014
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We assessed gene expression profiles in 2,752 twins, using a classic twin design to quantify expression heritability and quantitative trait loci (eQTLs) in peripheral blood. The most highly heritable genes (?777) were grouped into distinct expression clusters, enriched in gene-poor regions, associated with specific gene function or ontology classes, and strongly associated with disease designation. The design enabled a comparison of twin-based heritability to estimates based on dizygotic identity-by-descent sharing and distant genetic relatedness. Consideration of sampling variation suggests that previous heritability estimates have been upwardly biased. Genotyping of 2,494 twins enabled powerful identification of eQTLs, which we further examined in a replication set of 1,895 unrelated subjects. A large number of non-redundant local eQTLs (6,756) met replication criteria, whereas a relatively small number of distant eQTLs (165) met quality control and replication standards. Our results provide a new resource toward understanding the genetic control of transcription.
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The dopaminergic reward system and leisure time exercise behavior: a candidate allele study.
Biomed Res Int
PUBLISHED: 03-09-2014
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Twin studies provide evidence that genetic influences contribute strongly to individual differences in exercise behavior. We hypothesize that part of this heritability is explained by genetic variation in the dopaminergic reward system. Eight single nucleotide polymorphisms (SNPs in DRD1: rs265981, DRD2: rs6275, rs1800497, DRD3: rs6280, DRD4: rs1800955, DBH: rs1611115, rs2519152, and in COMT: rs4680) and three variable number of tandem repeats (VNTRs in DRD4, upstream of DRD5, and in DAT1) were investigated for an association with regular leisure time exercise behavior.
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Multi-site study of additive genetic effects on fractional anisotropy of cerebral white matter: Comparing meta and megaanalytical approaches for data pooling.
Neuroimage
PUBLISHED: 02-21-2014
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Combining datasets across independent studies can boost statistical power by increasing the numbers of observations and can achieve more accurate estimates of effect sizes. This is especially important for genetic studies where a large number of observations are required to obtain sufficient power to detect and replicate genetic effects. There is a need to develop and evaluate methods for joint-analytical analyses of rich datasets collected in imaging genetics studies. The ENIGMA-DTI consortium is developing and evaluating approaches for obtaining pooled estimates of heritability through meta-and mega-genetic analytical approaches, to estimate the general additive genetic contributions to the intersubject variance in fractional anisotropy (FA) measured from diffusion tensor imaging (DTI). We used the ENIGMA-DTI data harmonization protocol for uniform processing of DTI data from multiple sites. We evaluated this protocol in five family-based cohorts providing data from a total of 2248 children and adults (ages: 9-85) collected with various imaging protocols. We used the imaging genetics analysis tool, SOLAR-Eclipse, to combine twin and family data from Dutch, Australian and Mexican-American cohorts into one large "mega-family". We showed that heritability estimates may vary from one cohort to another. We used two meta-analytical (the sample-size and standard-error weighted) approaches and a mega-genetic analysis to calculate heritability estimates across-population. We performed leave-one-out analysis of the joint estimates of heritability, removing a different cohort each time to understand the estimate variability. Overall, meta- and mega-genetic analyses of heritability produced robust estimates of heritability.
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Dysregulated physiological stress systems and accelerated cellular aging.
Neurobiol. Aging
PUBLISHED: 01-21-2014
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Exposure to chronic stressors is associated with accelerated biological aging as indicated by reduced leukocyte telomere length (LTL). This impact could be because of chronic overactivation of the body's physiological stress systems. This study examined the associations between LTL and the immune system, hypothalamic-pituitary-adrenal axis and autonomic nervous system. LTL was assessed in 2936 adults from the Netherlands Study of Depression and Anxiety. Inflammation markers (interleukin-6, c-reactive protein, tumor necrosis factor-alpha), hypothalamic-pituitary-adrenal-axis indicators (salivary cortisol awakening curve [area under the curve indicators, with respect to the ground and increase], evening levels, 0.5 mg dexamethasone cortisol suppression ratio), and autonomic nervous system measures (heart rate, respiratory sinus arrhythmia, pre-ejection period) were determined. Linear regression analyses were performed and adjusted for sociodemographic, lifestyle and clinical factors. Shorter LTL was significantly associated with higher c-reactive protein, interleukin-6, area under the curve with respect to increase, and heart rate. A cumulative index score was calculated based on the number of highest tertiles of these 4 stress markers. LTL demonstrated a significant gradient within subjects ranging from having zero (5528 base pairs) to having 4 elevated stress markers (5371 base pairs, p for trend = 0.002), corresponding to a difference of 10 years of accelerated biological aging. Contrary to the expectations, shorter LTL was also associated with longer pre-ejection period, indicating lower sympathetic tone. This large-scale study showed that inflammation, high awakening cortisol response, and increased heart rate are associated with shorter LTL, especially when they are dysregulated cumulatively.
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Polygenic risk scores for smoking: predictors for alcohol and cannabis use?
Addiction
PUBLISHED: 01-15-2014
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A strong correlation exists between smoking and the use of alcohol and cannabis. This paper uses polygenic risk scores to explore the possibility of overlapping genetic factors. Those scores reflect a combined effect of selected risk alleles for smoking.
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Sex differences in the human peripheral blood transcriptome.
BMC Genomics
PUBLISHED: 01-14-2014
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Genomes of men and women differ in only a limited number of genes located on the sex chromosomes, whereas the transcriptome is far more sex-specific. Identification of sex-biased gene expression will contribute to understanding the molecular basis of sex-differences in complex traits and common diseases.
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The ENIGMA Consortium: large-scale collaborative analyses of neuroimaging and genetic data.
Paul M Thompson, Jason L Stein, Sarah E Medland, Derrek P Hibar, Alejandro Arias Vasquez, Miguel E Rentería, Roberto Toro, Neda Jahanshad, Gunter Schumann, Barbara Franke, Margaret J Wright, Nicholas G Martin, Ingrid Agartz, Martin Alda, Saud Alhusaini, Laura Almasy, Jorge Almeida, Kathryn Alpert, Nancy C Andreasen, Ole A Andreassen, Liana G Apostolova, Katja Appel, Nicola J Armstrong, Benjamin Aribisala, Mark E Bastin, Michael Bauer, Carrie E Bearden, Orjan Bergmann, Elisabeth B Binder, John Blangero, Henry J Bockholt, Erlend Bøen, Catherine Bois, Dorret I Boomsma, Tom Booth, Ian J Bowman, Janita Bralten, Rachel M Brouwer, Han G Brunner, David G Brohawn, Randy L Buckner, Jan Buitelaar, Kazima Bulayeva, Juan R Bustillo, Vince D Calhoun, Dara M Cannon, Rita M Cantor, Melanie A Carless, Xavier Caseras, Gianpiero L Cavalleri, M Mallar Chakravarty, Kiki D Chang, Christopher R K Ching, Andrea Christoforou, Sven Cichon, Vincent P Clark, Patricia Conrod, Giovanni Coppola, Benedicto Crespo-Facorro, Joanne E Curran, Michael Czisch, Ian J Deary, Eco J C de Geus, Anouk den Braber, Giuseppe Delvecchio, Chantal Depondt, Lieuwe de Haan, Greig I de Zubicaray, Danai Dima, Rali Dimitrova, Srdjan Djurovic, Hongwei Dong, Gary Donohoe, Ravindranath Duggirala, Thomas D Dyer, Stefan Ehrlich, Carl Johan Ekman, Torbjørn Elvsåshagen, Louise Emsell, Susanne Erk, Thomas Espeseth, Jesen Fagerness, Scott Fears, Iryna Fedko, Guillén Fernández, Simon E Fisher, Tatiana Foroud, Peter T Fox, Clyde Francks, Sophia Frangou, Eva Maria Frey, Thomas Frodl, Vincent Frouin, Hugh Garavan, Sudheer Giddaluru, David C Glahn, Beata Godlewska, Rita Z Goldstein, Randy L Gollub, Hans J Grabe, Oliver Grimm, Oliver Gruber, Tulio Guadalupe, Raquel E Gur, Ruben C Gur, Harald H H Göring, Saskia Hagenaars, Tomáš Hájek, Geoffrey B Hall, Jeremy Hall, John Hardy, Catharina A Hartman, Johanna Hass, Sean N Hatton, Unn K Haukvik, Katrin Hegenscheid, Andreas Heinz, Ian B Hickie, Beng-Choon Ho, David Hoehn, Pieter J Hoekstra, Marisa Hollinshead, Avram J Holmes, Georg Homuth, Martine Hoogman, L Elliot Hong, Norbert Hosten, Jouke-Jan Hottenga, Hilleke E Hulshoff Pol, Kristy S Hwang, Clifford R Jack, Mark Jenkinson, Caroline Johnston, Erik G Jönsson, René S Kahn, Dalia Kasperaviciute, Sinead Kelly, Sungeun Kim, Peter Kochunov, Laura Koenders, Bernd Krämer, John B J Kwok, Jim Lagopoulos, Gonzalo Laje, Mikael Landén, Bennett A Landman, John Lauriello, Stephen M Lawrie, Phil H Lee, Stephanie Le Hellard, Herve Lemaitre, Cassandra D Leonardo, Chiang-Shan Li, Benny Liberg, David C Liewald, Xinmin Liu, Lorna M Lopez, Eva Loth, Anbarasu Lourdusamy, Michelle Luciano, Fabio Macciardi, Marise W J Machielsen, Glenda M Macqueen, Ulrik F Malt, René Mandl, Dara S Manoach, Jean-Luc Martinot, Mar Matarin, Karen A Mather, Manuel Mattheisen, Morten Mattingsdal, Andreas Meyer-Lindenberg, Colm McDonald, Andrew M McIntosh, Francis J McMahon, Katie L McMahon, Eva Meisenzahl, Ingrid Melle, Yuri Milaneschi, Sebastian Mohnke, Grant W Montgomery, Derek W Morris, Eric K Moses, Bryon A Mueller, Susana Muñoz Maniega, Thomas W Mühleisen, Bertram Müller-Myhsok, Benson Mwangi, Matthias Nauck, Kwangsik Nho, Thomas E Nichols, Lars-Göran Nilsson, Allison C Nugent, Lars Nyberg, Rene L Olvera, Jaap Oosterlaan, Roel A Ophoff, Massimo Pandolfo, Melina Papalampropoulou-Tsiridou, Martina Papmeyer, Tomas Paus, Zdenka Pausova, Godfrey D Pearlson, Brenda W Penninx, Charles P Peterson, Andrea Pfennig, Mary Phillips, G Bruce Pike, Jean-Baptiste Poline, Steven G Potkin, Benno Pütz, Adaikalavan Ramasamy, Jerod Rasmussen, Marcella Rietschel, Mark Rijpkema, Shannon L Risacher, Joshua L Roffman, Roberto Roiz-Santiañez, Nina Romanczuk-Seiferth, Emma J Rose, Natalie A Royle, Dan Rujescu, Mina Ryten, Perminder S Sachdev, Alireza Salami, Theodore D Satterthwaite, Jonathan Savitz, Andrew J Saykin, Cathy Scanlon, Lianne Schmaal, Hugo G Schnack, Andrew J Schork, S Charles Schulz, Remmelt Schür, Larry Seidman, Li Shen, Jody M Shoemaker, Andrew Simmons, Sanjay M Sisodiya, Colin Smith, Jordan W Smoller, Jair C Soares, Scott R Sponheim, Emma Sprooten, John M Starr, Vidar M Steen, Stephen Strakowski, Lachlan Strike, Jessika Sussmann, Philipp G Sämann, Alexander Teumer, Arthur W Toga, Diana Tordesillas-Gutierrez, Daniah Trabzuni, Sarah Trost, Jessica Turner, Martijn van den Heuvel, Nic J van der Wee, Kristel van Eijk, Theo G M van Erp, Neeltje E M van Haren, Dennis van 't Ent, Marie-José van Tol, Maria C Valdés Hernández, Dick J Veltman, Amelia Versace, Henry Völzke, Robert Walker, Henrik Walter, Lei Wang, Joanna M Wardlaw, Michael E Weale, Michael W Weiner, Wei Wen, Lars T Westlye, Heather C Whalley, Christopher D Whelan, Tonya White, Anderson M Winkler, Katharina Wittfeld, Girma Woldehawariat, Christiane Wolf, David Zilles, Marcel P Zwiers, Anbupalam Thalamuthu, Peter R Schofield, Nelson B Freimer, Natalia S Lawrence, Wayne Drevets, .
Brain Imaging Behav
PUBLISHED: 01-09-2014
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The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
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Identifying genetic variants for heart rate variability in the acetylcholine pathway.
PLoS ONE
PUBLISHED: 01-01-2014
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Heart rate variability is an important risk factor for cardiovascular disease and all-cause mortality. The acetylcholine pathway plays a key role in explaining heart rate variability in humans. We assessed whether 443 genotyped and imputed common genetic variants in eight key genes (CHAT, SLC18A3, SLC5A7, CHRNB4, CHRNA3, CHRNA, CHRM2 and ACHE) of the acetylcholine pathway were associated with variation in an established measure of heart rate variability reflecting parasympathetic control of the heart rhythm, the root mean square of successive differences (RMSSD) of normal RR intervals. The association was studied in a two stage design in individuals of European descent. First, analyses were performed in a discovery sample of four cohorts (n?=?3429, discovery stage). Second, findings were replicated in three independent cohorts (n?=?3311, replication stage), and finally the two stages were combined in a meta-analysis (n?=?6740). RMSSD data were obtained under resting conditions. After correction for multiple testing, none of the SNPs showed an association with RMSSD. In conclusion, no common genetic variants for heart rate variability were identified in the largest and most comprehensive candidate gene study on the acetylcholine pathway to date. Future gene finding efforts for RMSSD may want to focus on hypothesis free approaches such as the genome-wide association study.
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Telomere length in circulating leukocytes is associated with lung function and disease.
Eur. Respir. J.
PUBLISHED: 12-05-2013
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Several clinical studies suggest the involvement of premature aging processes in COPD. Using an epidemiological approach we studied whether accelerated aging indicated by telomere length, a marker of biological age, is associated with COPD and asthma, and whether intrinsic age-related processes contribute to the inter-individual variability of lung function.Our meta-analysis of 14 studies included 934 COPD cases with 15,846 controls defined according to GLI criteria (or 1,189 COPD cases according to GOLD), 2,834 asthma cases with 28,195 controls, and spirometric parameters (FEV1, FVC and FEV1/FVC) of 12,595 individuals. Associations with telomere length were tested by linear regression, adjusting for age, sex, and smoking status.We observed negative associations between telomere length and asthma (?=?-0.0452, p=0.024) as well as COPD (?=?-0.0982, p=0.001), with associations being stronger and more significant when using GLI in comparison to GOLD. In both diseases, effects were stronger in females compared to males. The investigation of spirometric indices showed positive associations between telomere length and FEV1 (p=1.07×10(-7)), FVC (p=2.07×10(-5)), and their ratio FEV1/FVC (p=5.27×10(-3)). The effect was somewhat weaker in apparently healthy subjects compared to COPD or asthma patients.Our results provide indirect evidence for the hypothesis that cellular senescence may contribute to the pathogenesis of COPD and asthma and that lung function may reflect biological aging primarily due to intrinsic processes which are likely to be aggravated in lung diseases.
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Genetic and environmental influences on individual differences in sleep duration during adolescence.
Twin Res Hum Genet
PUBLISHED: 11-04-2013
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This study assessed to what extent genetic and environmental factors contributed to individual differences in adolescent sleep duration, and whether genetic and environmental contributions to sleep duration changed throughout adolescence. A twin-family design was used to gain insight into the genetic and environmental contributions to variation in sleep duration. The study sample consisted of 6,319 adolescent twins (44% males) and 1,359 non-twin siblings (44% males) in the age range of 12 to 20 years (mean age = 16.85, SD = 1.40). The participants self-reported usual sleep duration, which was categorized as less than 8 hours per night, 8-9 hours per night, and more than 9 hours per night. Results showed that the prevalence of shorter than optimum sleep duration, that is, less than 8 hours per night, was high, with the highest prevalence rates in later adolescence. The contribution of genetic and environmental factors to individual differences in sleep duration was dependent on age. Variation in sleep duration at the age of 12 years was accounted for by genetic (boys: 34%, girls: 36%), shared environmental (boys: 28%, girls: 45%), and non-shared environmental factors (boys: 38%, girls: 19%). At the age of 20 years, the role of genetic (boys: 47%, girls: 33%) and non-shared environmental factors (boys: 53%, girls: 67%) was more pronounced. It can be concluded from the results that individual differences in sleep duration were accounted for by genetic and non-shared environmental factors throughout adolescence, whereas shared environmental factors account for a substantial part of variation during early adolescence only.
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Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease.
Maria Sabater-Lleal, Jie Huang, Daniel Chasman, Silvia Naitza, Abbas Dehghan, Andrew D Johnson, Alexander Teumer, Alex P Reiner, Lasse Folkersen, Saonli Basu, Alicja R Rudnicka, Stella Trompet, Anders Malarstig, Jens Baumert, Joshua C Bis, Xiuqing Guo, Jouke J Hottenga, So-Youn Shin, Lorna M Lopez, Jari Lahti, Toshiko Tanaka, Lisa R Yanek, Tiphaine Oudot-Mellakh, James F Wilson, Pau Navarro, Jennifer E Huffman, Tatijana Zemunik, Susan Redline, Reena Mehra, Drazen Pulanić, Igor Rudan, Alan F Wright, Ivana Kolčić, Ozren Polašek, Sarah H Wild, Harry Campbell, J David Curb, Robert Wallace, Simin Liu, Charles B Eaton, Diane M Becker, Lewis C Becker, Stefania Bandinelli, Katri Räikkönen, Elisabeth Widén, Aarno Palotie, Myriam Fornage, David Green, Myron Gross, Gail Davies, Sarah E Harris, David C Liewald, John M Starr, Frances M K Williams, Peter J Grant, Timothy D Spector, Rona J Strawbridge, Angela Silveira, Bengt Sennblad, Fernando Rivadeneira, André G Uitterlinden, Oscar H Franco, Albert Hofman, Jenny van Dongen, Gonneke Willemsen, Dorret I Boomsma, Jie Yao, Nancy Swords Jenny, Talin Haritunians, Barbara McKnight, Thomas Lumley, Kent D Taylor, Jerome I Rotter, Bruce M Psaty, Annette Peters, Christian Gieger, Thomas Illig, Anne Grotevendt, Georg Homuth, Henry Völzke, Thomas Kocher, Anuj Goel, Maria Grazia Franzosi, Udo Seedorf, Robert Clarke, Maristella Steri, Kirill V Tarasov, Serena Sanna, David Schlessinger, David J Stott, Naveed Sattar, Brendan M Buckley, Ann Rumley, Gordon D Lowe, Wendy L McArdle, Ming-Huei Chen, Geoffrey H Tofler, Jaejoon Song, Eric Boerwinkle, Aaron R Folsom, Lynda M Rose, Anders Franco-Cereceda, Martina Teichert, M Arfan Ikram, Thomas H Mosley, Steve Bevan, Martin Dichgans, Peter M Rothwell, Cathie L M Sudlow, Jemma C Hopewell, John C Chambers, Danish Saleheen, Jaspal S Kooner, John Danesh, Christopher P Nelson, Jeanette Erdmann, Muredach P Reilly, Sekar Kathiresan, Heribert Schunkert, Pierre-Emmanuel Morange, Luigi Ferrucci, Johan G Eriksson, David Jacobs, Ian J Deary, Nicole Soranzo, Jacqueline C M Witteman, Eco J C de Geus, Russell P Tracy, Caroline Hayward, Wolfgang Koenig, Francesco Cucca, J Wouter Jukema, Per Eriksson, Sudha Seshadri, Hugh S Markus, Hugh Watkins, Nilesh J Samani, , Henri Wallaschofski, Nicholas L Smith, David Tregouet, Paul M Ridker, Weihong Tang, David P Strachan, Anders Hamsten, Christopher J O'Donnell.
Circulation
PUBLISHED: 08-22-2013
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Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation.
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Genetic architecture of the pro-inflammatory state in an extended twin-family design.
Twin Res Hum Genet
PUBLISHED: 08-16-2013
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In this study we examined the genetic architecture of variation in the pro-inflammatory state, using an extended twin-family design. Within the Netherlands Twin Register Biobank, fasting Tumor Necrosis Factor-? (TNF-?), Interleukin-6 (IL-6), C-Reactive Protein (CRP), and fibrinogen levels were available for 3,534 twins, 1,568 of their non-twin siblings, and 2,227 parents from 3,095 families. Heritability analyses took into account the effects of current and recent illness, anti-inflammatory medication, female sex hormone status, age, sex, body mass index, smoking status, month of data collection, and batch processing. Moderate broad-sense heritability was found for all inflammatory parameters (39%, 21%, 45%, and 46% for TNF-?, IL-6, CRP and fibrinogen, respectively). For all parameters, the remaining variance was explained by unique environmental influences and not by environment shared by family members. There was no resemblance between spouses for any of the inflammatory parameters, except for fibrinogen. Also, there was no evidence for twin-specific effects. A considerable part of genetic variation was explained by non-additive genetic effects for TNF-?, CRP, and fibrinogen. For IL-6, all genetic variance was additive. This study may have implications for future genome-wide association studies by setting a clear numerical target for genome-wide screens that aim to find genetic variants regulating the levels of these pro-inflammatory markers.
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Heritability of resting state EEG functional connectivity patterns.
Twin Res Hum Genet
PUBLISHED: 08-09-2013
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We examined the genetic architecture of functional brain connectivity measures in resting state electroencephalographic (EEG) recordings. Previous studies in Dutch twins have suggested that genetic factors are a main source of variance in functional brain connectivity derived from EEG recordings. In addition, qualitative descriptors of the brain network derived from graph analysis - network clustering and average path length - are also heritable traits. Here we replicated previous findings for connectivity, quantified by the synchronization likelihood, and the graph theoretical parameters cluster coefficient and path length in an Australian sample of 16-year-old twins (879) and their siblings (93). Modeling of monozygotic and dizygotic twins and sibling resemblance indicated heritability estimates of the synchronization likelihood (27-74%) and cluster coefficient and path length in the alpha and theta band (40-44% and 23-40% respectively) and path length in the beta band frequency (41%). This corroborates synchronization likelihood and its graph theoretical derivatives cluster coefficient and path length as potential endophenotypes for behavioral traits and neurological disorders.
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Inference of the genetic architecture underlying BMI and height with the use of 20,240 sibling pairs.
Am. J. Hum. Genet.
PUBLISHED: 08-07-2013
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Evidence that complex traits are highly polygenic has been presented by population-based genome-wide association studies (GWASs) through the identification of many significant variants, as well as by family-based de novo sequencing studies indicating that several traits have a large mutational target size. Here, using a third study design, we show results consistent with extreme polygenicity for body mass index (BMI) and height. On a sample of 20,240 siblings (from 9,570 nuclear families), we used a within-family method to obtain narrow-sense heritability estimates of 0.42 (SE = 0.17, p = 0.01) and 0.69 (SE = 0.14, p = 6 × 10(-)(7)) for BMI and height, respectively, after adjusting for covariates. The genomic inflation factors from locus-specific linkage analysis were 1.69 (SE = 0.21, p = 0.04) for BMI and 2.18 (SE = 0.21, p = 2 × 10(-10)) for height. This inflation is free of confounding and congruent with polygenicity, consistent with observations of ever-increasing genomic-inflation factors from GWASs with large sample sizes, implying that those signals are due to true genetic signals across the genome rather than population stratification. We also demonstrate that the distribution of the observed test statistics is consistent with both rare and common variants underlying a polygenic architecture and that previous reports of linkage signals in complex traits are probably a consequence of polygenic architecture rather than the segregation of variants with large effects. The convergent empirical evidence from GWASs, de novo studies, and within-family segregation implies that family-based sequencing studies for complex traits require very large sample sizes because the effects of causal variants are small on average.
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Heritability of metabolic syndrome traits in a large population-based sample.
J. Lipid Res.
PUBLISHED: 08-05-2013
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Heritability estimates of metabolic syndrome traits vary widely across studies. Some studies have suggested that the contribution of genes may vary with age or sex. We estimated the heritability of 11 metabolic syndrome-related traits and height as a function of age and sex in a large population-based sample of twin families (N = 2,792-27,021, for different traits). A moderate-to-high heritability was found for all traits [from H(2) = 0.47 (insulin) to H(2) = 0.78 (BMI)]. The broad-sense heritability (H(2)) showed little variation between age groups in women; it differed somewhat more in men (e.g., for glucose, H(2) = 0.61 in young females, H(2) = 0.56 in older females, H(2) = 0.64 in young males, and H(2)= 0.27 in older males). While nonadditive genetic effects explained little variation in the younger subjects, nonadditive genetic effects became more important at a greater age. Our findings show that in an unselected sample (age range, ~18-98 years), the genetic contribution to individual differences in metabolic syndrome traits is moderate to large in both sexes and across age. Although the prevalence of the metabolic syndrome has greatly increased in the past decades due to lifestyle changes, our study indicates that most of the variation in metabolic syndrome traits between individuals is due to genetic differences.
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Long-range temporal correlations in resting-state ? oscillations predict human timing-error dynamics.
J. Neurosci.
PUBLISHED: 07-05-2013
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Human behavior is imperfect. This is notably clear during repetitive tasks in which sequences of errors or deviations from perfect performance result. These errors are not random, but show patterned fluctuations with long-range temporal correlations that are well described using power-law spectra P(f)?1/f(?), where ? is the power-law scaling exponent describing the decay in temporal correlations. The neural basis of temporal correlations in such behaviors is not known. Interestingly, long-range temporal correlations are a hallmark of amplitude fluctuations in resting-state neuronal oscillations. Here, we investigated whether the temporal dynamics in brain and behavior are related. Thirty-nine subjects eyes-open rest EEG was measured. Next, subjects reproduced without feedback a 1 s interval by tapping with their right index finger. In line with previous reports, we found evidence for the presence of long-range temporal correlations both in the amplitude modulation of resting-state oscillations in multiple frequency bands and in the timing-error sequences. Frequency scaling exponents of finger tapping and amplitude modulation of oscillations exhibited large individual differences. Neuronal dynamics of resting-state alpha-band oscillations (9-13 Hz) recorded at precentral sites strongly predicted scaling exponents of tapping behavior. The results suggest that individual variation in resting-state brain dynamics offer a neural explanation for individual variation in the error dynamics of human behavior.
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Serotonin transporter gene: will epigenetics prove less depressing than genetics?
Psychosom Med
PUBLISHED: 06-20-2013
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The serotonin transporter gene has been hypothesized to influence, possibly in interaction with environmental factors, the vulnerability for depression. So far, genetic studies have tested the association of the repeat polymorphism (5-HTTLPR) with depression and whether it is moderated by exposure to stressful events. This has not yielded unequivocal results, even across meta-analyses. However, environmental factors may induce epigenetic changes in the structure of DNA that can influence gene expression. These epigenetic effects may be independent of the genetic polymorphisms in the gene region. This editorial reviews an article in this issue that compared the intrapair differences in depressive symptoms in monozygotic twin pairs with the intrapair differences of methylation at cytosine-guanine dinucleotide sites in the promoter region of the serotonin transporter gene. Differences in depressive symptoms were correlated with differences in methylation status, such that higher methylation, which, in this sample of identical twins, must be environmental in origin, is associated with more depressive symptoms. Noteworthy is the fact that the epigenetic effects were independent of the 5-HTTLPR. These results should encourage genome-wide testing of the contribution of epigenetic effects to depression.
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Association between autozygosity and major depression: stratification due to religious assortment.
Behav. Genet.
PUBLISHED: 06-16-2013
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The effects of inbreeding on the health of offspring can be studied by measuring genome-wide autozygosity as the proportion of the genome in runs of homozygosity (F roh) and relate F roh to outcomes such as psychiatric phenotypes. To successfully conduct these studies, the main patterns of variation for genome-wide autozygosity between and within populations should be well understood and accounted for. Within population variation was investigated in the Dutch population by comparing autozygosity between religious and non-religious groups. The Netherlands have a history of societal segregation and assortment based on religious affiliation, which may have increased parental relatedness within religious groups. Religion has been associated with several psychiatric phenotypes, such as major depressive disorder (MDD). We investigated whether there is an association between autozygosity and MDD, and the extent to which this association can be explained by religious affiliation. All F roh analyses included adjustment for ancestry-informative principal components (PCs) and geographic factors. Religious affiliation was significantly associated with autozygosity, showing that F roh has the ability to capture within population differences that are not captured by ancestry-informative PCs or geographic factors. The non-religious group had significantly lower F roh values and significantly more MDD cases, leading to a nominally significant negative association between autozygosity and depression. After accounting for religious affiliation, MDD was not associated with F roh, indicating that the relation between MDD and inbreeding was due to stratification. This study shows how past religious assortment and recent secularization can have genetic consequences in a relatively small country. This warrants accounting for the historical social context and its effects on genetic variation in association studies on psychiatric and other related traits.
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The role of adiposity in cardiometabolic traits: a mendelian randomization analysis.
Tove Fall, Sara Hägg, Reedik Mägi, Alexander Ploner, Krista Fischer, Momoko Horikoshi, Antti-Pekka Sarin, Gudmar Thorleifsson, Claes Ladenvall, Mart Kals, Maris Kuningas, Harmen H M Draisma, Janina S Ried, Natalie R Van Zuydam, Ville Huikari, Massimo Mangino, Emily Sonestedt, Beben Benyamin, Christopher P Nelson, Natalia V Rivera, Kati Kristiansson, Huei-Yi Shen, Aki S Havulinna, Abbas Dehghan, Louise A Donnelly, Marika Kaakinen, Marja-Liisa Nuotio, Neil Robertson, Renée F A G de Bruijn, M Arfan Ikram, Najaf Amin, Anthony J Balmforth, Peter S Braund, Alexander S F Doney, Angela Döring, Paul Elliott, Tonu Esko, Oscar H Franco, Solveig Gretarsdottir, Anna-Liisa Hartikainen, Kauko Heikkilä, Karl-Heinz Herzig, Hilma Holm, Jouke Jan Hottenga, Elina Hyppönen, Thomas Illig, Aaron Isaacs, Bo Isomaa, Lennart C Karssen, Johannes Kettunen, Wolfgang Koenig, Kari Kuulasmaa, Tiina Laatikainen, Jaana Laitinen, Cecilia Lindgren, Valeriya Lyssenko, Esa Läärä, Nigel W Rayner, Satu Mannisto, Anneli Pouta, Wolfgang Rathmann, Fernando Rivadeneira, Aimo Ruokonen, Markku J Savolainen, Eric J G Sijbrands, Kerrin S Small, Jan H Smit, Valgerdur Steinthorsdottir, Ann-Christine Syvänen, Anja Taanila, Martin D Tobin, André G Uitterlinden, Sara M Willems, Gonneke Willemsen, Jacqueline Witteman, Markus Perola, Alun Evans, Jean Ferrières, Jarmo Virtamo, Frank Kee, David-Alexandre Trégouët, Dominique Arveiler, Philippe Amouyel, Marco M Ferrario, Paolo Brambilla, Alistair S Hall, Andrew C Heath, Pamela A F Madden, Nicholas G Martin, Grant W Montgomery, John B Whitfield, Antti Jula, Paul Knekt, Ben Oostra, Cornelia M van Duijn, Brenda W J H Penninx, George Davey Smith, Jaakko Kaprio, Nilesh J Samani, Christian Gieger, Annette Peters, H Erich Wichmann, Dorret I Boomsma, Eco J C de Geus, Tiinamaija Tuomi, Chris Power, Christopher J Hammond, Tim D Spector, Lars Lind, Marju Orho-Melander, Colin Neil Alexander Palmer, Andrew D Morris, Leif Groop, Marjo-Riitta Järvelin, Veikko Salomaa, Erkki Vartiainen, Albert Hofman, Samuli Ripatti, Andres Metspalu, Unnur Thorsteinsdottir, Kari Stefansson, Nancy L Pedersen, Mark I McCarthy, Erik Ingelsson, Inga Prokopenko, .
PLoS Med.
PUBLISHED: 06-01-2013
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The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach.
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DeepSAGE reveals genetic variants associated with alternative polyadenylation and expression of coding and non-coding transcripts.
PLoS Genet.
PUBLISHED: 06-01-2013
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Many disease-associated variants affect gene expression levels (expression quantitative trait loci, eQTLs) and expression profiling using next generation sequencing (NGS) technology is a powerful way to detect these eQTLs. We analyzed 94 total blood samples from healthy volunteers with DeepSAGE to gain specific insight into how genetic variants affect the expression of genes and lengths of 3-untranslated regions (3-UTRs). We detected previously unknown cis-eQTL effects for GWAS hits in disease- and physiology-associated traits. Apart from cis-eQTLs that are typically easily identifiable using microarrays or RNA-sequencing, DeepSAGE also revealed many cis-eQTLs for antisense and other non-coding transcripts, often in genomic regions containing retrotransposon-derived elements. We also identified and confirmed SNPs that affect the usage of alternative polyadenylation sites, thereby potentially influencing the stability of messenger RNAs (mRNA). We then combined the power of RNA-sequencing with DeepSAGE by performing a meta-analysis of three datasets, leading to the identification of many more cis-eQTLs. Our results indicate that DeepSAGE data is useful for eQTL mapping of known and unknown transcripts, and for identifying SNPs that affect alternative polyadenylation. Because of the inherent differences between DeepSAGE and RNA-sequencing, our complementary, integrative approach leads to greater insight into the molecular consequences of many disease-associated variants.
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The CTRB1/2 locus affects diabetes susceptibility and treatment via the incretin pathway.
Diabetes
PUBLISHED: 05-14-2013
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The incretin hormone glucagon-like peptide 1 (GLP-1) promotes glucose homeostasis and enhances ?-cell function. GLP-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, which inhibit the physiological inactivation of endogenous GLP-1, are used for the treatment of type 2 diabetes. Using the Metabochip, we identified three novel genetic loci with large effects (30-40%) on GLP-1-stimulated insulin secretion during hyperglycemic clamps in nondiabetic Caucasian individuals (TMEM114; CHST3 and CTRB1/2; n = 232; all P ? 8.8 × 10(-7)). rs7202877 near CTRB1/2, a known diabetes risk locus, also associated with an absolute 0.51 ± 0.16% (5.6 ± 1.7 mmol/mol) lower A1C response to DPP-4 inhibitor treatment in G-allele carriers, but there was no effect on GLP-1 RA treatment in type 2 diabetic patients (n = 527). Furthermore, in pancreatic tissue, we show that rs7202877 acts as expression quantitative trait locus for CTRB1 and CTRB2, encoding chymotrypsinogen, and increases fecal chymotrypsin activity in healthy carriers. Chymotrypsin is one of the most abundant digestive enzymes in the gut where it cleaves food proteins into smaller peptide fragments. Our data identify chymotrypsin in the regulation of the incretin pathway, development of diabetes, and response to DPP-4 inhibitor treatment.
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Measuring cardiac autonomic nervous system (ANS) activity in children.
J Vis Exp
PUBLISHED: 05-14-2013
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The autonomic nervous system (ANS) controls mainly automatic bodily functions that are engaged in homeostasis, like heart rate, digestion, respiratory rate, salivation, perspiration and renal function. The ANS has two main branches: the sympathetic nervous system, preparing the human body for action in times of danger and stress, and the parasympathetic nervous system, which regulates the resting state of the body. ANS activity can be measured invasively, for instance by radiotracer techniques or microelectrode recording from superficial nerves, or it can be measured non-invasively by using changes in an organs response as a proxy for changes in ANS activity, for instance of the sweat glands or the heart. Invasive measurements have the highest validity but are very poorly feasible in large scale samples where non-invasive measures are the preferred approach. Autonomic effects on the heart can be reliably quantified by the recording of the electrocardiogram (ECG) in combination with the impedance cardiogram (ICG), which reflects the changes in thorax impedance in response to respiration and the ejection of blood from the ventricle into the aorta. From the respiration and ECG signals, respiratory sinus arrhythmia can be extracted as a measure of cardiac parasympathetic control. From the ECG and the left ventricular ejection signals, the preejection period can be extracted as a measure of cardiac sympathetic control. ECG and ICG recording is mostly done in laboratory settings. However, having the subjects report to a laboratory greatly reduces ecological validity, is not always doable in large scale epidemiological studies, and can be intimidating for young children. An ambulatory device for ECG and ICG simultaneously resolves these three problems. Here, we present a study design for a minimally invasive and rapid assessment of cardiac autonomic control in children, using a validated ambulatory device (1-5), the VU University Ambulatory Monitoring System (VU-AMS, Amsterdam, the Netherlands, www.vu-ams.nl).
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A prospective study of the effects of breastfeeding and FADS2 polymorphisms on cognition and hyperactivity/attention problems.
Am. J. Med. Genet. B Neuropsychiatr. Genet.
PUBLISHED: 05-02-2013
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Breastfeeding has been associated with improved cognitive functioning. There is a beneficial effect on IQ, and possibly on associated phenotypes such as attention problems. It has been suggested that the effect on IQ is moderated by polymorphisms in the FADS2 gene, which is involved in fatty acid metabolism. In this study we tested the relation between breastfeeding and FADS2 polymorphisms on the one hand and IQ, educational attainment, overactivity, and attention problems on the other hand. IQ at age 5, 7, 10, 12, and/or 18 (n = 1,313), educational attainment at age 12 (n = 1,857), overactive behavior at age 3 (n = 2,560), and attention problems assessed at age 7, 10, and 12 years (n = 2,479, n = 2,423, n = 2,226) were predicted by breastfeeding and two SNPs in FADS2 (rs174575 and rs1535). Analyses were performed using structural equation modeling. After correction for maternal education, a main effect of breastfeeding was found for educational attainment at age 12 and overactive behavior at age 3. For IQ, the effect of breastfeeding across age was marginally significant (P = 0.05) and amounted to 1.6 points after correcting for maternal education. Neither a main effect of the FADS2 polymorphisms nor an interaction with breastfeeding was detected for any of the phenotypes. This developmentally informed study confirms that breastfeeding is associated with higher educational attainment at age 12, less overactive behavior at age 3 and a trend toward higher IQ after correction for maternal education. In general, the benefits of breastfeeding were small and did not interact with SNPs in FADS2.
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The genetic architecture of liver enzyme levels: GGT, ALT and AST.
Behav. Genet.
PUBLISHED: 04-04-2013
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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 (N = 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) 60 %) and AST in both sexes (total h(2) 43 %). The heritability of GGT in males and ALT for both sexes was due to additive effects only (GGT males 30 %; ALT males 40 %, females 22 %). Evidence emerged for shared environmental factors influencing GGT in the male offspring generation (variance explained 28 %). 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.
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Dysregulation of the autonomic nervous system predicts the development of the metabolic syndrome.
J. Clin. Endocrinol. Metab.
PUBLISHED: 04-03-2013
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Stress is suggested to lead to metabolic dysregulations as clustered in the metabolic syndrome. Although dysregulation of the autonomic nervous system is found to associate with the metabolic syndrome and its dysregulations, no longitudinal study has been performed to date to examine the predictive value of this stress system in the development of the metabolic syndrome.
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Obsessive-compulsive symptoms and related sex differences in brain structure: an MRI study in Dutch twins.
Twin Res Hum Genet
PUBLISHED: 03-27-2013
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Neuroimaging studies have indicated abnormalities in cortico-striato-thalamo-cortical circuits in obsessive-compulsive disorder patients, but results have not been consistent. Since there are significant sex differences in human brain anatomy and obsessive-compulsive symptomatology and its developmental trajectories tend to be distinct in males and females, we investigated whether sex is a potential source of heterogeneity in neuroimaging studies on obsessive-compulsive symptoms. We selected male and female twin pairs who were concordant for scoring either high or low for obsessive-compulsive symptoms and a group of discordant pairs where one twin scored high and the co-twin scored low. The design included 24 opposite-sex twin pairs. Magnetic resonance imaging scans of 31 males scoring high for obsessive-compulsive symptoms, 41 low-scoring males, 58 high-scoring females, and 73 low-scoring females were analyzed and the interaction of obsessive-compulsive symptoms by sex on gray matter volume was assessed using voxel-based morphometry. An obsessive-compulsive symptom by sex interaction was observed for the left middle temporal gyrus, the right middle temporal gyrus, and the right precuneus. These interactions acted to reduce or hide a main effect in our study and illustrate the importance of taking sex into account when investigating the neurobiology of obsessive-compulsive symptoms.
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The association of alcohol intake with gamma-glutamyl transferase (GGT) levels: Evidence for correlated genetic effects.
Drug Alcohol Depend
PUBLISHED: 03-26-2013
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Blood levels of gamma-glutamyl transferase (GGT) are used as a marker for (heavy) alcohol use. The role of GGT in the anti-oxidant defense mechanism that is part of normal metabolism supposes a causal effect of alcohol intake on GGT. However, there is variability in the response of GGT to alcohol use, which may result from genetic differences between individuals. This study aimed to determine whether the epidemiological association between alcohol intake and GGT at the population level is necessarily a causal one or may also reflect effects of genetic pleiotropy (genes influencing multiple traits).
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Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders.
Marcel den Hoed, Mark Eijgelsheim, Tonu Esko, Bianca J J M Brundel, David S Peal, David M Evans, Ilja M Nolte, Ayellet V Segrè, Hilma Holm, Robert E Handsaker, Harm-Jan Westra, Toby Johnson, Aaron Isaacs, Jian Yang, Alicia Lundby, Jing Hua Zhao, Young Jin Kim, Min Jin Go, Peter Almgren, Murielle Bochud, Gabrielle Boucher, Marilyn C Cornelis, Daniel Gudbjartsson, David Hadley, Pim van der Harst, Caroline Hayward, Martin den Heijer, Wilmar Igl, Anne U Jackson, Zoltan Kutalik, Jian'an Luan, John P Kemp, Kati Kristiansson, Claes Ladenvall, Mattias Lorentzon, May E Montasser, Omer T Njajou, Paul F O'Reilly, Sandosh Padmanabhan, Beate St Pourcain, Tuomo Rankinen, Perttu Salo, Toshiko Tanaka, Nicholas J Timpson, Veronique Vitart, Lindsay Waite, William Wheeler, Weihua Zhang, Harmen H M Draisma, Mary F Feitosa, Kathleen F Kerr, Penelope A Lind, Evelin Mihailov, N Charlotte Onland-Moret, Ci Song, Michael N Weedon, Weijia Xie, Loïc Yengo, Devin Absher, Christine M Albert, Alvaro Alonso, Dan E Arking, Paul I W de Bakker, Beverley Balkau, Cristina Barlassina, Paola Benaglio, Joshua C Bis, Nabila Bouatia-Naji, Søren Brage, Stephen J Chanock, Peter S Chines, Mina Chung, Dawood Darbar, Christian Dina, Marcus Dörr, Paul Elliott, Stephan B Felix, Krista Fischer, Christian Fuchsberger, Eco J C de Geus, Philippe Goyette, Vilmundur Gudnason, Tamara B Harris, Anna-Liisa Hartikainen, Aki S Havulinna, Susan R Heckbert, Andrew A Hicks, Albert Hofman, Suzanne Holewijn, Femke Hoogstra-Berends, Jouke-Jan Hottenga, Majken K Jensen, Asa Johansson, Juhani Junttila, Stefan Kääb, Bart Kanon, Shamika Ketkar, Kay-Tee Khaw, Joshua W Knowles, Angrad S Kooner, Jan A Kors, Meena Kumari, Lili Milani, Päivi Laiho, Edward G Lakatta, Claudia Langenberg, Maarten Leusink, Yongmei Liu, Robert N Luben, Kathryn L Lunetta, Stacey N Lynch, Marcello R P Markus, Pedro Marques-Vidal, Irene Mateo Leach, Wendy L McArdle, Steven A McCarroll, Sarah E Medland, Kathryn A Miller, Grant W Montgomery, Alanna C Morrison, Martina Müller-Nurasyid, Pau Navarro, Mari Nelis, Jeffrey R O'Connell, Christopher J O'Donnell, Ken K Ong, Anne B Newman, Annette Peters, Ozren Polašek, Anneli Pouta, Peter P Pramstaller, Bruce M Psaty, Dabeeru C Rao, Susan M Ring, Elizabeth J Rossin, Diana Rudan, Serena Sanna, Robert A Scott, Jaban S Sehmi, Stephen Sharp, Jordan T Shin, Andrew B Singleton, Albert V Smith, Nicole Soranzo, Tim D Spector, Chip Stewart, Heather M Stringham, Kirill V Tarasov, André G Uitterlinden, Liesbeth Vandenput, Shih-Jen Hwang, John B Whitfield, Cisca Wijmenga, Sarah H Wild, Gonneke Willemsen, James F Wilson, Jacqueline C M Witteman, Andrew Wong, Quenna Wong, Yalda Jamshidi, Paavo Zitting, Jolanda M A Boer, Dorret I Boomsma, Ingrid B Borecki, Cornelia M van Duijn, Ulf Ekelund, Nita G Forouhi, Philippe Froguel, Aroon Hingorani, Erik Ingelsson, Mika Kivimäki, Richard A Kronmal, Diana Kuh, Lars Lind, Nicholas G Martin, Ben A Oostra, Nancy L Pedersen, Thomas Quertermous, Jerome I Rotter, Yvonne T van der Schouw, W M Monique Verschuren, Mark Walker, Demetrius Albanes, David O Arnar, Themistocles L Assimes, Stefania Bandinelli, Michael Boehnke, Rudolf A de Boer, Claude Bouchard, W L Mark Caulfield, John C Chambers, Gary Curhan, Daniele Cusi, Johan Eriksson, Luigi Ferrucci, Wiek H van Gilst, Nicola Glorioso, Jacqueline de Graaf, Leif Groop, Ulf Gyllensten, Wen-Chi Hsueh, Frank B Hu, Heikki V Huikuri, David J Hunter, Carlos Iribarren, Bo Isomaa, Marjo-Riitta Järvelin, Antti Jula, Mika Kähönen, Lambertus A Kiemeney, Melanie M van der Klauw, Jaspal S Kooner, Peter Kraft, Licia Iacoviello, Terho Lehtimäki, Marja-Liisa L Lokki, Braxton D Mitchell, Gerjan Navis, Markku S Nieminen, Claes Ohlsson, Neil R Poulter, Lu Qi, Olli T Raitakari, Eric B Rimm, John D Rioux, Federica Rizzi, Igor Rudan, Veikko Salomaa, Peter S Sever, Denis C Shields, Alan R Shuldiner, Juha Sinisalo, Alice V Stanton, Ronald P Stolk, David P Strachan, Jean-Claude Tardif, Unnur Thorsteinsdottir, Jaako Tuomilehto, Dirk J van Veldhuisen, Jarmo Virtamo, Jorma Viikari, Peter Vollenweider, Gérard Waeber, Elisabeth Widén, Yoon Shin Cho, Jesper V Olsen, Peter M Visscher, Cristen Willer, Lude Franke, , Jeanette Erdmann, John R Thompson, Arne Pfeufer, Nona Sotoodehnia, Christopher Newton-Cheh, Patrick T Ellinor, Bruno H Ch Stricker, Andres Metspalu, Markus Perola, Jacques S Beckmann, George Davey Smith, Kari Stefansson, Nicholas J Wareham, Patricia B Munroe, Ody C M Sibon, David J Milan, Harold Snieder, Nilesh J Samani, Ruth J F Loos.
Nat. Genet.
PUBLISHED: 03-21-2013
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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.
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A Twin-Sibling Study on the Relationship Between Exercise Attitudes and Exercise Behavior.
Behav. Genet.
PUBLISHED: 02-27-2013
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Social cognitive models of health behavior propose that individual differences in leisure time exercise behavior are influenced by the attitudes towards exercise. At the same time, large scale twin-family studies show a significant influence of genetic factors on regular exercise behavior. This twin-sibling study aimed to unite these findings by demonstrating that exercise attitudes can be heritable themselves. Secondly, the genetic and environmental cross-trait correlations and the monozygotic (MZ) twin intrapair differences model were used to test whether the association between exercise attitudes and exercise behavior can be causal. Survey data were obtained from 5,095 twins and siblings (18-50 years). A genetic contribution was found for exercise behavior (50 % in males, 43 % in females) and for the six exercise attitude components derived from principal component analysis: perceived benefits (21, 27 %), lack of skills, support and/or resources (45, 48 %), time constraints (25, 30 %), lack of energy (34, 44 %), lack of enjoyment (47, 44 %), and embarrassment (42, 49 %). These components were predictive of leisure time exercise behavior (R² = 28 %). Bivariate modeling further showed that all the genetic (0.36 < |rA| < 0.80) and all but two unique environmental (0.00 < |rE| < 0.27) correlations between exercise attitudes and exercise behavior were significantly different from zero, which is a necessary condition for the existence of a causal effect driving the association. The correlations between the MZ twins difference scores were in line with this finding. It is concluded that exercise attitudes and exercise behavior are heritable, that attitudes and behavior are partly correlated through pleiotropic genetic effects, but that the data are compatible with a causal association between exercise attitudes and behavior.
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Genes contributing to subcortical volumes and intellectual ability implicate the thalamus.
Hum Brain Mapp
PUBLISHED: 02-12-2013
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It has been shown that brain volume and general intellectual ability are to a significant extent influenced by the same genetic factors. Several cortical regions of the brain also show a genetic correlation with intellectual ability, demonstrating that intellectual functioning is probably represented in a heritable distributed network of cortical regions throughout the brain. This study is the first to investigate a genetic association between subcortical volumes and intellectual ability, taking into account the thalamus, caudate nucleus, putamen, globus pallidus, hippocampus, amygdala, and nucleus accumbens using an extended twin design. Genetic modeling was performed on a healthy adult twin sample consisting of 106 twin pairs and 30 of their siblings, IQ data was obtained from 132 subjects. Our results demonstrate that of all subcortical volumes measured, only thalamus volume is significantly correlated with intellectual functioning. Importantly, the association found between thalamus volume and intellectual ability is significantly influenced by a common genetic factor. This genetic factor is also implicated in cerebral brain volume. The thalamus, with its widespread cortical connections, may thus play a key role in human intelligence. Hum Brain Mapp, 2013. © 2013 Wiley Periodicals, Inc.
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Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs.
, S Hong Lee, Stephan Ripke, Benjamin M Neale, Stephen V Faraone, Shaun M Purcell, Roy H Perlis, Bryan J Mowry, Anita Thapar, Michael E Goddard, John S Witte, Devin Absher, Ingrid Agartz, Huda Akil, Farooq Amin, Ole A Andreassen, Adebayo Anjorin, Richard Anney, Verneri Anttila, Dan E Arking, Philip Asherson, Maria H Azevedo, Lena Backlund, Judith A Badner, Anthony J Bailey, Tobias Banaschewski, Jack D Barchas, Michael R Barnes, Thomas B Barrett, Nicholas Bass, Agatino Battaglia, Michael Bauer, Mònica Bayés, Frank Bellivier, Sarah E Bergen, Wade Berrettini, Catalina Betancur, Thomas Bettecken, Joseph Biederman, Elisabeth B Binder, Donald W Black, Douglas H R Blackwood, Cinnamon S Bloss, Michael Boehnke, Dorret I Boomsma, Gerome Breen, René Breuer, Richard Bruggeman, Paul Cormican, Nancy G Buccola, Jan K Buitelaar, William E Bunney, Joseph D Buxbaum, William F Byerley, Enda M Byrne, Sian Caesar, Wiepke Cahn, Rita M Cantor, Miguel Casas, Aravinda Chakravarti, Kimberly Chambert, Khalid Choudhury, Sven Cichon, C Robert Cloninger, David A Collier, Edwin H Cook, Hilary Coon, Bru Cormand, Aiden Corvin, William H Coryell, David W Craig, Ian W Craig, Jennifer Crosbie, Michael L Cuccaro, David Curtis, Darina Czamara, Susmita Datta, Geraldine Dawson, Richard Day, Eco J De Geus, Franziska Degenhardt, Srdjan Djurovic, Gary J Donohoe, Alysa E Doyle, Jubao Duan, Frank Dudbridge, Eftichia Duketis, Richard P Ebstein, Howard J Edenberg, Josephine Elia, Sean Ennis, Bruno Etain, Ayman Fanous, Anne E Farmer, I Nicol Ferrier, Matthew Flickinger, Eric Fombonne, Tatiana Foroud, Josef Frank, Barbara Franke, Christine Fraser, Robert Freedman, Nelson B Freimer, Christine M Freitag, Marion Friedl, Louise Frisén, Louise Gallagher, Pablo V Gejman, Lyudmila Georgieva, Elliot S Gershon, Daniel H Geschwind, Ina Giegling, Michael Gill, Scott D Gordon, Katherine Gordon-Smith, Elaine K Green, Tiffany A Greenwood, Dorothy E Grice, Magdalena Gross, Detelina Grozeva, Weihua Guan, Hugh Gurling, Lieuwe de Haan, Jonathan L Haines, Hakon Hakonarson, Joachim Hallmayer, Steven P Hamilton, Marian L Hamshere, Thomas F Hansen, Annette M Hartmann, Martin Hautzinger, Andrew C Heath, Anjali K Henders, Stefan Herms, Ian B Hickie, Maria Hipolito, Susanne Hoefels, Peter A Holmans, Florian Holsboer, Witte J Hoogendijk, Jouke-Jan Hottenga, Christina M Hultman, Vanessa Hus, Andrés Ingason, Marcus Ising, Stéphane Jamain, Edward G Jones, Ian Jones, Lisa Jones, Jung-Ying Tzeng, Anna K Kähler, René S Kahn, Radhika Kandaswamy, Matthew C Keller, James L Kennedy, Elaine Kenny, Lindsey Kent, Yunjung Kim, George K Kirov, Sabine M Klauck, Lambertus Klei, James A Knowles, Martin A Kohli, Daniel L Koller, Bettina Konte, Ania Korszun, Lydia Krabbendam, Robert Krasucki, Jonna Kuntsi, Phoenix Kwan, Mikael Landén, Niklas Långström, Mark Lathrop, Jacob Lawrence, William B Lawson, Marion Leboyer, David H Ledbetter, Phil H Lee, Todd Lencz, Klaus-Peter Lesch, Douglas F Levinson, Cathryn M Lewis, Jun Li, Paul Lichtenstein, Jeffrey A Lieberman, Dan-Yu Lin, Don H Linszen, Chunyu Liu, Falk W Lohoff, Sandra K Loo, Catherine Lord, Jennifer K Lowe, Susanne Lucae, Donald J MacIntyre, Pamela A F Madden, Elena Maestrini, Patrik K E Magnusson, Pamela B Mahon, Wolfgang Maier, Anil K Malhotra, Shrikant M Mane, Christa L Martin, Nicholas G Martin, Manuel Mattheisen, Keith Matthews, Morten Mattingsdal, Steven A McCarroll, Kevin A McGhee, James J McGough, Patrick J McGrath, Peter McGuffin, Melvin G McInnis, Andrew McIntosh, Rebecca McKinney, Alan W McLean, Francis J McMahon, William M McMahon, Andrew McQuillin, Helena Medeiros, Sarah E Medland, Sandra Meier, Ingrid Melle, Fan Meng, Jobst Meyer, Christel M Middeldorp, Lefkos Middleton, Vihra Milanova, Ana Miranda, Anthony P Monaco, Grant W Montgomery, Jennifer L Moran, Daniel Moreno-De-Luca, Gunnar Morken, Derek W Morris, Eric M Morrow, Valentina Moskvina, Pierandrea Muglia, Thomas W Mühleisen, Walter J Muir, Bertram Müller-Myhsok, Michael Murtha, Richard M Myers, Inez Myin-Germeys, Michael C Neale, Stan F Nelson, Caroline M Nievergelt, Ivan Nikolov, Vishwajit Nimgaonkar, Willem A Nolen, Markus M Nöthen, John I Nurnberger, Evaristus A Nwulia, Dale R Nyholt, Colm O'Dushlaine, Robert D Oades, Ann Olincy, Guiomar Oliveira, Line Olsen, Roel A Ophoff, Urban Osby, Michael J Owen, Aarno Palotie, Jeremy R Parr, Andrew D Paterson, Carlos N Pato, Michele T Pato, Brenda W Penninx, Michele L Pergadia, Margaret A Pericak-Vance, Benjamin S Pickard, Jonathan Pimm, Joseph Piven, Danielle Posthuma, James B Potash, Fritz Poustka, Peter Propping, Vinay Puri, Digby J Quested, Emma M Quinn, Josep Antoni Ramos-Quiroga, Henrik B Rasmussen, Soumya Raychaudhuri, Karola Rehnström, Andreas Reif, Marta Ribasés, John P Rice, Marcella Rietschel, Kathryn Roeder, Herbert Roeyers, Lizzy Rossin, Aribert Rothenberger, Guy Rouleau, Douglas Ruderfer, Dan Rujescu, Alan R Sanders, Stephan J Sanders, Susan L Santangelo, Joseph A Sergeant, Russell Schachar, Martin Schalling, Alan F Schatzberg, William A Scheftner, Gerard D Schellenberg, Stephen W Scherer, Nicholas J Schork, Thomas G Schulze, Johannes Schumacher, Markus Schwarz, Edward Scolnick, Laura J Scott, Jianxin Shi, Paul D Shilling, Stanley I Shyn, Jeremy M Silverman, Susan L Slager, Susan L Smalley, Johannes H Smit, Erin N Smith, Edmund J S Sonuga-Barke, David St Clair, Matthew State, Michael Steffens, Hans-Christoph Steinhausen, John S Strauss, Jana Strohmaier, T Scott Stroup, James S Sutcliffe, Peter Szatmari, Szabocls Szelinger, Srinivasa Thirumalai, Robert C Thompson, Alexandre A Todorov, Federica Tozzi, Jens Treutlein, Manfred Uhr, Edwin J C G van den Oord, Gerard van Grootheest, Jim van Os, Astrid M Vicente, Veronica J Vieland, John B Vincent, Peter M Visscher, Christopher A Walsh, Thomas H Wassink, Stanley J Watson, Myrna M Weissman, Thomas Werge, Thomas F Wienker, Ellen M Wijsman, Gonneke Willemsen, Nigel Williams, A Jeremy Willsey, Stephanie H Witt, Wei Xu, Allan H Young, Timothy W Yu, Stanley Zammit, Peter P Zandi, Peng Zhang, Frans G Zitman, Sebastian Zöllner, Bernie Devlin, John R Kelsoe, Pamela Sklar, Mark J Daly, Michael C O'Donovan, Nicholas Craddock, Patrick F Sullivan, Jordan W Smoller, Kenneth S Kendler, Naomi R Wray.
Nat. Genet.
PUBLISHED: 02-10-2013
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Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohns disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
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Growing trees in child brains: graph theoretical analysis of electroencephalography-derived minimum spanning tree in 5- and 7-year-old children reflects brain maturation.
Brain Connect
PUBLISHED: 01-22-2013
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The child brain is a small-world network, which is hypothesized to change toward 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 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 MSTs 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. The MST diameter and eccentricity significantly increased, while the 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 the theta band. The developmental changes indicate a shift toward more decentralized line-like trees, which supports the previously hypothesized increase toward 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.
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Meta-analysis of telomere length in 19,713 subjects reveals high heritability, stronger maternal inheritance and a paternal age effect.
Eur. J. Hum. Genet.
PUBLISHED: 01-16-2013
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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 19,713 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 × 10(-61)) than father-offspring correlation (r=0.33; P-value=7.01 × 10(-5)), and a significant positive association with paternal age at offspring birth (?=0.005; P-value=7.01 × 10(-5)). Interestingly, a significant and quite substantial correlation in TL between spouses (r=0.25; P-value=2.82 × 10(-30)) was seen, which appeared stronger in older spouse pairs (mean age ?55 years; r=0.31; P-value=4.27 × 10(-23)) than in younger pairs (mean age<55 years; r=0.20; P-value=3.24 × 10(-10)). In summary, we find a high and very consistent heritability estimate for TL, evidence for a maternal inheritance component and a positive association with paternal age.
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Heritability of subcortical brain measures: a perspective for future genome-wide association studies.
Neuroimage
PUBLISHED: 01-10-2013
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Several large imaging-genetics consortia aim to identify genetic variants influencing subcortical brain volumes. We investigated the extent to which genetic variation accounts for the variation in subcortical volumes, including thalamus, amygdala, putamen, caudate nucleus, globus pallidus and nucleus accumbens and obtained the stability of these brain volumes over a five-year period. The heritability estimates for all subcortical regions were high, with the highest heritability estimates observed for the thalamus (.80) and caudate nucleus (.88) and lowest for the left nucleus accumbens (.44). Five-year stability was substantial and higher for larger [e.g., thalamus (.88), putamen (.86), caudate nucleus (.87)] compared to smaller [nucleus accumbens (.45)] subcortical structures. These results provide additional evidence that subcortical structures are promising starting points for identifying genetic variants that influence brain structure.
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The Adult Netherlands Twin Register: twenty-five years of survey and biological data collection.
Twin Res Hum Genet
PUBLISHED: 01-08-2013
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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.
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Population structure, migration, and diversifying selection in the Netherlands.
Eur. J. Hum. Genet.
PUBLISHED: 01-04-2013
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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 (?: r=0.142, ?: 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.
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A genome-wide association study of depressive symptoms.
Biol. Psychiatry
PUBLISHED: 01-03-2013
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Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms.
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Resequencing three candidate genes for major depressive disorder in a dutch cohort.
PLoS ONE
PUBLISHED: 01-01-2013
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Major depressive disorder (MDD) is a psychiatric disorder, characterized by periods of low mood of more than two weeks, loss of interest in normally enjoyable activities and behavioral changes. MDD is a complex disorder and does not have a single genetic cause. In 2009 a genome wide association study (GWAS) was performed on the Dutch GAIN-MDD cohort. Many of the top signals of this GWAS mapped to a region spanning the gene PCLO, and the non-synonymous coding single nucleotide polymorphism (SNP) rs2522833 in the PCLO gene became genome wide significant after post-hoc analysis. We performed resequencing of PCLO, GRM7, and SLC6A4 in 50 control samples from the GAIN-MDD cohort, to detect new genomic variants. Subsequently, we genotyped these variants in the entire GAIN-MDD cohort and performed association analysis to investigate if rs2522833 is the causal variant or simply in linkage disequilibrium with a more associated variant. GRM7 and SLC6A4 are both candidate genes for MDD from literature. We aimed to gather more evidence that rs2522833 is indeed the causal variant in the GAIN-MDD cohort or to find a previously undetected common variant in either PCLO, GRM7, or SLC6A4 with a higher association in this cohort. After next generation sequencing and association analysis we excluded the possibility of an undetected common variant to be more associated. For neither PCLO nor GRM7 we found a more associated variant. For SLC6A4, we found a new SNP that showed a lower P-value (P?=?0.07) than in the GAIN-MDD GWAS (P?=?0.09). However, no evidence for genome-wide significance was found. Although we did not take into account rare variants, we conclude that our results provide further support for the hypothesis that the non-synonymous coding SNP rs2522833 in the PCLO gene is indeed likely to be the causal variant in the GAIN-MDD cohort.
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The Amsterdam Resting-State Questionnaire reveals multiple phenotypes of resting-state cognition.
Front Hum Neurosci
PUBLISHED: 01-01-2013
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Resting-state neuroimaging is a dominant paradigm for studying brain function in health and disease. It is attractive for clinical research because of its simplicity for patients, straightforward standardization, and sensitivity to brain disorders. Importantly, non-sensory experiences like mind wandering may arise from ongoing brain activity. However, little is known about the link between ongoing brain activity and cognition, as phenotypes of resting-state cognition-and tools to quantify them-have been lacking. To facilitate rapid and structured measurements of resting-state cognition we developed a 50-item self-report survey, the Amsterdam Resting-State Questionnaire (ARSQ). Based on ARSQ data from 813 participants assessed after 5 min eyes-closed rest in their home, we identified seven dimensions of resting-state cognition using factor analysis: Discontinuity of Mind, Theory of Mind, Self, Planning, Sleepiness, Comfort, and Somatic Awareness. Further, we showed that the structure of cognition was similar during resting-state fMRI and EEG, and that the test-retest correlations were remarkably high for all dimensions. To explore whether inter-individual variation of resting-state cognition is related to health status, we correlated ARSQ-derived factor scores with psychometric scales measuring depression, anxiety, and sleep quality. Mental health correlated positively with Comfort and negatively with Discontinuity of Mind. Finally, we show that sleepiness may partially explain a resting-state EEG profile previously associated with Alzheimers disease. These findings indicate that the ARSQ readily provides information about cognitive phenotypes and that it is a promising tool for research on the neural correlates of resting-state cognition in health and disease.
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The molecular genetic architecture of self-employment.
PLoS ONE
PUBLISHED: 01-01-2013
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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 (?(g)(2)/?(P)(2)?=?25%, h(2)?=?55%). 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<10(-5) were tested in a replication sample (n?=?3,271), but none replicated. Furthermore, a gene-based test shows that none of the genes that were previously suggested in the literature to influence entrepreneurship reveal significant associations. Finally, SNP-based genetic scores that use results from the meta-analysis capture less than 0.2% of the variance in self-employment in an independent sample (p?0.039). Our results are consistent with a highly polygenic molecular genetic architecture of self-employment, with many genetic variants of small effect. Although self-employment is a multi-faceted, heavily environmentally influenced, and biologically distal trait, our results are similar to those for other genetically complex and biologically more proximate outcomes, such as height, intelligence, personality, and several diseases.
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New gene functions in megakaryopoiesis and platelet formation.
Christian Gieger, Aparna Radhakrishnan, Ana Cvejic, Weihong Tang, Eleonora Porcu, Giorgio Pistis, Jovana Serbanovic-Canic, Ulrich Elling, Alison H Goodall, Yann Labrune, Lorna M Lopez, Reedik Mägi, Stuart Meacham, Yukinori Okada, Nicola Pirastu, Rossella Sorice, Alexander Teumer, Katrin Voss, Weihua Zhang, Ramiro Ramirez-Solis, Joshua C Bis, David Ellinghaus, Martin Gögele, Jouke-Jan Hottenga, Claudia Langenberg, Peter Kovacs, Paul F O'Reilly, So-Youn Shin, Tonu Esko, Jaana Hartiala, Stavroula Kanoni, Federico Murgia, Afshin Parsa, Jonathan Stephens, Pim van der Harst, C Ellen van der Schoot, Hooman Allayee, Antony Attwood, Beverley Balkau, François Bastardot, Saonli Basu, Sebastian E Baumeister, Ginevra Biino, Lorenzo Bomba, Amélie Bonnefond, Francois Cambien, John C Chambers, Francesco Cucca, Pio D'Adamo, Gail Davies, Rudolf A de Boer, Eco J C de Geus, Angela Döring, Paul Elliott, Jeanette Erdmann, David M Evans, Mario Falchi, Wei Feng, Aaron R Folsom, Ian H Frazer, Quince D Gibson, Nicole L Glazer, Chris Hammond, Anna-Liisa Hartikainen, Susan R Heckbert, Christian Hengstenberg, Micha Hersch, Thomas Illig, Ruth J F Loos, Jennifer Jolley, Kay Tee Khaw, Brigitte Kühnel, Marie-Christine Kyrtsonis, Vasiliki Lagou, Heather Lloyd-Jones, Thomas Lumley, Massimo Mangino, Andrea Maschio, Irene Mateo Leach, Barbara McKnight, Yasin Memari, Braxton D Mitchell, Grant W Montgomery, Yusuke Nakamura, Matthias Nauck, Gerjan Navis, Ute Nöthlings, Ilja M Nolte, David J Porteous, Anneli Pouta, Peter P Pramstaller, Janne Pullat, Susan M Ring, Jerome I Rotter, Daniela Ruggiero, Aimo Ruokonen, Cinzia Sala, Nilesh J Samani, Jennifer Sambrook, David Schlessinger, Stefan Schreiber, Heribert Schunkert, James Scott, Nicholas L Smith, Harold Snieder, John M Starr, Michael Stumvoll, Atsushi Takahashi, W H Wilson Tang, Kent Taylor, Albert Tenesa, Swee Lay Thein, Anke Tönjes, Manuela Uda, Sheila Ulivi, Dirk J van Veldhuisen, Peter M Visscher, Uwe Völker, H-Erich Wichmann, Kerri L Wiggins, Gonneke Willemsen, Tsun-Po Yang, Jing Hua Zhao, Paavo Zitting, John R Bradley, George V Dedoussis, Paolo Gasparini, Stanley L Hazen, Andres Metspalu, Mario Pirastu, Alan R Shuldiner, L Joost van Pelt, Jaap-Jan Zwaginga, Dorret I Boomsma, Ian J Deary, Andre Franke, Philippe Froguel, Santhi K Ganesh, Marjo-Riitta Järvelin, Nicholas G Martin, Christa Meisinger, Bruce M Psaty, Timothy D Spector, Nicholas J Wareham, Jan-Willem N Akkerman, Marina Ciullo, Panos Deloukas, Andreas Greinacher, Steve Jupe, Naoyuki Kamatani, Jyoti Khadake, Jaspal S Kooner, Josef Penninger, Inga Prokopenko, Derek Stemple, Daniela Toniolo, Lorenz Wernisch, Serena Sanna, Andrew A Hicks, Augusto Rendon, Manuel A Ferreira, Willem H Ouwehand, Nicole Soranzo.
Nature
PUBLISHED: 10-21-2011
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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.
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Loci affecting gamma-glutamyl transferase in adults and adolescents show age × SNP interaction and cardiometabolic disease associations.
Hum. Mol. Genet.
PUBLISHED: 10-18-2011
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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 × 10(-8); rs944002 in C14orf73 on chromosome 14, P = 4.7 × 10(-13); rs340005 in RORA on chromosome 15, P = 2.4 × 10(-8)), and a highly significant heterogeneity between adult and adolescent results at the GGT1 locus on chromosome 22 (maximum P(HET) = 5.6 × 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.
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Scale-free modulation of resting-state neuronal oscillations reflects prolonged brain maturation in humans.
J. Neurosci.
PUBLISHED: 09-16-2011
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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 (?25 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.
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Heritability of problem drinking and the genetic overlap with personality in a general population sample.
Front Genet
PUBLISHED: 08-01-2011
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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 (r?=?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.
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A genome-wide screen for interactions reveals a new locus on 4p15 modifying the effect of waist-to-hip ratio on total cholesterol.
PLoS Genet.
PUBLISHED: 06-23-2011
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Recent genome-wide association (GWA) studies described 95 loci controlling serum lipid levels. These common variants explain ?25% 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 N?=?32,225). We collected 8 further cohorts (N?=?17,102) 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 4.79×10(-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.
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Genome-wide association study identifies a single major locus contributing to survival into old age; the APOE locus revisited.
Aging Cell
PUBLISHED: 05-06-2011
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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<1×10(-4) ) showed genome-wide significance with survival into old age in the meta-analysis of 4149 nonagenarian cases and 7582 younger controls [OR=0.71 (95% CI 0.65-0.77), P=3.39 × 10(-17) ]. This SNP, rs2075650, is located in TOMM40 at chromosome 19q13.32 close to the apolipoprotein E (APOE) gene. Although there was only moderate linkage disequilibrium between rs2075650 and the ApoE ?4 defining SNP rs429358, we could not find an APOE-independent effect of rs2075650 on longevity, either in cross-sectional or in longitudinal analyses. As expected, rs429358 associated with metabolic phenotypes in the offspring of the nonagenarian cases from the LLS and their partners. In addition, we observed a novel association between this locus and serum levels of IGF-1 in women (P=0.005). In conclusion, the major locus determining familial longevity up to high age as detected by GWAS was marked by rs2075650, which tags the deleterious effects of the ApoE ?4 allele. No other major longevity locus was found.
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LPAR1 and ITGA4 regulate peripheral blood monocyte counts.
Hum. Mutat.
PUBLISHED: 04-12-2011
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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<0.0001), specifically implicating this gene in monocyte development. Furthermore, we tested 10 additional loci identified in the original analysis for replication in 1,122 individuals and confirm that rs6740847 near the alpha-4-integrin gene (ITGA4) associates with variation in monocyte counts (combined P=2.7×10(-10)). This variant is in complete linkage disequilibrium (r(2) =1) with a previously reported eQTL for ITGA4 (rs2124440), indicating that this is the likely causal gene in the region. Our results indicate that rs7023923 and rs6740847 respectively upregulate LPAR1 and downregulate ITGA4 expression and this increases the number of monocytes circulating in the peripheral blood. Further studies that investigate the downstream mechanism involved and the impact on immune function are warranted.
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Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption.
Gunter Schumann, Lachlan J Coin, Anbarasu Lourdusamy, Pimphen Charoen, Karen H Berger, David Stacey, Sylvane Desrivières, Fazil A Aliev, Anokhi A Khan, Najaf Amin, Yurii S Aulchenko, Georgy Bakalkin, Stephan J Bakker, Beverley Balkau, Joline W Beulens, Ainhoa Bilbao, Rudolf A de Boer, Delphine Beury, Michiel L Bots, Elemi J Breetvelt, Stéphane Cauchi, Christine Cavalcanti-Proença, John C Chambers, Toni-Kim Clarke, Norbert Dahmen, Eco J De Geus, Danielle Dick, Francesca Ducci, Alanna Easton, Howard J Edenberg, Tonu Esko, Tõnu Esk, Alberto Fernandez-Medarde, Tatiana Foroud, Nelson B Freimer, Jean-Antoine Girault, Diederick E Grobbee, Simonetta Guarrera, Daniel F Gudbjartsson, Anna-Liisa Hartikainen, Andrew C Heath, Victor Hesselbrock, Albert Hofman, Jouke-Jan Hottenga, Matti K Isohanni, Jaakko Kaprio, Kay-Tee Khaw, Brigitte Kuehnel, Jaana Laitinen, Stéphane Lobbens, Jian'an Luan, Massimo Mangino, Matthieu Maroteaux, Giuseppe Matullo, Mark I McCarthy, Christian Mueller, Gerjan Navis, Mattijs E Numans, Alejandro Núñez, Dale R Nyholt, Charlotte N Onland-Moret, Ben A Oostra, Paul F O'Reilly, Miklós Palkovits, Brenda W Penninx, Silvia Polidoro, Anneli Pouta, Inga Prokopenko, Fulvio Ricceri, Eugenio Santos, Johannes H Smit, Nicole Soranzo, Kijoung Song, Ulla Sovio, Michael Stumvoll, Ida Surakk, Thorgeir E Thorgeirsson, Unnur Thorsteinsdottir, Claire Troakes, Thorarinn Tyrfingsson, Anke Tönjes, Cuno S Uiterwaal, André G Uitterlinden, Pim van der Harst, Yvonne T van der Schouw, Oliver Staehlin, Nicole Vogelzangs, Peter Vollenweider, Gérard Waeber, Nicholas J Wareham, Dawn M Waterworth, John B Whitfield, Erich H Wichmann, Gonneke Willemsen, Jacqueline C Witteman, Xin Yuan, Guangju Zhai, Jing H Zhao, Weihua Zhang, Nicholas G Martin, Andres Metspalu, Angela Doering, James Scott, Tim D Spector, Ruth J Loos, Dorret I Boomsma, Vincent Mooser, Leena Peltonen, Kari Stefansson, Cornelia M van Duijn, Paolo Vineis, Wolfgang H Sommer, Jaspal S Kooner, Rainer Spanagel, Ulrike A Heberlein, Marjo-Riitta Järvelin, Paul Elliott.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 04-06-2011
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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 ?2.5 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 × 10(-8) to P = 4 × 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.
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Meta-analysis of genome-wide association for migraine in six population-based European cohorts.
Eur. J. Hum. Genet.
PUBLISHED: 03-30-2011
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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<10(-5). The best result was obtained for SNP rs9908234, which had a P-value of 8.00 × 10(-8). This top SNP is located in the nerve growth factor receptor (NGFR) gene. However, this SNP did not replicate in three cohorts from the Netherlands and Australia. Of the other 31 SNPs, 18 SNPs were tested in two replication cohorts, but none replicated. In addition, we explored previously identified candidate genes in the meta-analysis data set. This revealed a modest gene-based significant association between migraine and the metadherin (MTDH) gene, previously identified in the first clinic-based GWA study (GWAS) for migraine (Bonferroni-corrected gene-based P-value=0.026). This finding is consistent with the involvement of the glutamate pathway in migraine. Additional research is necessary to further confirm the involvement of glutamate.
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Genetic architecture of circulating lipid levels.
Eur. J. Hum. Genet.
PUBLISHED: 03-30-2011
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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.
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White matter differences in monozygotic twins discordant or concordant for obsessive-compulsive symptoms: a combined diffusion tensor imaging/voxel-based morphometry study.
Biol. Psychiatry
PUBLISHED: 03-22-2011
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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.
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Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma.
John C Chambers, Weihua Zhang, Joban Sehmi, Xinzhong Li, Mark N Wass, Pim van der Harst, Hilma Holm, Serena Sanna, Maryam Kavousi, Sebastian E Baumeister, Lachlan J Coin, Guohong Deng, Christian Gieger, Nancy L Heard-Costa, Jouke-Jan Hottenga, Brigitte Kühnel, Vinod Kumar, Vasiliki Lagou, Liming Liang, Jian'an Luan, Pedro Marques Vidal, Irene Mateo Leach, Paul F O'Reilly, John F Peden, Nilufer Rahmioglu, Pasi Soininen, Elizabeth K Speliotes, Xin Yuan, Gudmar Thorleifsson, Behrooz Z Alizadeh, Larry D Atwood, Ingrid B Borecki, Morris J Brown, Pimphen Charoen, Francesco Cucca, Debashish Das, Eco J C de Geus, Anna L Dixon, Angela Döring, Georg Ehret, Gudmundur I Eyjolfsson, Martin Farrall, Nita G Forouhi, Nele Friedrich, Wolfram Goessling, Daniel F Gudbjartsson, Tamara B Harris, Anna-Liisa Hartikainen, Simon Heath, Gideon M Hirschfield, Albert Hofman, Georg Homuth, Elina Hyppönen, Harry L A Janssen, Toby Johnson, Antti J Kangas, Ido P Kema, Jens P Kühn, Sandra Lai, Mark Lathrop, Markus M Lerch, Yun Li, T Jake Liang, Jing-Ping Lin, Ruth J F Loos, Nicholas G Martin, Miriam F Moffatt, Grant W Montgomery, Patricia B Munroe, Kiran Musunuru, Yusuke Nakamura, Christopher J O'Donnell, Isleifur Olafsson, Brenda W Penninx, Anneli Pouta, Bram P Prins, Inga Prokopenko, Ralf Puls, Aimo Ruokonen, Markku J Savolainen, David Schlessinger, Jeoffrey N L Schouten, Udo Seedorf, Srijita Sen-Chowdhry, Katherine A Siminovitch, Johannes H Smit, Timothy D Spector, Wenting Tan, Tanya M Teslovich, Taru Tukiainen, André G Uitterlinden, Melanie M van der Klauw, Ramachandran S Vasan, Chris Wallace, Henri Wallaschofski, H-Erich Wichmann, Gonneke Willemsen, Peter Würtz, Chun Xu, Laura M Yerges-Armstrong, , Gonçalo R Abecasis, Kourosh R Ahmadi, Dorret I Boomsma, Mark Caulfield, William O Cookson, Cornelia M van Duijn, Philippe Froguel, Koichi Matsuda, Mark I McCarthy, Christa Meisinger, Vincent Mooser, Kirsi H Pietiläinen, Gunter Schumann, Harold Snieder, Michael J E Sternberg, Ronald P Stolk, Howard C Thomas, Unnur Thorsteinsdottir, Manuela Uda, Gérard Waeber, Nicholas J Wareham, Dawn M Waterworth, Hugh Watkins, John B Whitfield, Jacqueline C M Witteman, Bruce H R Wolffenbuttel, Caroline S Fox, Mika Ala-Korpela, Kari Stefansson, Peter Vollenweider, Henry Völzke, Eric E Schadt, James Scott, Marjo-Riitta Järvelin, Paul Elliott, Jaspal S Kooner.
Nat. Genet.
PUBLISHED: 03-08-2011
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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.
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Heavy alcohol use, rather than alcohol dependence, is associated with dysregulation of the hypothalamic-pituitary-adrenal axis and the autonomic nervous system.
Drug Alcohol Depend
PUBLISHED: 02-16-2011
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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.
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Variance components models for physical activity with age as modifier: a comparative twin study in seven countries.
Twin Res Hum Genet
PUBLISHED: 02-15-2011
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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.
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Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.
Louise V Wain, Germaine C Verwoert, Paul F O'Reilly, Gang Shi, Toby Johnson, Andrew D Johnson, Murielle Bochud, Kenneth M Rice, Peter Henneman, Albert V Smith, Georg B Ehret, Najaf Amin, Martin G Larson, Vincent Mooser, David Hadley, Marcus Dörr, Joshua C Bis, Thor Aspelund, Tonu Esko, A Cecile J W Janssens, Jing Hua Zhao, Simon Heath, Maris Laan, Jingyuan Fu, Giorgio Pistis, Jian'an Luan, Pankaj Arora, Gavin Lucas, Nicola Pirastu, Irene Pichler, Anne U Jackson, Rebecca J Webster, Feng Zhang, John F Peden, Helena Schmidt, Toshiko Tanaka, Harry Campbell, Wilmar Igl, Yuri Milaneschi, Jouke-Jan Hottenga, Veronique Vitart, Daniel I Chasman, Stella Trompet, Jennifer L Bragg-Gresham, Behrooz Z Alizadeh, John C Chambers, Xiuqing Guo, Terho Lehtimäki, Brigitte Kühnel, Lorna M Lopez, Ozren Polašek, Mladen Boban, Christopher P Nelson, Alanna C Morrison, Vasyl Pihur, Santhi K Ganesh, Albert Hofman, Suman Kundu, Francesco U S Mattace-Raso, Fernando Rivadeneira, Eric J G Sijbrands, André G Uitterlinden, Shih-Jen Hwang, Ramachandran S Vasan, Thomas J Wang, Sven Bergmann, Peter Vollenweider, Gérard Waeber, Jaana Laitinen, Anneli Pouta, Paavo Zitting, Wendy L McArdle, Heyo K Kroemer, Uwe Völker, Henry Völzke, Nicole L Glazer, Kent D Taylor, Tamara B Harris, Helene Alavere, Toomas Haller, Aime Keis, Mari-Liis Tammesoo, Yurii Aulchenko, Inês Barroso, Kay-Tee Khaw, Pilar Galán, Serge Hercberg, Mark Lathrop, Susana Eyheramendy, Elin Org, Siim Sõber, Xiaowen Lu, Ilja M Nolte, Brenda W Penninx, Tanguy Corre, Corrado Masciullo, Cinzia Sala, Leif Groop, Benjamin F Voight, Olle Melander, Christopher J O'Donnell, Veikko Salomaa, Adamo Pio D'adamo, Antonella Fabretto, Flavio Faletra, Sheila Ulivi, Fabiola M Del Greco, Maurizio Facheris, Francis S Collins, Richard N Bergman, John P Beilby, Joseph Hung, A William Musk, Massimo Mangino, So-Youn Shin, Nicole Soranzo, Hugh Watkins, Anuj Goel, Anders Hamsten, Pierre Gider, Marisa Loitfelder, Marion Zeginigg, Dena Hernandez, Samer S Najjar, Pau Navarro, Sarah H Wild, Anna Maria Corsi, Andrew Singleton, Eco J C de Geus, Gonneke Willemsen, Alex N Parker, Lynda M Rose, Brendan Buckley, David Stott, Marco Orrù, Manuela Uda, , Melanie M van der Klauw, Weihua Zhang, Xinzhong Li, James Scott, Yii-Der Ida Chen, Gregory L Burke, Mika Kähönen, Jorma Viikari, Angela Döring, Thomas Meitinger, Gail Davies, John M Starr, Valur Emilsson, Andrew Plump, Jan H Lindeman, Peter A C 't Hoen, Inke R König, Janine F Felix, Robert Clarke, Jemma C Hopewell, Halit Ongen, Monique Breteler, Stéphanie Debette, Anita L Destefano, Myriam Fornage, Gary F Mitchell, Nicholas L Smith, Hilma Holm, Kari Stefansson, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Nilesh J Samani, Michael Preuss, Igor Rudan, Caroline Hayward, Ian J Deary, H-Erich Wichmann, Olli T Raitakari, Walter Palmas, Jaspal S Kooner, Ronald P Stolk, J Wouter Jukema, Alan F Wright, Dorret I Boomsma, Stefania Bandinelli, Ulf B Gyllensten, James F Wilson, Luigi Ferrucci, Reinhold Schmidt, Martin Farrall, Tim D Spector, Lyle J Palmer, Jaakko Tuomilehto, Arne Pfeufer, Paolo Gasparini, David Siscovick, David Altshuler, Ruth J F Loos, Daniela Toniolo, Harold Snieder, Christian Gieger, Pierre Meneton, Nicholas J Wareham, Ben A Oostra, Andres Metspalu, Lenore Launer, Rainer Rettig, David P Strachan, Jacques S Beckmann, Jacqueline C M Witteman, Jeanette Erdmann, Ko Willems van Dijk, Eric Boerwinkle, Michael Boehnke, Paul M Ridker, Marjo-Riitta Järvelin, Aravinda Chakravarti, Gonçalo R Abecasis, Vilmundur Gudnason, Christopher Newton-Cheh, Daniel Levy, Patricia B Munroe, Bruce M Psaty, Mark J Caulfield, Dabeeru C Rao, Martin D Tobin, Paul Elliott, Cornelia M van Duijn.
Nat. Genet.
PUBLISHED: 02-10-2011
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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 × 10(-8) to P = 2.3 × 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.
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Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels.
Abbas Dehghan, Josée Dupuis, Maja Barbalic, Joshua C Bis, Gudny Eiriksdottir, Chen Lu, Niina Pellikka, Henri Wallaschofski, Johannes Kettunen, Peter Henneman, Jens Baumert, David P Strachan, Christian Fuchsberger, Veronique Vitart, James F Wilson, Guillaume Paré, Silvia Naitza, Megan E Rudock, Ida Surakka, Eco J C de Geus, Behrooz Z Alizadeh, Jack Guralnik, Alan Shuldiner, Toshiko Tanaka, Robert Y L Zee, Renate B Schnabel, Vijay Nambi, Maryam Kavousi, Samuli Ripatti, Matthias Nauck, Nicholas L Smith, Albert V Smith, Jouko Sundvall, Paul Scheet, Yongmei Liu, Aimo Ruokonen, Lynda M Rose, Martin G Larson, Ron C Hoogeveen, Nelson B Freimer, Alexander Teumer, Russell P Tracy, Lenore J Launer, Julie E Buring, Jennifer F Yamamoto, Aaron R Folsom, Eric J G Sijbrands, James Pankow, Paul Elliott, John F Keaney, Wei Sun, Antti-Pekka Sarin, João D Fontes, Sunita Badola, Brad C Astor, Albert Hofman, Anneli Pouta, Karl Werdan, Karin H Greiser, Oliver Kuss, Henriette E Meyer Zu Schwabedissen, Joachim Thiery, Yalda Jamshidi, Ilja M Nolte, Nicole Soranzo, Timothy D Spector, Henry Völzke, Alexander N Parker, Thor Aspelund, David Bates, Lauren Young, Kim Tsui, David S Siscovick, Xiuqing Guo, Jerome I Rotter, Manuela Uda, David Schlessinger, Igor Rudan, Andrew A Hicks, Brenda W Penninx, Barbara Thorand, Christian Gieger, Joe Coresh, Gonneke Willemsen, Tamara B Harris, André G Uitterlinden, Marjo-Riitta Järvelin, Kenneth Rice, Dörte Radke, Veikko Salomaa, Ko Willems van Dijk, Eric Boerwinkle, Ramachandran S Vasan, Luigi Ferrucci, Quince D Gibson, Stefania Bandinelli, Harold Snieder, Dorret I Boomsma, Xiangjun Xiao, Harry Campbell, Caroline Hayward, Peter P Pramstaller, Cornelia M van Duijn, Leena Peltonen, Bruce M Psaty, Vilmundur Gudnason, Paul M Ridker, Georg Homuth, Wolfgang Koenig, Christie M Ballantyne, Jacqueline C M Witteman, Emelia J Benjamin, Markus Perola, Daniel I Chasman.
Circulation
PUBLISHED: 02-07-2011
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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.
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?-Amylase as a reliable and convenient measure of sympathetic activity: dont start salivating just yet!
Psychoneuroendocrinology
PUBLISHED: 02-03-2011
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Recent years have seen a growing interest in salivary ?-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) ?-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.
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ADHD in Dutch adults: heritability and linkage study.
Am. J. Med. Genet. B Neuropsychiatr. Genet.
PUBLISHED: 02-03-2011
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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 (?750 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 LOD?=?4.58, p(emp) ?=?0.0026) and 2p25.1 (LOD?=?3.58, p(emp) ?=?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.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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