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Find video protocols related to scientific articles indexed in Pubmed.
A novel common variant in DCST2 is associated with length in early life and height in adulthood.
Ralf J P van der Valk, Eskil Kreiner-Møller, Marjolein N Kooijman, Mònica Guxens, Evangelia Stergiakouli, Annika Sääf, Jonathan P Bradfield, Frank Geller, M Geoffrey Hayes, Diana L Cousminer, Antje Körner, Elisabeth Thiering, John A Curtin, Ronny Myhre, Ville Huikari, Raimo Joro, Marjan Kerkhof, Nicole M Warrington, Niina Pitkänen, Ioanna Ntalla, Momoko Horikoshi, Riitta Veijola, Rachel M Freathy, Yik-Ying Teo, Sheila J Barton, David M Evans, John P Kemp, Beate St Pourcain, Susan M Ring, George Davey Smith, Anna Bergström, Inger Kull, Hakon Hakonarson, Frank D Mentch, Hans Bisgaard, Bo Chawes, Jakob Stokholm, Johannes Waage, Patrick Eriksen, Astrid Sevelsted, Mads Melbye, , Cornelia M van Duijn, Carolina Medina-Gomez, Albert Hofman, Johan C de Jongste, H Rob Taal, André G Uitterlinden, Loren L Armstrong, Johan Eriksson, Aarno Palotie, Mariona Bustamante, Xavier Estivill, Juan R Gonzalez, Sabrina Llop, Wieland Kiess, Anubha Mahajan, Claudia Flexeder, Carla M T Tiesler, Clare S Murray, Angela Simpson, Per Magnus, Verena Sengpiel, Anna-Liisa Hartikainen, Sirkka Keinänen-Kiukaanniemi, Alexandra Lewin, Alexessander Da Silva Couto Alves, Alexandra I Blakemore, Jessica L Buxton, Marika Kaakinen, Alina Rodriguez, Sylvain Sebert, Marja Vaarasmaki, Timo Lakka, Virpi Lindi, Ulrike Gehring, Dirkje S Postma, Wei Ang, John P Newnham, Leo-Pekka Lyytikäinen, Katja Pahkala, Olli T Raitakari, Kalliope Panoutsopoulou, Eleftheria Zeggini, Dorret I Boomsma, Maria Groen-Blokhuis, Jorma Ilonen, Lude Franke, Joel N Hirschhorn, Tune H Pers, Liming Liang, Jinyan Huang, Berthold Hocher, Mikael Knip, Seang-Mei Saw, John W Holloway, Erik Melén, Struan F A Grant, Bjarke Feenstra, William L Lowe, Elisabeth Widén, Elena Sergeyev, Harald Grallert, Adnan Custovic, Bo Jacobsson, Marjo-Riitta Järvelin, Mustafa Atalay, Gerard H Koppelman, Craig E Pennell, Harri Niinikoski, George V Dedoussis, Mark I McCarthy, Timothy M Frayling, Jordi Sunyer, Nicholas J Timpson, Fernando Rivadeneira, Klaus Bønnelykke, Vincent W V Jaddoe.
Hum. Mol. Genet.
PUBLISHED: 10-03-2014
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Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; ? = 0.046, SE = 0.008, P = 2.46 × 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10(-4)) and adult height (N = 127 513; P = 1.45 × 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.
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Novel approach identifies SNPs in SLC2A10 and KCNK9 with evidence for parent-of-origin effect on body mass index.
PLoS Genet.
PUBLISHED: 07-01-2014
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The phenotypic effect of some single nucleotide polymorphisms (SNPs) depends on their parental origin. We present a novel approach to detect parent-of-origin effects (POEs) in genome-wide genotype data of unrelated individuals. The method exploits increased phenotypic variance in the heterozygous genotype group relative to the homozygous groups. We applied the method to >56,000 unrelated individuals to search for POEs influencing body mass index (BMI). Six lead SNPs were carried forward for replication in five family-based studies (of ?4,000 trios). Two SNPs replicated: the paternal rs2471083-C allele (located near the imprinted KCNK9 gene) and the paternal rs3091869-T allele (located near the SLC2A10 gene) increased BMI equally (beta?=?0.11 (SD), P<0.0027) compared to the respective maternal alleles. Real-time PCR experiments of lymphoblastoid cell lines from the CEPH families showed that expression of both genes was dependent on parental origin of the SNPs alleles (P<0.01). Our scheme opens new opportunities to exploit GWAS data of unrelated individuals to identify POEs and demonstrates that they play an important role in adult obesity.
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Cis and trans effects of human genomic variants on gene expression.
PLoS Genet.
PUBLISHED: 07-01-2014
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Gene expression is a heritable cellular phenotype that defines the function of a cell and can lead to diseases in case of misregulation. In order to detect genetic variations affecting gene expression, we performed association analysis of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) with gene expression measured in 869 lymphoblastoid cell lines of the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort in cis and in trans. We discovered that 3,534 genes (false discovery rate (FDR)?=?5%) are affected by an expression quantitative trait locus (eQTL) in cis and 48 genes are affected in trans. We observed that CNVs are more likely to be eQTLs than SNPs. In addition, we found that variants associated to complex traits and diseases are enriched for trans-eQTLs and that trans-eQTLs are enriched for cis-eQTLs. As a variant affecting both a gene in cis and in trans suggests that the cis gene is functionally linked to the trans gene expression, we looked specifically for trans effects of cis-eQTLs. We discovered that 26 cis-eQTLs are associated to 92 genes in trans with the cis-eQTLs of the transcriptions factors BATF3 and HMX2 affecting the most genes. We then explored if the variation of the level of expression of the cis genes were causally affecting the level of expression of the trans genes and discovered several causal relationships between variation in the level of expression of the cis gene and variation of the level of expression of the trans gene. This analysis shows that a large sample size allows the discovery of secondary effects of human variations on gene expression that can be used to construct short directed gene regulatory networks.
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Phenotypic dissection of bone mineral density reveals skeletal site specificity and facilitates the identification of novel loci in the genetic regulation of bone mass attainment.
PLoS Genet.
PUBLISHED: 06-01-2014
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Heritability of bone mineral density (BMD) varies across skeletal sites, reflecting different relative contributions of genetic and environmental influences. To quantify the degree to which common genetic variants tag and environmental factors influence BMD, at different sites, we estimated the genetic (rg) and residual (re) correlations between BMD measured at the upper limbs (UL-BMD), lower limbs (LL-BMD) and skull (SK-BMD), using total-body DXA scans of ? 4,890 participants recruited by the Avon Longitudinal Study of Parents and their Children (ALSPAC). Point estimates of rg indicated that appendicular sites have a greater proportion of shared genetic architecture (LL-/UL-BMD rg = 0.78) between them, than with the skull (UL-/SK-BMD rg = 0.58 and LL-/SK-BMD rg = 0.43). Likewise, the residual correlation between BMD at appendicular sites (r(e) = 0.55) was higher than the residual correlation between SK-BMD and BMD at appendicular sites (r(e) = 0.20-0.24). To explore the basis for the observed differences in rg and re, genome-wide association meta-analyses were performed (n ? 9,395), combining data from ALSPAC and the Generation R Study identifying 15 independent signals from 13 loci associated at genome-wide significant level across different skeletal regions. Results suggested that previously identified BMD-associated variants may exert site-specific effects (i.e. differ in the strength of their association and magnitude of effect across different skeletal sites). In particular, variants at CPED1 exerted a larger influence on SK-BMD and UL-BMD when compared to LL-BMD (P = 2.01 × 10(-37)), whilst variants at WNT16 influenced UL-BMD to a greater degree when compared to SK- and LL-BMD (P = 2.31 × 10(-14)). In addition, we report a novel association between RIN3 (previously associated with Paget's disease) and LL-BMD (rs754388: ? = 0.13, SE = 0.02, P = 1.4 × 10(-10)). Our results suggest that BMD at different skeletal sites is under a mixture of shared and specific genetic and environmental influences. Allowing for these differences by performing genome-wide association at different skeletal sites may help uncover new genetic influences on BMD.
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Intracerebral injection of preformed synthetic tau fibrils initiates widespread tauopathy and neuronal loss in the brains of tau transgenic mice.
Neurobiol. Dis.
PUBLISHED: 05-13-2014
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Neurofibrillary tangles composed of hyperphosphorylated fibrillized tau are found in numerous tauopathies including Alzheimer's disease. Increasing evidence suggests that tau pathology can be transmitted from cell-to-cell; however the mechanisms involved in the initiation of tau fibrillization and spreading of disease linked to progression of tau pathology are poorly understood. We show here that intracerebral injections of preformed synthetic tau fibrils into the hippocampus or frontal cortex of young tau transgenic mice expressing mutant human P301L tau induces tau hyperphosphorylation and aggregation around the site of injection, as well as a time-dependent propagation of tau pathology to interconnected brain areas distant from the injection site. Furthermore, we show that the tau pathology as a consequence of injection of tau preformed fibrils into the hippocampus induces selective loss of CA1 neurons. Together, our data confirm previous studies on the seeded induction and the spreading of tau pathology in a different tau transgenic mouse model and reveals neuronal loss associated with seeded tau pathology in tau transgenic mouse brain. These results further validate the utility of the tau seeding model in studying disease transmission, and provide a more complete in vivo tauopathy model with associated neurodegeneration which can be used to investigate the mechanisms involved in tau aggregation and spreading, as well as aid in the search for disease modifying treatments for Alzheimer's disease and related tauopathies.
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Genetic variation in prostate-specific antigen-detected prostate cancer and the effect of control selection on genetic association studies.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 04-21-2014
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Only a minority of the genetic components of prostate cancer risk have been explained. Some observed associations of SNPs with prostate cancer might arise from associations of these SNPs with circulating prostate-specific antigen (PSA) because PSA values are used to select controls.
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Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium.
Hum. Genet.
PUBLISHED: 04-14-2014
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To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged <25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged <25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E-8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E-07), TOX (rs7823467, P = 3.47E-07) and LINC00340 (rs12212674, P = 1.49E-06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = -0.59, P = 2.10E-04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors.
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Genome-wide association study of height-adjusted BMI in childhood identifies functional variant in ADCY3.
Obesity (Silver Spring)
PUBLISHED: 04-04-2014
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Genome-wide association studies (GWAS) of BMI are mostly undertaken under the assumption that "kg/m(2) " is an index of weight fully adjusted for height, but in general this is not true. The aim here was to assess the contribution of common genetic variation to a adjusted version of that phenotype which appropriately accounts for covariation in height in children.
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Birth weight is positively related to bone size in adolescents but inversely related to cortical bone mineral density: findings from a large prospective cohort study.
Bone
PUBLISHED: 02-06-2014
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To examine the influence of intrauterine environment on subsequent bone development, we investigated the relationship between birth weight and cortical bone parameters, and the role of puberty, bone resorption and insulin as possible mediators. Bone outcomes were obtained from mid-tibial pQCT scans performed at age 15.5 years in 1960 males and 2192 females from the ALSPAC birth cohort. Birth weight was positively related to periosteal circumference (PC) [beta=0.40 (0.34, 0.46)], which was largely but not completely attenuated after adjustment for height and weight [beta=0.07 (0.02, 0.12)] (SD change in outcome per 1 kg increase in birth weight with 95% CI). Based on our height and weight adjusted model, the association was stronger in females compared to males (P=0.02 for gender interaction), and persisted in 2842 participants with equivalent results at age 17.7 years. Conversely, birth weight was inversely related to cortical bone mineral density (BMDC) at age 15.5 years after adjusting for height and weight [beta=-0.18 (-0.23, -0.13)], with a stronger association in males compared to females (P=0.01 for gender interaction), but an equivalent association was not seen at 17.7 years. In further analyses performed on data from age 15.5 years, the association between birth weight and PC was unaffected by adjustment for puberty (Tanner stage at age 13.5 years), bone resorption (fasting beta-carboxyterminal cross linking telopeptide (?CTX) at age 15.5 years) or insulin (fasting insulin at age 15.5 years). In contrast, the association with BMDC was attenuated by approximately 30% after adjustment for puberty or bone resorption, and by 50% after adjustment for both factors combined. We conclude that the inverse relationship between birth weight and BMDC is in part mediated by effects of puberty and bone resorption, which may help to explain the transitory nature of this association, in contrast to the more persisting relationship with PC.
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Variability in the common genetic architecture of social-communication spectrum phenotypes during childhood and adolescence.
Mol Autism
PUBLISHED: 02-04-2014
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Social-communication abilities are heritable traits, and their impairments overlap with the autism continuum. To characterise the genetic architecture of social-communication difficulties developmentally and identify genetic links with the autistic dimension, we conducted a genome-wide screen of social-communication problems at multiple time-points during childhood and adolescence.
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Common variation near ROBO2 is associated with expressive vocabulary in infancy.
Nat Commun
PUBLISHED: 01-15-2014
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Twin studies suggest that expressive vocabulary at ~24 months is modestly heritable. However, the genes influencing this early linguistic phenotype are unknown. Here we conduct a genome-wide screen and follow-up study of expressive vocabulary in toddlers of European descent from up to four studies of the EArly Genetics and Lifecourse Epidemiology consortium, analysing an early (15-18 months, 'one-word stage', N(Total) = 8,889) and a later (24-30 months, 'two-word stage', N(Total)=10,819) phase of language acquisition. For the early phase, one single-nucleotide polymorphism (rs7642482) at 3p12.3 near ROBO2, encoding a conserved axon-binding receptor, reaches the genome-wide significance level (P=1.3 × 10(-8)) in the combined sample. This association links language-related common genetic variation in the general population to a potential autism susceptibility locus and a linkage region for dyslexia, speech-sound disorder and reading. The contribution of common genetic influences is, although modest, supported by genome-wide complex trait analysis (meta-GCTA h(2)(15-18-months) = 0.13, meta-GCTA h(2)(24-30-months) = 0.14) and in concordance with additional twin analysis (5,733 pairs of European descent, h(2)(24-months) = 0.20).
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Genetic influences on trajectories of systolic blood pressure across childhood and adolescence.
Circ Cardiovasc Genet
PUBLISHED: 11-07-2013
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Background- Blood pressure (BP) tends to increase across childhood and adolescence, but the genetic influences on rates of BP change are not known. Potentially important genetic influences could include genetic variants identified in genome-wide association studies of adults as being associated with BP, height, and body mass index. Understanding the contribution of these genetic variants to changes in BP across childhood and adolescence could yield understanding into the life course development of cardiovascular risk. Methods and Results- Pooling data from 2 cohorts (the Avon Longitudinal Study of Parents and Children [n=7013] and the Western Australian Pregnancy Cohort [n=1459]), we examined the associations of allelic scores of 29 single-nucleotide polymorphisms (SNPs) for adult BP, 180 height SNPs, and 32 body mass index SNPs, with trajectories of systolic BP (SBP) from 6 to 17 years of age, using linear spline multilevel models. The allelic scores of BP and body mass index SNPs were associated with SBP at 6 years of age (per-allele effect sizes, 0.097 mm Hg [SE, 0.039 mm Hg] and 0.107 mm Hg [SE, 0.037 mm Hg]); associations with age-related changes in SBP between 6 and 17 years of age were of small magnitude and imprecisely estimated. The allelic score of height SNPs was only weakly associated with SBP changes. No sex or cohort differences in genetic effects were observed. Conclusions- Allelic scores of BP and body mass index SNPs demonstrated associations with SBP at 6 years of age with a similar magnitude but were not strongly associated with changes in SBP with age between 6 and 17 years. Further work is required to identify variants associated with changes with age in BP.
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The North Pacific Acoustic Laboratory deep-water acoustic propagation experiments in the Philippine Sea.
J. Acoust. Soc. Am.
PUBLISHED: 10-15-2013
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A series of experiments conducted in the Philippine Sea during 2009-2011 investigated deep-water acoustic propagation and ambient noise in this oceanographically and geologically complex region: (i) the 2009 North Pacific Acoustic Laboratory (NPAL) Pilot Study/Engineering Test, (ii) the 2010-2011 NPAL Philippine Sea Experiment, and (iii) the Ocean Bottom Seismometer Augmentation of the 2010-2011 NPAL Philippine Sea Experiment. The experimental goals included (a) understanding the impacts of fronts, eddies, and internal tides on acoustic propagation, (b) determining whether acoustic methods, together with other measurements and ocean modeling, can yield estimates of the time-evolving ocean state useful for making improved acoustic predictions, (c) improving our understanding of the physics of scattering by internal waves and spice, (d) characterizing the depth dependence and temporal variability of ambient noise, and (e) understanding the relationship between the acoustic field in the water column and the seismic field in the seafloor. In these experiments, moored and ship-suspended low-frequency acoustic sources transmitted to a newly developed distributed vertical line array receiver capable of spanning the water column in the deep ocean. The acoustic transmissions and ambient noise were also recorded by a towed hydrophone array, by acoustic Seagliders, and by ocean bottom seismometers.
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Mining the human phenome using allelic scores that index biological intermediates.
PLoS Genet.
PUBLISHED: 10-01-2013
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It is common practice in genome-wide association studies (GWAS) to focus on the relationship between disease risk and genetic variants one marker at a time. When relevant genes are identified it is often possible to implicate biological intermediates and pathways likely to be involved in disease aetiology. However, single genetic variants typically explain small amounts of disease risk. Our idea is to construct allelic scores that explain greater proportions of the variance in biological intermediates, and subsequently use these scores to data mine GWAS. To investigate the approachs properties, we indexed three biological intermediates where the results of large GWAS meta-analyses were available: body mass index, C-reactive protein and low density lipoprotein levels. We generated allelic scores in the Avon Longitudinal Study of Parents and Children, and in publicly available data from the first Wellcome Trust Case Control Consortium. We compared the explanatory ability of allelic scores in terms of their capacity to proxy for the intermediate of interest, and the extent to which they associated with disease. We found that allelic scores derived from known variants and allelic scores derived from hundreds of thousands of genetic markers explained significant portions of the variance in biological intermediates of interest, and many of these scores showed expected correlations with disease. Genome-wide allelic scores however tended to lack specificity suggesting that they should be used with caution and perhaps only to proxy biological intermediates for which there are no known individual variants. Power calculations confirm the feasibility of extending our strategy to the analysis of tens of thousands of molecular phenotypes in large genome-wide meta-analyses. We conclude that our method represents a simple way in which potentially tens of thousands of molecular phenotypes could be screened for causal relationships with disease without having to expensively measure these variables in individual disease collections.
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Common variants in left/right asymmetry genes and pathways are associated with relative hand skill.
PLoS Genet.
PUBLISHED: 09-01-2013
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Humans display structural and functional asymmetries in brain organization, strikingly with respect to language and handedness. The molecular basis of these asymmetries is unknown. We report a genome-wide association study meta-analysis for a quantitative measure of relative hand skill in individuals with dyslexia [reading disability (RD)] (n = 728). The most strongly associated variant, rs7182874 (P = 8.68 × 10(-9)), is located in PCSK6, further supporting an association we previously reported. We also confirmed the specificity of this association in individuals with RD; the same locus was not associated with relative hand skill in a general population cohort (n = 2,666). As PCSK6 is known to regulate NODAL in the development of left/right (LR) asymmetry in mice, we developed a novel approach to GWAS pathway analysis, using gene-set enrichment to test for an over-representation of highly associated variants within the orthologs of genes whose disruption in mice yields LR asymmetry phenotypes. Four out of 15 LR asymmetry phenotypes showed an over-representation (FDR ? 5%). We replicated three of these phenotypes; situs inversus, heterotaxia, and double outlet right ventricle, in the general population cohort (FDR ? 5%). Our findings lead us to propose that handedness is a polygenic trait controlled in part by the molecular mechanisms that establish LR body asymmetry early in development.
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Meta-analysis of genome-wide studies identifies WNT16 and ESR1 SNPs associated with bone mineral density in premenopausal women.
J. Bone Miner. Res.
PUBLISHED: 08-30-2013
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Previous genome-wide association studies (GWAS) have identified common variants in genes associated with variation in bone mineral density (BMD), although most have been carried out in combined samples of older women and men. Meta-analyses of these results have identified numerous single-nucleotide polymorphisms (SNPs) of modest effect at genome-wide significance levels in genes involved in both bone formation and resorption, as well as other pathways. We performed a meta-analysis restricted to premenopausal white women from four cohorts (n?=?4061 women, aged 20 to 45 years) to identify genes influencing peak bone mass at the lumbar spine and femoral neck. After imputation, age- and weight-adjusted bone-mineral density (BMD) values were tested for association with each SNP. Association of an SNP in the WNT16 gene (rs3801387; p?=?1.7?×?10(-9) ) and multiple SNPs in the ESR1/C6orf97 region (rs4870044; p?=?1.3?×?10(-8) ) achieved genome-wide significance levels for lumbar spine BMD. These SNPs, along with others demonstrating suggestive evidence of association, were then tested for association in seven replication cohorts that included premenopausal women of European, Hispanic-American, and African-American descent (combined n?=?5597 for femoral neck; n?=?4744 for lumbar spine). When the data from the discovery and replication cohorts were analyzed jointly, the evidence was more significant (WNT16 joint p?=?1.3?×?10(-11) ; ESR1/C6orf97 joint p?=?1.4?×?10(-10) ). Multiple independent association signals were observed with spine BMD at the ESR1 region after conditioning on the primary signal. Analyses of femoral neck BMD also supported association with SNPs in WNT16 and ESR1/C6orf97 (p?
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Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization.
Nat. Genet.
PUBLISHED: 06-10-2013
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Allergen-specific immunoglobulin E (present in allergic sensitization) has a central role in the pathogenesis of allergic disease. We performed the first large-scale genome-wide association study (GWAS) of allergic sensitization in 5,789 affected individuals and 10,056 controls and followed up the top SNP at each of 26 loci in 6,114 affected individuals and 9,920 controls. We increased the number of susceptibility loci with genome-wide significant association with allergic sensitization from three to ten, including SNPs in or near TLR6, C11orf30, STAT6, SLC25A46, HLA-DQB1, IL1RL1, LPP, MYC, IL2 and HLA-B. All the top SNPs were associated with allergic symptoms in an independent study. Risk-associated variants at these ten loci were estimated to account for at least 25% of allergic sensitization and allergic rhinitis. Understanding the molecular mechanisms underlying these associations may provide new insights into the etiology of allergic disease.
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Genome-wide association study identifies loci affecting blood copper, selenium and zinc.
Hum. Mol. Genet.
PUBLISHED: 05-29-2013
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Genetic variation affecting absorption, distribution or excretion of essential trace elements may lead to health effects related to sub-clinical deficiency. We have tested for allelic effects of single-nucleotide polymorphisms (SNPs) on blood copper, selenium and zinc in a genome-wide association study using two adult cohorts from Australia and the UK. Participants were recruited in Australia from twins and their families and in the UK from pregnant women. We measured erythrocyte Cu, Se and Zn (Australian samples) or whole blood Se (UK samples) using inductively coupled plasma mass spectrometry. Genotyping was performed with Illumina chips and > 2.5 m SNPs were imputed from HapMap data. Genome-wide significant associations were found for each element. For Cu, there were two loci on chromosome 1 (most significant SNPs rs1175550, P = 5.03 × 10(-10), and rs2769264, P = 2.63 × 10(-20)); for Se, a locus on chromosome 5 was significant in both cohorts (combined P = 9.40 × 10(-28) at rs921943); and for Zn three loci on chromosomes 8, 15 and X showed significant results (rs1532423, P = 6.40 × 10(-12); rs2120019, P = 1.55 × 10(-18); and rs4826508, P = 1.40 × 10(-12), respectively). The Se locus covers three genes involved in metabolism of sulphur-containing amino acids and potentially of the analogous Se compounds; the chromosome 8 locus for Zn contains multiple genes for the Zn-containing enzyme carbonic anhydrase. Where potentially relevant genes were identified, they relate to metabolism of the element (Se) or to the presence at high concentration of a metal-containing protein (Cu).
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Comment on "ApoE-directed therapeutics rapidly clear ?-amyloid and reverse deficits in AD mouse models".
Science
PUBLISHED: 05-25-2013
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Cramer et al. (Reports, 23 March 2012, p. 1503; published online 9 February 2012) tested bexarotene as a potential ?-amyloid-lowering drug for Alzheimers disease (AD). We were not able to reproduce the described effects in several animal models. Drug formulation appears very critical. Our data call for extreme caution when considering this compound for use in AD patients.
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Genome-wide association study of primary tooth eruption identifies pleiotropic loci associated with height and craniofacial distances.
Hum. Mol. Genet.
PUBLISHED: 05-23-2013
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Twin and family studies indicate that the timing of primary tooth eruption is highly heritable, with estimates typically exceeding 80%. To identify variants involved in primary tooth eruption, we performed a population-based genome-wide association study of age at first tooth and number of teeth using 5998 and 6609 individuals, respectively, from the Avon Longitudinal Study of Parents and Children (ALSPAC) and 5403 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966). We tested 2 446 724 SNPs imputed in both studies. Analyses were controlled for the effect of gestational age, sex and age of measurement. Results from the two studies were combined using fixed effects inverse variance meta-analysis. We identified a total of 15 independent loci, with 10 loci reaching genome-wide significance (P < 5 × 10(-8)) for age at first tooth and 11 loci for number of teeth. Together, these associations explain 6.06% of the variation in age of first tooth and 4.76% of the variation in number of teeth. The identified loci included eight previously unidentified loci, some containing genes known to play a role in tooth and other developmental pathways, including an SNP in the protein-coding region of BMP4 (rs17563, P = 9.080 × 10(-17)). Three of these loci, containing the genes HMGA2, AJUBA and ADK, also showed evidence of association with craniofacial distances, particularly those indexing facial width. Our results suggest that the genome-wide association approach is a powerful strategy for detecting variants involved in tooth eruption, and potentially craniofacial growth and more generally organ development.
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Common variation contributes to the genetic architecture of social communication traits.
Mol Autism
PUBLISHED: 04-16-2013
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Social communication difficulties represent an autistic trait that is highly heritable and persistent during the course of development. However, little is known about the underlying genetic architecture of this phenotype.
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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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Nine loci for ocular axial length identified through genome-wide association studies, including shared loci with refractive error.
Ching-Yu Cheng, Maria Schache, M Kamran Ikram, Terri L Young, Jeremy A Guggenheim, Veronique Vitart, Stuart MacGregor, Virginie J M Verhoeven, Veluchamy A Barathi, Jiemin Liao, Pirro G Hysi, Joan E Bailey-Wilson, Beate St Pourcain, John P Kemp, George McMahon, Nicholas J Timpson, David M Evans, Grant W Montgomery, Aniket Mishra, Ya Xing Wang, Jie Jin Wang, Elena Rochtchina, Ozren Polašek, Alan F Wright, Najaf Amin, Elisabeth M van Leeuwen, James F Wilson, Craig E Pennell, Cornelia M van Duijn, Paulus T V M de Jong, Johannes R Vingerling, Xin Zhou, Peng Chen, Ruoying Li, Wan-Ting Tay, Yingfeng Zheng, Merwyn Chew, , Kathryn P Burdon, Jamie E Craig, Sudha K Iyengar, Robert P Igo, Jonathan H Lass, Emily Y Chew, Toomas Haller, Evelin Mihailov, Andres Metspalu, Juho Wedenoja, Claire L Simpson, Robert Wojciechowski, René Höhn, Alireza Mirshahi, Tanja Zeller, Norbert Pfeiffer, Karl J Lackner, Thomas Bettecken, Thomas Meitinger, Konrad Oexle, Mario Pirastu, Laura Portas, Abhishek Nag, Katie M Williams, Ekaterina Yonova-Doing, Ronald Klein, Barbara E Klein, S Mohsen Hosseini, Andrew D Paterson, Kari-Matti Mäkelä, Terho Lehtimäki, Mika Kähönen, Olli Raitakari, Nagahisa Yoshimura, Fumihiko Matsuda, Li Jia Chen, Chi Pui Pang, Shea Ping Yip, Maurice K H Yap, Akira Meguro, Nobuhisa Mizuki, Hidetoshi Inoko, Paul J Foster, Jing Hua Zhao, Eranga Vithana, E-Shyong Tai, Qiao Fan, Liang Xu, Harry Campbell, Brian Fleck, Igor Rudan, Tin Aung, Albert Hofman, André G Uitterlinden, Goran Bencic, Chiea-Chuen Khor, Hannah Forward, Olavi Pärssinen, Paul Mitchell, Fernando Rivadeneira, Alex W Hewitt, Cathy Williams, Ben A Oostra, Yik-Ying Teo, Christopher J Hammond, Dwight Stambolian, David A Mackey, Caroline C W Klaver, Tien-Yin Wong, Seang-Mei Saw, Paul N Baird.
Am. J. Hum. Genet.
PUBLISHED: 03-15-2013
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Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways.
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Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity.
Hum. Mol. Genet.
PUBLISHED: 02-27-2013
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The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. Although little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlying mechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth and maturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P < 1.67 × 10(-8)) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased body mass index, reduced pubertal growth and earlier puberty. Whereas epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall, this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty and childhood obesity and provides new information to pinpoint processes linking these traits.
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Using genetic proxies for lifecourse sun exposure to assess the causal relationship of sun exposure with circulating vitamin d and prostate cancer risk.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 02-25-2013
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Ecological and epidemiological studies have identified an inverse association of intensity and duration of sunlight exposure with prostate cancer, which may be explained by a reduction in vitamin D synthesis. Pigmentation traits influence sun exposure and therefore may affect prostate cancer risk. Because observational studies are vulnerable to confounding and measurement error, we used Mendelian randomization to examine the relationship of sun exposure with both prostate cancer risk and the intermediate phenotype, plasma levels of vitamin D.
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Genetic determinants of trabecular and cortical volumetric bone mineral densities and bone microstructure.
PLoS Genet.
PUBLISHED: 02-21-2013
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Most previous genetic epidemiology studies within the field of osteoporosis have focused on the genetics of the complex trait areal bone mineral density (aBMD), not being able to differentiate genetic determinants of cortical volumetric BMD (vBMD), trabecular vBMD, and bone microstructural traits. The objective of this study was to separately identify genetic determinants of these bone traits as analysed by peripheral quantitative computed tomography (pQCT). Separate GWA meta-analyses for cortical and trabecular vBMDs were performed. The cortical vBMD GWA meta-analysis (n?=?5,878) followed by replication (n?=?1,052) identified genetic variants in four separate loci reaching genome-wide significance (RANKL, rs1021188, p?=?3.6×10?¹?; LOC285735, rs271170, p?=?2.7×10?¹²; OPG, rs7839059, p?=?1.2×10?¹?; and ESR1/C6orf97, rs6909279, p?=?1.1×10??). The trabecular vBMD GWA meta-analysis (n?=?2,500) followed by replication (n?=?1,022) identified one locus reaching genome-wide significance (FMN2/GREM2, rs9287237, p?=?1.9×10??). High-resolution pQCT analyses, giving information about bone microstructure, were available in a subset of the GOOD cohort (n?=?729). rs1021188 was significantly associated with cortical porosity while rs9287237 was significantly associated with trabecular bone fraction. The genetic variant in the FMN2/GREM2 locus was associated with fracture risk in the MrOS Sweden cohort (HR per extra T allele 0.75, 95% confidence interval 0.60-0.93) and GREM2 expression in human osteoblasts. In conclusion, five genetic loci associated with trabecular or cortical vBMD were identified. Two of these (FMN2/GREM2 and LOC285735) are novel bone-related loci, while the other three have previously been reported to be associated with aBMD. The genetic variants associated with cortical and trabecular bone parameters differed, underscoring the complexity of the genetics of bone parameters. We propose that a genetic variant in the RANKL locus influences cortical vBMD, at least partly, via effects on cortical porosity, and that a genetic variant in the FMN2/GREM2 locus influences GREM2 expression in osteoblasts and thereby trabecular number and thickness as well as fracture risk.
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Body stature growth trajectories during childhood and the development of myopia.
Ophthalmology
PUBLISHED: 02-14-2013
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Stature at a particular age can be considered the cumulative result of growth during a number of preceding growth trajectory periods. We investigated whether height and weight growth trajectories from birth to age 10 years were related to refractive error at ages 11 and 15 years, and eye size at age 15 years.
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Coordinated genetic scaling of the human eye: shared determination of axial eye length and corneal curvature.
Invest. Ophthalmol. Vis. Sci.
PUBLISHED: 02-07-2013
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To examine the extent to which the two major determinants of refractive error, corneal curvature and axial length, are scaled relative to one another by shared genetic variants, along with their relationship to the genetic scaling of height.
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A genome-wide association study for corneal curvature identifies the platelet-derived growth factor receptor ? gene as a quantitative trait locus for eye size in white Europeans.
Mol. Vis.
PUBLISHED: 02-01-2013
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Corneal curvature is a key determinant of the refractive power of the eye. Variants in two genes, FKBP12-rapamycin complex-associated protein 1 (FRAP1) on chromosome 1p36.2 and platelet-derived growth factor receptor alpha (PDGFRA) on chromosome 4q12, have shown genome-wide significant association with normal variation in corneal curvature in a study of subjects of Asian origin. Variants at the PDGFRA locus have also shown genome-wide significant association with corneal astigmatism. Whether these variants influence other ocular parameters such as axial length has yet to be reported. We performed a genome-wide association study for corneal curvature in white European subjects from a population-based birth cohort, with the aim of replicating and extending the above findings.
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Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia.
Virginie J M Verhoeven, Pirro G Hysi, Robert Wojciechowski, Qiao Fan, Jeremy A Guggenheim, René Höhn, Stuart MacGregor, Alex W Hewitt, Abhishek Nag, Ching-Yu Cheng, Ekaterina Yonova-Doing, Xin Zhou, M Kamran Ikram, Gabriëlle H S Buitendijk, George McMahon, John P Kemp, Beate St Pourcain, Claire L Simpson, Kari-Matti Mäkelä, Terho Lehtimäki, Mika Kähönen, Andrew D Paterson, S Mohsen Hosseini, Hoi Suen Wong, Liang Xu, Jost B Jonas, Olavi Pärssinen, Juho Wedenoja, Shea Ping Yip, Daniel W H Ho, Chi Pui Pang, Li Jia Chen, Kathryn P Burdon, Jamie E Craig, Barbara E K Klein, Ronald Klein, Toomas Haller, Andres Metspalu, Chiea-Chuen Khor, E-Shyong Tai, Tin Aung, Eranga Vithana, Wan-Ting Tay, Veluchamy A Barathi, , Peng Chen, Ruoying Li, Jiemin Liao, Yingfeng Zheng, Rick T Ong, Angela Döring, David M Evans, Nicholas J Timpson, Annemieke J M H Verkerk, Thomas Meitinger, Olli Raitakari, Felicia Hawthorne, Tim D Spector, Lennart C Karssen, Mario Pirastu, Federico Murgia, Wei Ang, Aniket Mishra, Grant W Montgomery, Craig E Pennell, Phillippa M Cumberland, Ioana Cotlarciuc, Paul Mitchell, Jie Jin Wang, Maria Schache, Sarayut Janmahasatian, Sarayut Janmahasathian, Robert P Igo, Jonathan H Lass, Emily Chew, Sudha K Iyengar, Theo G M F Gorgels, Igor Rudan, Caroline Hayward, Alan F Wright, Ozren Polašek, Zoran Vatavuk, James F Wilson, Brian Fleck, Tanja Zeller, Alireza Mirshahi, Christian Müller, André G Uitterlinden, Fernando Rivadeneira, Johannes R Vingerling, Albert Hofman, Ben A Oostra, Najaf Amin, Arthur A B Bergen, Yik-Ying Teo, Jugnoo S Rahi, Veronique Vitart, Cathy Williams, Paul N Baird, Tien-Yin Wong, Konrad Oexle, Norbert Pfeiffer, David A Mackey, Terri L Young, Cornelia M van Duijn, Seang-Mei Saw, Joan E Bailey-Wilson, Dwight Stambolian, Caroline C Klaver, Christopher J Hammond.
Nat. Genet.
PUBLISHED: 01-16-2013
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Refractive error is the most common eye disorder worldwide and is a prominent cause of blindness. Myopia affects over 30% of Western populations and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses, including 37,382 individuals from 27 studies of European ancestry and 8,376 from 5 Asian cohorts. We identified 16 new loci for refractive error in individuals of European ancestry, of which 8 were shared with Asians. Combined analysis identified 8 additional associated loci. The new loci include candidate genes with functions in neurotransmission (GRIA4), ion transport (KCNQ5), retinoic acid metabolism (RDH5), extracellular matrix remodeling (LAMA2 and BMP2) and eye development (SIX6 and PRSS56). We also confirmed previously reported associations with GJD2 and RASGRF1. Risk score analysis using associated SNPs showed a tenfold increased risk of myopia for individuals carrying the highest genetic load. Our results, based on a large meta-analysis across independent multiancestry studies, considerably advance understanding of the mechanisms involved in refractive error and myopia.
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Disposition and metabolism of the specific endothelin A receptor antagonist zibotentan (ZD4054) in healthy volunteers.
Xenobiotica
PUBLISHED: 10-20-2011
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Zibotentan (ZD4054) is a specific endothelin A (ET(A)) receptor antagonist that is in clinical development for the treatment of castration-resistant prostate cancer (CRPC) and has shown a promising signal for improvement in overall survival compared with placebo in a Phase II study of patients with metastatic CRPC. In this study, the pharmacokinetics, disposition and metabolism of zibotentan were evaluated following administration of a single oral dose of [(14)C]-zibotentan 15 mg to six healthy subjects. Zibotentan was rapidly absorbed, with the maximum zibotentan plasma concentration being observed 1 hour after administration. Excretion was rapid with the majority of the dose being excreted in the urine (71-94%). Total recovery of radioactivity over the 5 days of the study was high (mean 93%), with 78% of the dose being recovered within 24 hours. Concentrations of radioactivity in the plasma were similar up to 12 hours post dose, and diverged thereafter, indicating the presence of circulating metabolites. The main circulating component was zibotentan with a number of metabolites being identified in excreta. Zibotentan was well absorbed and was cleared via metabolism and urinary excretion with zibotentan-related material predominantly excreted via the urine.
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Adult height variants affect birth length and growth rate in children.
Hum. Mol. Genet.
PUBLISHED: 07-14-2011
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Previous studies identified 180 single nucleotide polymorphisms (SNPs) associated with adult height, explaining ?10% of the variance. The age at which these begin to affect growth is unclear. We modelled the effect of these SNPs on birth length and childhood growth. A total of 7768 participants in the Avon Longitudinal Study of Parents and Children had data available. Individual growth trajectories from 0 to 10 years were estimated using mixed-effects linear spline models and differences in trajectories by individual SNPs and allelic score were determined. The allelic score was associated with birth length (0.026 cm increase per tall allele, SE = 0.003, P = 1 × 10(-15), equivalent to 0.017 SD). There was little evidence of association between the allelic score and early infancy growth (0-3 months), but there was evidence of association between the allelic score and later growth. This association became stronger with each consecutive growth period, per tall allele per month effects were 0.015 SD (3 months-1 year, SE = 0.004), 0.023 SD (1-3 years, SE = 0.003) and 0.028 SD (3-10 years, SE = 0.003). By age 10, the mean height difference between individuals with ?170 versus ?191 tall alleles (the top and bottom 10%) was 4.7 cm (0.8 SD), explaining ?5% of the variance. There was evidence of associations with specific growth periods for some SNPs (rs3791675, EFEMP1 and rs6569648, L3MBTL3) and supportive evidence for previously reported age-dependent effects of HHIP and SOCS2 SNPs. SNPs associated with adult height influence birth length and have an increasing effect on growth from late infancy through to late childhood. By age 10, they explain half the height variance (?5%) of that explained in adults (?10%).
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Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis.
Lavinia Paternoster, Marie Standl, Chih-Mei Chen, Adaikalavan Ramasamy, Klaus Bønnelykke, Liesbeth Duijts, Manuel A Ferreira, Alexessander Couto Alves, Jacob P Thyssen, Eva Albrecht, Hansjörg Baurecht, Bjarke Feenstra, Patrick M A Sleiman, Pirro Hysi, Nicole M Warrington, Ivan Curjuric, Ronny Myhre, John A Curtin, Maria M Groen-Blokhuis, Marjan Kerkhof, Annika Sääf, Andre Franke, David Ellinghaus, Regina Fölster-Holst, Emmanouil Dermitzakis, Stephen B Montgomery, Holger Prokisch, Katharina Heim, Anna-Liisa Hartikainen, Anneli Pouta, Juha Pekkanen, Alexandra I F Blakemore, Jessica L Buxton, Marika Kaakinen, David L Duffy, Pamela A Madden, Andrew C Heath, Grant W Montgomery, Philip J Thompson, Melanie C Matheson, Peter Le Souef, , Beate St Pourcain, George Davey Smith, John Henderson, John P Kemp, Nicholas J Timpson, Panos Deloukas, Susan M Ring, H-Erich Wichmann, Martina Müller-Nurasyid, Natalija Novak, Norman Klopp, Elke Rodríguez, Wendy McArdle, Allan Linneberg, Torkil Menné, Ellen A Nohr, Albert Hofman, André G Uitterlinden, Cornelia M van Duijn, Fernando Rivadeneira, Johan C de Jongste, Ralf J P van der Valk, Matthias Wjst, Rain Jõgi, Frank Geller, Heather A Boyd, Jeffrey C Murray, Cecilia Kim, Frank Mentch, Michael March, Massimo Mangino, Tim D Spector, Veronique Bataille, Craig E Pennell, Patrick G Holt, Peter Sly, Carla M T Tiesler, Elisabeth Thiering, Thomas Illig, Medea Imboden, Wenche Nystad, Angela Simpson, Jouke-Jan Hottenga, Dirkje Postma, Gerard H Koppelman, Henriëtte A Smit, Cilla Söderhäll, Bo Chawes, Eskil Kreiner-Møller, Hans Bisgaard, Erik Melén, Dorret I Boomsma, Adnan Custovic, Bo Jacobsson, Nicole M Probst-Hensch, Lyle J Palmer, Daniel Glass, Hakon Hakonarson, Mads Melbye, Deborah L Jarvis, Vincent W V Jaddoe, Christian Gieger, David P Strachan, Nicholas G Martin, Marjo-Riitta Järvelin, Joachim Heinrich, David M Evans, Stephan Weidinger.
Nat. Genet.
PUBLISHED: 07-08-2011
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Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 × 10(-13)) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 × 10(-9)), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 × 10(-8)). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis.
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Genome-wide population-based association study of extremely overweight young adults--the GOYA study.
PLoS ONE
PUBLISHED: 04-06-2011
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Thirty-two common variants associated with body mass index (BMI) have been identified in genome-wide association studies, explaining ?1.45% of BMI variation in general population cohorts. We performed a genome-wide association study in a sample of young adults enriched for extremely overweight individuals. We aimed to identify new loci associated with BMI and to ascertain whether using an extreme sampling design would identify the variants known to be associated with BMI in general populations.
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Pharmacokinetics and tolerability of zibotentan (ZD4054) in subjects with hepatic or renal impairment: two open-label comparative studies.
BMC Clin Pharmacol
PUBLISHED: 03-17-2011
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Zibotentan (ZD4054) is a specific endothelin A (ETA) receptor antagonist being investigated for the treatment of prostate cancer. As zibotentan is eliminated by renal and metabolic routes, clearance may be reduced in patients with hepatic or renal impairment, leading to greater drug exposure.
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Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk.
PLoS Genet.
PUBLISHED: 03-13-2011
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Osteoporotic fracture is a major cause of morbidity and mortality worldwide. Low bone mineral density (BMD) is a major predisposing factor to fracture and is known to be highly heritable. Site-, gender-, and age-specific genetic effects on BMD are thought to be significant, but have largely not been considered in the design of genome-wide association studies (GWAS) of BMD to date. We report here a GWAS using a novel study design focusing on women of a specific age (postmenopausal women, age 55-85 years), with either extreme high or low hip BMD (age- and gender-adjusted BMD z-scores of +1.5 to +4.0, n = 1055, or -4.0 to -1.5, n = 900), with replication in cohorts of women drawn from the general population (n = 20,898). The study replicates 21 of 26 known BMD-associated genes. Additionally, we report suggestive association of a further six new genetic associations in or around the genes CLCN7, GALNT3, IBSP, LTBP3, RSPO3, and SOX4, with replication in two independent datasets. A novel mouse model with a loss-of-function mutation in GALNT3 is also reported, which has high bone mass, supporting the involvement of this gene in BMD determination. In addition to identifying further genes associated with BMD, this study confirms the efficiency of extreme-truncate selection designs for quantitative trait association studies.
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Nuclear factors involved in mitochondrial translation cause a subgroup of combined respiratory chain deficiency.
Brain
PUBLISHED: 12-17-2010
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Mutations in several mitochondrial DNA and nuclear genes involved in mitochondrial protein synthesis have recently been reported in combined respiratory chain deficiency, indicating a generalized defect in mitochondrial translation. However, the number of patients with pathogenic mutations is small, implying that nuclear defects of mitochondrial translation are either underdiagnosed or intrauterine lethal. No comprehensive studies have been reported on large cohorts of patients with combined respiratory chain deficiency addressing the role of nuclear genes affecting mitochondrial protein synthesis to date. We investigated a cohort of 52 patients with combined respiratory chain deficiency without causative mitochondrial DNA mutations, rearrangements or depletion, to determine whether a defect in mitochondrial translation defines the pathomechanism of their clinical disease. We followed a combined approach of sequencing known nuclear genes involved in mitochondrial protein synthesis (EFG1, EFTu, EFTs, MRPS16, TRMU), as well as performing in vitro functional studies in 22 patient cell lines. The majority of our patients were children (<15 years), with an early onset of symptoms <1 year of age (65%). The most frequent clinical presentation was mitochondrial encephalomyopathy (63%); however, a number of patients showed cardiomyopathy (33%), isolated myopathy (15%) or hepatopathy (13%). Genomic sequencing revealed compound heterozygous mutations in the mitochondrial transfer ribonucleic acid modifying factor (TRMU) in a single patient only, presenting with early onset, reversible liver disease. No pathogenic mutation was detected in any of the remaining 51 patients in the other genes analysed. In vivo labelling of mitochondrial polypeptides in 22 patient cell lines showed overall (three patients) or selective (four patients) defects of mitochondrial translation. Immunoblotting for mitochondrial proteins revealed decreased steady state levels of proteins in some patients, but normal or increased levels in others, indicating a possible compensatory mechanism. In summary, candidate gene sequencing in this group of patients has a very low detection rate (1/52), although in vivo labelling of mitochondrial translation in 22 patient cell lines indicate that a nuclear defect affecting mitochondrial protein synthesis is responsible for about one-third of combined respiratory chain deficiencies (7/22). In the remaining patients, the impaired respiratory chain activity is most likely the consequence of several different events downstream of mitochondrial translation. Clinical classification of patients with biochemical analysis, genetic testing and, more importantly, in vivo labelling and immunoblotting of mitochondrial proteins show incoherent results, but a systematic review of these data in more patients may reveal underlying mechanisms, and facilitate the identification of novel factors involved in combined respiratory chain deficiency.
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Genome-wide association meta-analysis of cortical bone mineral density unravels allelic heterogeneity at the RANKL locus and potential pleiotropic effects on bone.
PLoS Genet.
PUBLISHED: 07-06-2010
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Previous genome-wide association (GWA) studies have identified SNPs associated with areal bone mineral density (aBMD). However, this measure is influenced by several different skeletal parameters, such as periosteal expansion, cortical bone mineral density (BMD(C)) cortical thickness, trabecular number, and trabecular thickness, which may be under distinct biological and genetic control. We have carried out a GWA and replication study of BMD(C), as measured by peripheral quantitative computed tomography (pQCT), a more homogenous and valid measure of actual volumetric bone density. After initial GWA meta-analysis of two cohorts (ALSPAC n?=?999, aged ?15 years and GOOD n?=?935, aged ?19 years), we attempted to replicate the BMD(C) associations that had p<1×10(-5) in an independent sample of ALSPAC children (n?=?2803) and in a cohort of elderly men (MrOS Sweden, n?=?1052). The rs1021188 SNP (near RANKL) was associated with BMD(C) in all cohorts (overall p?=?2×10(-14), n?=?5739). Each minor allele was associated with a decrease in BMD(C) of ?0.14SD. There was also evidence for an interaction between this variant and sex (p?=?0.01), with a stronger effect in males than females (at age 15, males -6.77mg/cm(3) per C allele, p?=?2×10(-6); females -2.79 mg/cm(3) per C allele, p?=?0.004). Furthermore, in a preliminary analysis, the rs1021188 minor C allele was associated with higher circulating levels of sRANKL (p<0.005). We show this variant to be independent from the previously aBMD associated SNP (rs9594738) and possibly from a third variant in the same RANKL region, which demonstrates important allelic heterogeneity at this locus. Associations with skeletal parameters reflecting bone dimensions were either not found or were much less pronounced. This finding implicates RANKL as a locus containing variation associated with volumetric bone density and provides further insight into the mechanism by which the RANK/RANKL/OPG pathway may be involved in skeletal development.
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An open-label, randomized, single-center, two-period, phase I, crossover study of the effect of zibotentan (ZD4054) on the pharmacokinetics of midazolam in healthy male volunteers.
Clin Ther
PUBLISHED: 06-15-2010
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Zibotentan (ZD4054) is an oral, specific endothelin A receptor antagonist presently under investigation for the treatment of hormone-resistant prostate cancer. Preclinical in vitro studies suggest that zibotentan has the potential to act as a time-dependent inhibitor of the cytochrome P450 isozyme 3A4 (CYP3A4) metabolic pathway. In clinical practice, it is likely that zibotentan will be coadministered with drugs metabolized by this pathway; the potential exists, therefore, that zibotentan-induced drug interactions could occur.
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Frequency, timing, and type of prodromal symptoms associated with hereditary angioedema attacks.
Allergy Asthma Proc
PUBLISHED: 10-22-2009
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Hereditary angioedema (HAE) types I and II are autosomal dominant conditions characterized by recurrent attacks of edema formation in the subcutaneous tissue of the body or walls of the upper respiratory or gastrointestinal tract. Frequently, prodromal symptoms occur before an HAE attack. If certain prodromal symptoms were determined to be both sensitive and specific in predicting an acute HAE attack, treatment at the time of the prodrome could prevent development of an attack and decrease morbidity and mortality associated with HAE. The goal is to determine the frequency and timing of prodromal symptoms occurring before HAE attacks. After Institutional Review Board approval, a four-page survey was produced, using a focus group of patients with HAE and was assessed by HAE patients and physicians with expertise in HAE for cognitive reliability. Once devised, the questionnaire was sent to 158 HAE patients. The survey focused on questions related to prodromal symptoms that patients developed before their last HAE attack. Forty-six patients returned the survey and 40 (87.0%) reported the presence of prodromal symptoms before their last HAE attack. Forty-four of 46 (95.7%) reported having had prodromal symptoms before HAE attacks in the past. The most commonly reported prodromal symptoms included unusual fatigue, rash, and muscle aches. Prodromes occur frequently before HAE attacks. This high frequency suggests that prodromal symptoms could be a reliable indication to begin treatment to prevent an acute HAE attack, thus decreasing the anxiety associated with having an HAE attack.
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Variability of prodromal signs and symptoms associated with hereditary angioedema attacks: a literature review.
Allergy Asthma Proc
PUBLISHED: 10-22-2009
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Hereditary angioedema (HAE) is a rare disease caused by deficiency in the production or function of C1 inhibitor. It predisposes individuals to paroxysmal acute attacks causing painful, debilitating, disfiguring, and life-threatening angioedema. Prodromes occurring hours to days before attacks have been described in the literature; however, their significance as predictive signals of impending attacks is uncertain. Given the morbidity and mortality associated with HAE attacks and the increasing availability of therapeutic products for their treatment, identifying prodromes that accurately predict the onset of attacks could provide the basis for the development of a validated instrument to identify the onset of such attacks requiring abortive therapeutic intervention before the development of clinically significant angioedema. The aim of this study was to review the literature to identify the prodromes reported to occur with HAE attacks. A literature review of English language journal articles was performed using search terms hereditary angioedema, HAE, angioneurotic edema, prodrome, signs, and symptoms. Nineteen original English language articles that included both case reports and studies describing prodromes associated with HAE attacks were obtained. Our review indicates that there is significant variability in the expression, manifestation, prevalence, timing, and predictive reliability of the prodromes that have been described. There is considerable variability of the prodromal manifestations that may occur before or during HAE attacks. We have not found any evidence that their sensitivity and specificity for accurately predicting such attacks has been studied.
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Fragment-based discovery of BACE1 inhibitors using functional assays.
Biochemistry
PUBLISHED: 10-06-2009
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Novel nonpeptidic inhibitors of beta-secretase (BACE1) have been discovered by employing a fragment-based biochemical screening approach. A diverse library of 20000 low-molecular weight compounds were screened and yielded 26 novel hits that were confirmed by biochemical and surface plasmon resonance secondary assays. We describe here fragment inhibitors cocrystallized with BACE1 in a flap open and flap closed conformation as determined by X-ray crystallography.
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Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy.
Brain
PUBLISHED: 08-31-2009
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Childhood-onset mitochondrial encephalomyopathies are usually severe, relentlessly progressive conditions that have a fatal outcome. However, a puzzling infantile disorder, long known as benign cytochrome c oxidase deficiency myopathy is an exception because it shows spontaneous recovery if infants survive the first months of life. Current investigations cannot distinguish those with a good prognosis from those with terminal disease, making it very difficult to decide when to continue intensive supportive care. Here we define the principal molecular basis of the disorder by identifying a maternally inherited, homoplasmic m.14674T>C mt-tRNA(Glu) mutation in 17 patients from 12 families. Our results provide functional evidence for the pathogenicity of the mutation and show that tissue-specific mechanisms downstream of tRNA(Glu) may explain the spontaneous recovery. This study provides the rationale for a simple genetic test to identify infants with mitochondrial myopathy and good prognosis.
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Enhancing transfusion safety with an innovative bar-code-based tracking system.
Healthc Q
PUBLISHED: 08-12-2009
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In an effort to reduce transfusion errors, a novel, comprehensive, computerized wireless bar-code-based tracking system for matching patients, blood samples and blood products was created and deployed at a major academic medical centre. With a grant from the Agency for Healthcare Research and Quality, software was developed to track scans at the times of sample collection, sample arrival in the blood bank, blood product dispensation from the blood bank and blood product administration. The system was deployed in February 2005. The system was well accepted from the outset, and the sample rejection rate due to clerical errors fell from 1.82 to 0.17%; incident reports fell by 83%. At the final blood administration step, the accumulated data as of November 2008 indicated that identification errors were being detected and prevented every 42.4 days and that the scan completion rate was stable at about 99%. Process analysis suggested that these were independent events and, thus, would be expected to coincide (and potentially produce a mis-transfusion) every 4,240 days (11.6 years) on average. We estimate that the system is 10 times safer than the manual system previously employed at our institution and may be 15-20 times safer than most systems employed in the United States.
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Genetic analysis of a novel Xylella fastidiosa subspecies found in the southwestern United States.
Appl. Environ. Microbiol.
PUBLISHED: 07-06-2009
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Xylella fastidiosa, the causal agent of several scorch diseases, is associated with leaf scorch symptoms in Chitalpa tashkentensis, a common ornamental landscape plant used throughout the southwestern United States. For a number of years, many chitalpa trees in southern New Mexico and Arizona exhibited leaf scorch symptoms, and the results from a regional survey show that chitalpa trees from New Mexico, Arizona, and California are frequently infected with X. fastidiosa. Phylogenetic analysis of multiple loci was used to compare the X. fastidiosa infecting chitalpa strains from New Mexico, Arizona, and trees imported into New Mexico nurseries with previously reported X. fastidiosa strains. Loci analyzed included the 16S ribosome, 16S-23S ribosomal intergenic spacer region, gyrase-B, simple sequence repeat sequences, X. fastidiosa-specific sequences, and the virulence-associated protein (VapD). This analysis indicates that the X. fastidiosa isolates associated with infected chitalpa trees in the Southwest are a highly related group that is distinct from the four previously defined taxons X. fastidiosa subsp. fastidiosa (piercei), X. fastidiosa subsp. multiplex, X. fastidiosa subsp. sandyi, and X. fastidiosa subsp. pauca. Therefore, the classification proposed for this new subspecies is X. fastidiosa subsp. tashke.
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Early-onset and robust amyloid pathology in a new homozygous mouse model of Alzheimers disease.
PLoS ONE
PUBLISHED: 04-22-2009
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Transgenic mice expressing mutated amyloid precursor protein (APP) and presenilin (PS)-1 or -2 have been successfully used to model cerebral beta-amyloidosis, one of the characteristic hallmarks of Alzheimers disease (AD) pathology. However, the use of many transgenic lines is limited by premature death, low breeding efficiencies and late onset and high inter-animal variability of the pathology, creating a need for improved animal models. Here we describe the detailed characterization of a new homozygous double-transgenic mouse line that addresses most of these issues.
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Seventy-five genetic loci influencing the human red blood cell.
Pim van der Harst, Weihua Zhang, Irene Mateo Leach, Augusto Rendon, Niek Verweij, Joban Sehmi, Dirk S Paul, Ulrich Elling, Hooman Allayee, Xinzhong Li, Aparna Radhakrishnan, Sian-Tsung Tan, Katrin Voss, Christian X Weichenberger, Cornelis A Albers, Abtehale Al-Hussani, Folkert W Asselbergs, Marina Ciullo, Fabrice Danjou, Christian Dina, Tonu Esko, David M Evans, Lude Franke, Martin Gögele, Jaana Hartiala, Micha Hersch, Hilma Holm, Jouke-Jan Hottenga, Stavroula Kanoni, Marcus E Kleber, Vasiliki Lagou, Claudia Langenberg, Lorna M Lopez, Leo-Pekka Lyytikäinen, Olle Melander, Federico Murgia, Ilja M Nolte, Paul F O'Reilly, Sandosh Padmanabhan, Afshin Parsa, Nicola Pirastu, Eleonora Porcu, Laura Portas, Inga Prokopenko, Janina S Ried, So-Youn Shin, Clara S Tang, Alexander Teumer, Michela Traglia, Sheila Ulivi, Harm-Jan Westra, Jian Yang, Jing Hua Zhao, Franco Anni, Abdel Abdellaoui, Antony Attwood, Beverley Balkau, Stefania Bandinelli, François Bastardot, Beben Benyamin, Bernhard O Boehm, William O Cookson, Debashish Das, Paul I W de Bakker, Rudolf A de Boer, Eco J C de Geus, Marleen H de Moor, Maria Dimitriou, Francisco S Domingues, Angela Döring, Gunnar Engström, Gudmundur Ingi Eyjolfsson, Luigi Ferrucci, Krista Fischer, Renzo Galanello, Stephen F Garner, Bernd Genser, Quince D Gibson, Giorgia Girotto, Daniel Fannar Gudbjartsson, Sarah E Harris, Anna-Liisa Hartikainen, Claire E Hastie, Bo Hedblad, Thomas Illig, Jennifer Jolley, Mika Kähönen, Ido P Kema, John P Kemp, Liming Liang, Heather Lloyd-Jones, Ruth J F Loos, Stuart Meacham, Sarah E Medland, Christa Meisinger, Yasin Memari, Evelin Mihailov, Kathy Miller, Miriam F Moffatt, Matthias Nauck, Maria Novatchkova, Teresa Nutile, Isleifur Olafsson, Pall T Onundarson, Debora Parracciani, Brenda W Penninx, Lucia Perseu, Antonio Piga, Giorgio Pistis, Anneli Pouta, Ursula Puc, Olli Raitakari, Susan M Ring, Antonietta Robino, Daniela Ruggiero, Aimo Ruokonen, Aude Saint-Pierre, Cinzia Sala, Andres Salumets, Jennifer Sambrook, Hein Schepers, Carsten Oliver Schmidt, Herman H W Sillje, Rob Sladek, Johannes H Smit, John M Starr, Jonathan Stephens, Patrick Sulem, Toshiko Tanaka, Unnur Thorsteinsdottir, Vinicius Tragante, Wiek H van Gilst, L Joost van Pelt, Dirk J van Veldhuisen, Uwe Völker, John B Whitfield, Gonneke Willemsen, Bernhard R Winkelmann, Gerald Wirnsberger, Ale Algra, Francesco Cucca, Adamo Pio D'adamo, John Danesh, Ian J Deary, Anna F Dominiczak, Paul Elliott, Paolo Fortina, Philippe Froguel, Paolo Gasparini, Andreas Greinacher, Stanley L Hazen, Marjo-Riitta Järvelin, Kay Tee Khaw, Terho Lehtimäki, Winfried Maerz, Nicholas G Martin, Andres Metspalu, Braxton D Mitchell, Grant W Montgomery, Carmel Moore, Gerjan Navis, Mario Pirastu, Peter P Pramstaller, Ramiro Ramirez-Solis, Eric Schadt, James Scott, Alan R Shuldiner, George Davey Smith, J Gustav Smith, Harold Snieder, Rossella Sorice, Tim D Spector, Kari Stefansson, Michael Stumvoll, W H Wilson Tang, Daniela Toniolo, Anke Tönjes, Peter M Visscher, Peter Vollenweider, Nicholas J Wareham, Bruce H R Wolffenbuttel, Dorret I Boomsma, Jacques S Beckmann, George V Dedoussis, Panos Deloukas, Manuel A Ferreira, Serena Sanna, Manuela Uda, Andrew A Hicks, Josef Martin Penninger, Christian Gieger, Jaspal S Kooner, Willem H Ouwehand, Nicole Soranzo, John C Chambers.
Nature
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Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P?
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New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.
Momoko Horikoshi, Hanieh Yaghootkar, Dennis O Mook-Kanamori, Ulla Sovio, H Rob Taal, Branwen J Hennig, Jonathan P Bradfield, Beate St Pourcain, David M Evans, Pimphen Charoen, Marika Kaakinen, Diana L Cousminer, Terho Lehtimäki, Eskil Kreiner-Møller, Nicole M Warrington, Mariona Bustamante, Bjarke Feenstra, Diane J Berry, Elisabeth Thiering, Thiemo Pfab, Sheila J Barton, Beverley M Shields, Marjan Kerkhof, Elisabeth M van Leeuwen, Anthony J Fulford, Zoltan Kutalik, Jing Hua Zhao, Marcel den Hoed, Anubha Mahajan, Virpi Lindi, Liang-Kee Goh, Jouke-Jan Hottenga, Ying Wu, Olli T Raitakari, Marie N Harder, Aline Meirhaeghe, Ioanna Ntalla, Rany M Salem, Karen A Jameson, Kaixin Zhou, Dorota M Monies, Vasiliki Lagou, Mirna Kirin, Jani Heikkinen, Linda S Adair, Fowzan S Alkuraya, Ali Al-Odaib, Philippe Amouyel, Ehm Astrid Andersson, Amanda J Bennett, Alexandra I F Blakemore, Jessica L Buxton, Jean Dallongeville, Shikta Das, Eco J C de Geus, Xavier Estivill, Claudia Flexeder, Philippe Froguel, Frank Geller, Keith M Godfrey, Frederic Gottrand, Christopher J Groves, Torben Hansen, Joel N Hirschhorn, Albert Hofman, Mads V Hollegaard, David M Hougaard, Elina Hyppönen, Hazel M Inskip, Aaron Isaacs, Torben Jørgensen, Christina Kanaka-Gantenbein, John P Kemp, Wieland Kiess, Tuomas O Kilpeläinen, Norman Klopp, Bridget A Knight, Christopher W Kuzawa, George McMahon, John P Newnham, Harri Niinikoski, Ben A Oostra, Louise Pedersen, Dirkje S Postma, Susan M Ring, Fernando Rivadeneira, Neil R Robertson, Sylvain Sebert, Olli Simell, Torsten Slowinski, Carla M T Tiesler, Anke Tönjes, Allan Vaag, Jorma S Viikari, Jacqueline M Vink, Nadja Hawwa Vissing, Nicholas J Wareham, Gonneke Willemsen, Daniel R Witte, Haitao Zhang, Jianhua Zhao, , James F Wilson, Michael Stumvoll, Andrew M Prentice, Brian F Meyer, Ewan R Pearson, Colin A G Boreham, Cyrus Cooper, Matthew W Gillman, George V Dedoussis, Luis A Moreno, Oluf Pedersen, Maiju Saarinen, Karen L Mohlke, Dorret I Boomsma, Seang-Mei Saw, Timo A Lakka, Antje Körner, Ruth J F Loos, Ken K Ong, Peter Vollenweider, Cornelia M van Duijn, Gerard H Koppelman, Andrew T Hattersley, John W Holloway, Berthold Hocher, Joachim Heinrich, Chris Power, Mads Melbye, Mònica Guxens, Craig E Pennell, Klaus Bønnelykke, Hans Bisgaard, Johan G Eriksson, Elisabeth Widén, Hakon Hakonarson, André G Uitterlinden, Anneli Pouta, Debbie A Lawlor, George Davey Smith, Timothy M Frayling, Mark I McCarthy, Struan F A Grant, Vincent W V Jaddoe, Marjo-Riitta Järvelin, Nicholas J Timpson, Inga Prokopenko, Rachel M Freathy.
Nat. Genet.
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Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.
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Examination of the relationship between variation at 17q21 and childhood wheeze phenotypes.
J. Allergy Clin. Immunol.
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Genome-wide association studies have identified associations of genetic variants at 17q21 near ORMDL3 with childhood asthma.
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Population pharmacokinetic/pharmacodynamic modelling of the anti-TNF-? polyclonal fragment antibody AZD9773 in patients with severe sepsis.
J Pharmacokinet Pharmacodyn
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AZD9773 is an ovine-derived, polyclonal, anti-tumour necrosis factor-alpha (TNF-?) antibody fragment. Using data from an AZD9773 Phase IIa study in patients with severe sepsis (clinicaltrials.gov: NCT00615017), a population pharmacokinetic/pharmacodynamic (PK/PD) model was developed. The model assessed the influence of various covariates on the PK of AZD9773 and the relationship between AZD9773 exposure and serological TNF-? concentration. A linear two-compartment model was used to describe AZD9773 concentration-time data. A stepwise covariate analysis was performed on the PK parameters. Subsequently, the serological TNF-? concentrations and drug effect were captured using an indirect response model, with a variable production rate of TNF-? described by a quadratic function. Creatinine clearance (CrCL) was the only covariate with a significant effect on the PK of AZD9773. A typical patients drug clearance varied with CrCL; the relationship was non-linear. Diagnostic analysis of the PK/PD model showed that the fit was good, both across cohorts and in AZD9773-treated versus placebo patients. Serological TNF-? concentrations and the reduction of measurable serum TNF-? by AZD9773 were well characterized across all the cohorts evaluated in the Phase IIa study. This population PK/PD model was subsequently used to simulate alternative dosing options for a Phase IIb study (clinicaltrials.gov: NCT01145560).
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WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk.
PLoS Genet.
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We aimed to identify genetic variants associated with cortical bone thickness (CBT) and bone mineral density (BMD) by performing two separate genome-wide association study (GWAS) meta-analyses for CBT in 3 cohorts comprising 5,878 European subjects and for BMD in 5 cohorts comprising 5,672 individuals. We then assessed selected single-nucleotide polymorphisms (SNPs) for osteoporotic fracture in 2,023 cases and 3,740 controls. Association with CBT and forearm BMD was tested for ?2.5 million SNPs in each cohort separately, and results were meta-analyzed using fixed effect meta-analysis. We identified a missense SNP (Thr>Ile; rs2707466) located in the WNT16 gene (7q31), associated with CBT (effect size of -0.11 standard deviations [SD] per C allele, P = 6.2 × 10(-9)). This SNP, as well as another nonsynonymous SNP rs2908004 (Gly>Arg), also had genome-wide significant association with forearm BMD (-0.14 SD per C allele, P = 2.3 × 10(-12), and -0.16 SD per G allele, P = 1.2 × 10(-15), respectively). Four genome-wide significant SNPs arising from BMD meta-analysis were tested for association with forearm fracture. SNP rs7776725 in FAM3C, a gene adjacent to WNT16, was associated with a genome-wide significant increased risk of forearm fracture (OR = 1.33, P = 7.3 × 10(-9)), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9 × 10(-6) and rs2707466: OR = 1.22, P = 7.2 × 10(-6)). We next generated a homozygous mouse with targeted disruption of Wnt16. Female Wnt16(-/-) mice had 27% (P<0.001) thinner cortical bones at the femur midshaft, and bone strength measures were reduced between 43%-61% (6.5 × 10(-13)
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Meta-analysis of genome-wide scans for total body BMD in children and adults reveals allelic heterogeneity and age-specific effects at the WNT16 locus.
PLoS Genet.
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To identify genetic loci influencing bone accrual, we performed a genome-wide association scan for total-body bone mineral density (TB-BMD) variation in 2,660 children of different ethnicities. We discovered variants in 7q31.31 associated with BMD measurements, with the lowest P = 4.1 × 10(-11) observed for rs917727 with minor allele frequency of 0.37. We sought replication for all SNPs located ± 500 kb from rs917727 in 11,052 additional individuals from five independent studies including children and adults, together with de novo genotyping of rs3801387 (in perfect linkage disequilibrium (LD) with rs917727) in 1,014 mothers of children from the discovery cohort. The top signal mapping in the surroundings of WNT16 was replicated across studies with a meta-analysis P = 2.6 × 10(-31) and an effect size explaining between 0.6%-1.8% of TB-BMD variance. Conditional analyses on this signal revealed a secondary signal for total body BMD (P = 1.42 × 10(-10)) for rs4609139 and mapping to C7orf58. We also examined the genomic region for association with skull BMD to test if the associations were independent of skeletal loading. We identified two signals influencing skull BMD variation, including rs917727 (P = 1.9 × 10(-16)) and rs7801723 (P = 8.9 × 10(-28)), also mapping to C7orf58 (r(2) = 0.50 with rs4609139). Wnt16 knockout (KO) mice with reduced total body BMD and gene expression profiles in human bone biopsies support a role of C7orf58 and WNT16 on the BMD phenotypes observed at the human population level. In summary, we detected two independent signals influencing total body and skull BMD variation in children and adults, thus demonstrating the presence of allelic heterogeneity at the WNT16 locus. One of the skull BMD signals mapping to C7orf58 is mostly driven by children, suggesting temporal determination on peak bone mass acquisition. Our life-course approach postulates that these genetic effects influencing peak bone mass accrual may impact the risk of osteoporosis later in life.
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Single- and multiple-dose pharmacokinetics, safety and tolerability of zibotentan (ZD4054) in Chinese men with advanced solid tumors.
Cancer Chemother. Pharmacol.
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The endothelin axis and the endothelin A (ET(A)) receptor have been implicated in tumor development and bone metastasis. This study aimed to investigate the pharmacokinetic (PK) and safety profiles of the specific ET(A) receptor antagonist, zibotentan, in elderly, male Chinese patients with advanced solid tumors. The PK data generated in these Chinese patients were further compared with those previously reported in Japanese and Caucasian patient populations.
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Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.
Karol Estrada, Unnur Styrkarsdottir, Evangelos Evangelou, Yi-Hsiang Hsu, Emma L Duncan, Evangelia E Ntzani, Ling Oei, Omar M E Albagha, Najaf Amin, John P Kemp, Daniel L Koller, Guo Li, Ching-Ti Liu, Ryan L Minster, Alireza Moayyeri, Liesbeth Vandenput, Dana Willner, Su-Mei Xiao, Laura M Yerges-Armstrong, Hou-Feng Zheng, Nerea Alonso, Joel Eriksson, Candace M Kammerer, Stephen K Kaptoge, Paul J Leo, Gudmar Thorleifsson, Scott G Wilson, James F Wilson, Ville Aalto, Markku Alen, Aaron K Aragaki, Thor Aspelund, Jacqueline R Center, Zoe Dailiana, David J Duggan, Melissa Garcia, Natalia Garcia-Giralt, Sylvie Giroux, Göran Hallmans, Lynne J Hocking, Lise Bjerre Husted, Karen A Jameson, Rita Khusainova, Ghi Su Kim, Charles Kooperberg, Theodora Koromila, Marcin Kruk, Marika Laaksonen, Andrea Z LaCroix, Seung Hun Lee, Ping C Leung, Joshua R Lewis, Laura Masi, Simona Mencej-Bedrač, Tuan V Nguyen, Xavier Noguès, Millan S Patel, Janez Prezelj, Lynda M Rose, Serena Scollen, Kristin Siggeirsdottir, Albert V Smith, Olle Svensson, Stella Trompet, Olivia Trummer, Natasja M van Schoor, Jean Woo, Kun Zhu, Susana Balcells, Maria Luisa Brandi, Brendan M Buckley, Sulin Cheng, Claus Christiansen, Cyrus Cooper, George Dedoussis, Ian Ford, Morten Frost, David Goltzman, Jesús González-Macías, Mika Kähönen, Magnus Karlsson, Elza Khusnutdinova, Jung-Min Koh, Panagoula Kollia, Bente Lomholt Langdahl, William D Leslie, Paul Lips, Osten Ljunggren, Roman S Lorenc, Janja Marc, Dan Mellström, Barbara Obermayer-Pietsch, José M Olmos, Ulrika Pettersson-Kymmer, David M Reid, José A Riancho, Paul M Ridker, François Rousseau, P Eline Slagboom, Nelson L S Tang, Roser Urreizti, Wim Van Hul, Jorma Viikari, María T Zarrabeitia, Yurii S Aulchenko, Martha Castano-Betancourt, Elin Grundberg, Lizbeth Herrera, Thorvaldur Ingvarsson, Hrefna Johannsdottir, Tony Kwan, Rui Li, Robert Luben, Carolina Medina-Gomez, Stefan Th Palsson, Sjur Reppe, Jerome I Rotter, Gunnar Sigurdsson, Joyce B J van Meurs, Dominique Verlaan, Frances M K Williams, Andrew R Wood, Yanhua Zhou, Kaare M Gautvik, Tomi Pastinen, Soumya Raychaudhuri, Jane A Cauley, Daniel I Chasman, Graeme R Clark, Steven R Cummings, Patrick Danoy, Elaine M Dennison, Richard Eastell, John A Eisman, Vilmundur Gudnason, Albert Hofman, Rebecca D Jackson, Graeme Jones, J Wouter Jukema, Kay-Tee Khaw, Terho Lehtimäki, Yongmei Liu, Mattias Lorentzon, Eugene McCloskey, Braxton D Mitchell, Kannabiran Nandakumar, Geoffrey C Nicholson, Ben A Oostra, Munro Peacock, Huibert A P Pols, Richard L Prince, Olli Raitakari, Ian R Reid, John Robbins, Philip N Sambrook, Pak Chung Sham, Alan R Shuldiner, Frances A Tylavsky, Cornelia M van Duijn, Nick J Wareham, L Adrienne Cupples, Michael J Econs, David M Evans, Tamara B Harris, Annie Wai Chee Kung, Bruce M Psaty, Jonathan Reeve, Timothy D Spector, Elizabeth A Streeten, M Carola Zillikens, Unnur Thorsteinsdottir, Claes Ohlsson, David Karasik, J Brent Richards, Matthew A Brown, Kari Stefansson, André G Uitterlinden, Stuart H Ralston, John P A Ioannidis, Douglas P Kiel, Fernando Rivadeneira.
Nat. Genet.
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Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
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Common variants at 12q15 and 12q24 are associated with infant head circumference.
H Rob Taal, Beate St Pourcain, Elisabeth Thiering, Shikta Das, Dennis O Mook-Kanamori, Nicole M Warrington, Marika Kaakinen, Eskil Kreiner-Møller, Jonathan P Bradfield, Rachel M Freathy, Frank Geller, Mònica Guxens, Diana L Cousminer, Marjan Kerkhof, Nicholas J Timpson, M Arfan Ikram, Lawrence J Beilin, Klaus Bønnelykke, Jessica L Buxton, Pimphen Charoen, Bo Lund Krogsgaard Chawes, Johan Eriksson, David M Evans, Albert Hofman, John P Kemp, Cecilia E Kim, Norman Klopp, Jari Lahti, Stephen J Lye, George McMahon, Frank D Mentch, Martina Müller-Nurasyid, Paul F O'Reilly, Inga Prokopenko, Fernando Rivadeneira, Eric A P Steegers, Jordi Sunyer, Carla Tiesler, Hanieh Yaghootkar, , Monique M B Breteler, Charles DeCarli, Stéphanie Debette, Myriam Fornage, Vilmundur Gudnason, Lenore J Launer, Aad van der Lugt, Thomas H Mosley, Sudha Seshadri, Albert V Smith, Meike W Vernooij, Alexandra I F Blakemore, Rosetta M Chiavacci, Bjarke Feenstra, Julio Fernandez-Banet, Struan F A Grant, Anna-Liisa Hartikainen, Albert J van der Heijden, Carmen Iñíguez, Mark Lathrop, Wendy L McArdle, Anne Mølgaard, John P Newnham, Lyle J Palmer, Aarno Palotie, Annneli Pouta, Susan M Ring, Ulla Sovio, Marie Standl, André G Uitterlinden, H-Erich Wichmann, Nadja Hawwa Vissing, Cornelia M van Duijn, Mark I McCarthy, Gerard H Koppelman, Xavier Estivill, Andrew T Hattersley, Mads Melbye, Hans Bisgaard, Craig E Pennell, Elisabeth Widén, Hakon Hakonarson, George Davey Smith, Joachim Heinrich, Marjo-Riitta Järvelin, Vincent W V Jaddoe.
Nat. Genet.
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To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 × 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 × 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height, their effects on infant head circumference were largely independent of height (P = 3.8 × 10(-7) for rs7980687 and P = 1.3 × 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 × 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume, Parkinsons disease and other neurodegenerative diseases, indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.
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A genome-wide association meta-analysis identifies new childhood obesity loci.
Nat. Genet.
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Multiple genetic variants have been associated with adult obesity and a few with severe obesity in childhood; however, less progress has been made in establishing genetic influences on common early-onset obesity. We performed a North American, Australian and European collaborative meta-analysis of 14 studies consisting of 5,530 cases (?95th percentile of body mass index (BMI)) and 8,318 controls (<50th percentile of BMI) of European ancestry. Taking forward the eight newly discovered signals yielding association with P < 5 × 10(-6) in nine independent data sets (2,818 cases and 4,083 controls), we observed two loci that yielded genome-wide significant combined P values near OLFM4 at 13q14 (rs9568856; P = 1.82 × 10(-9); odds ratio (OR) = 1.22) and within HOXB5 at 17q21 (rs9299; P = 3.54 × 10(-9); OR = 1.14). Both loci continued to show association when two extreme childhood obesity cohorts were included (2,214 cases and 2,674 controls). These two loci also yielded directionally consistent associations in a previous meta-analysis of adult BMI(1).
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Genome-wide association study of three-dimensional facial morphology identifies a variant in PAX3 associated with nasion position.
Am. J. Hum. Genet.
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Craniofacial morphology is highly heritable, but little is known about which genetic variants influence normal facial variation in the general population. We aimed to identify genetic variants associated with normal facial variation in a population-based cohort of 15-year-olds from the Avon Longitudinal Study of Parents and Children. 3D high-resolution images were obtained with two laser scanners, these were merged and aligned, and 22 landmarks were identified and their x, y, and z coordinates used to generate 54 3D distances reflecting facial features. 14 principal components (PCs) were also generated from the landmark locations. We carried out genome-wide association analyses of these distances and PCs in 2,185 adolescents and attempted to replicate any significant associations in a further 1,622 participants. In the discovery analysis no associations were observed with the PCs, but we identified four associations with the distances, and one of these, the association between rs7559271 in PAX3 and the nasion to midendocanthion distance (n-men), was replicated (p = 4 × 10(-7)). In a combined analysis, each G allele of rs7559271 was associated with an increase in n-men distance of 0.39 mm (p = 4 × 10(-16)), explaining 1.3% of the variance. Independent associations were observed in both the z (nasion prominence) and y (nasion height) dimensions (p = 9 × 10(-9) and p = 9 × 10(-10), respectively), suggesting that the locus primarily influences growth in the yz plane. Rare variants in PAX3 are known to cause Waardenburg syndrome, which involves deafness, pigmentary abnormalities, and facial characteristics including a broad nasal bridge. Our findings show that common variants within this gene also influence normal craniofacial development.
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Does bone resorption stimulate periosteal expansion? A cross sectional analysis of ?-C-telopeptides of type I collagen (CTX), genetic markers of the RANKL pathway, and periosteal circumference as measured by pQCT.
J. Bone Miner. Res.
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We hypothesised that bone resorption acts to increase bone strength through stimulation of periosteal expansion. Hence, we examined whether bone resorption, as reflected by serum ?-C-telopeptides of type I collagen (CTX), is positively associated with periosteal circumference (PC), in contrast to inverse associations with parameters related to bone remodelling such as cortical bone mineral density (BMDC ). CTX and mid-tibial pQCT scans were available in 1130 adolescents (mean age 15.5 years) from the Avon Longitudinal Study of Parents and Children (ALSPAC). Analyses were adjusted for age, gender, time of sampling, tanner stage, lean mass, fat mass and height. CTX was positively related to PC [?= 0.19 (0.13, 0.24)] (coefficient?=?SD change per SD increase in CTX, 95% CI)], but inversely associated with BMDC [?= -0.46 (-0.52,-0.40)] and cortical thickness [?= -0.11 (-0.18, -0.03)]. CTX was positively related to bone strength as reflected by the strength-strain index (SSI) [?= 0.09 (0.03, 0.14)]. To examine the causal nature of this relationship, we then analysed whether SNPs within key osteoclast regulatory genes, known to reduce areal/cortical BMD, conversely increase PC. Fifteen such genetic variants within or proximal to genes encoding RANK, RANKL and OPG were identified by literature search. Six of the 15 alleles that were inversely related to BMD were positively related to CTX (P?
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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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