-
Diana L Cousminer,
Diane J Berry,
Nicholas J Timpson,
Wei Ang,
Elisabeth Thiering,
Enda Byrne,
H Rob Taal,
Ville Huikari,
Jonathan P Bradfield,
Marjan Kerkhof, [......],
Joachim Heinrich,
Craig E Pennell,
Olli Raitakari,
Johan G Eriksson,
George Davey Smith,
Elina Hyppönen,
Marjo-Riitta Järvelin,
Mark I McCarthy,
Samuli Ripatti,
Elisabeth Widén
[show abstract]
[hide abstract]
ABSTRACT: The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. While 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 place them in context of overall growth and maturation, we performed genome-wide association (GWA) meta-analyses in up to 18,737 European samples utilizing longitudinally collected height measurements. We found significant associations (P<1.67 x 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 BMI, reduced pubertal growth, and earlier puberty.While 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.
Human Molecular Genetics 02/2013; · 7.64 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Objective: We aimed to determine if previously identified adult obesity susceptibility loci were associated uniformly with childhood BMI across the BMI distribution. Design and Methods: Children were recruited through the Children's Hospital of Philadelphia (n=7225). Associations between the following loci and BMI were assessed using quantile regression: FTO (rs3751812), MC4R (rs12970134), TMEM18 (rs2867125), BDNF (rs6265), TNNI3K (rs1514175), NRXN3 (rs10146997), SEC16B (rs10913469), and GNPDA2 (rs13130484). BMI z-score (age and gender adjusted) was modeled as the dependent variable, and genotype risk score (sum of risk alleles carried at the 8 loci) was modeled as the independent variable. Results: Each additional increase in genotype risk score was associated with an increase in BMI z-score at the 5th, 15th, 25th, 50th, 75th, 85th and 95th BMI z-score percentiles by 0.04 (±0.02, p=0.08), 0.07 (±0.01, p=9.58 x 10-7), 0.07 (±0.01, p=1.10 x 10-8), 0.09 (±0.01, p=3.13 x 10-22), 0.11 (±0.01, p=1.35 x 10-25), 0.11 (±0.01, p=1.98 x 10-20), and 0.06 (±0.01, p=2.44 x 10-6), respectively. Each additional increase in genotype risk score was associated with an increase in mean BMI z-score by 0.08 (±0.01, p=4.27 x 10-20). Conclusion: Obesity risk alleles were more strongly associated with increases in BMI z-score at the upper tail compared to the lower tail of the distribution.
Obesity 02/2013; · 4.28 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: It has long been known that there is a genetic component to obesity, and that characterizing this underlying factor would likely offer the possibility of better intervention in the future. Monogenic obesity has proved to be relatively straightforward, with a combination of linkage analysis and mouse models facilitating the identification of multiple genes. In contrast, genome-wide association studies have successfully revealed a variety of genetic loci associated with the more common form of obesity, allowing for very strong consensus on the underlying genetic architecture of the phenotype for the first time. Although a number of significant findings have been made, it appears that very little of the apparent heritability of body mass index has actually been explained to date. New approaches for data analyses and advances in technology will be required to uncover the elusive missing heritability, and to aid in the identification of the key causative genetic underpinnings of obesity.
Annals of the New York Academy of Sciences 01/2013; · 3.15 Impact Factor
-
Joseph T. Glessner,
Kai Wang,
Guiqing Cai,
Olena Korvatska,
Cecilia E. Kim,
Shawn Wood,
Haitao Zhang,
Annette Estes,
Camille W. Brune,
Jonathan P. Bradfield, [......],
Hilary Coon,
James S. Sutcliffe,
Nancy J. Minshew, Struan F. A. Grant,
Maja Bucan,
Edwin H. Cook,
Joseph D. Buxbaum,
Bernie Devlin,
Gerard D. Schellenberg,
Hakon Hakonarson
-
[show abstract]
[hide abstract]
ABSTRACT: OBJECTIVE: To identify plasma uric acid-related genes in extremely obese and normal weight individuals using genome-wide association studies (GWASs). DESIGN AND METHODS: Using genotypes from a GWAS focusing on obesity and thinness, quantitative trait association analyses (PLINK) for plasma uric acid levels in 1,060 extremely obese individuals (BMI > 35 kg/m(2) ) and normal-weight controls (BMI < 25kg/m(2) ) were performed. In 961 samples with uric acid data, 924 were females. RESULTS: Significant associations were found in SLC2A9 gene SNPs and plasma uric acid levels (rs6449213, P = 3.15 × 10(-12) ). DIP2C gene SNP rs877282 also reached genome-wide significance (P = 4.56 × 10(-8) ). Weaker associations (P < 1× 10(-5) ) were found in F5, PXDNL, FRAS1, LCORL, and MICAL2 genes. Besides SLC2A9, three previously identified uric acid-related genes ABCG2 (rs2622605, P= 0.0026), SLC17A1 (rs3799344, P = 0.0017), and RREB1 (rs1615495, P = 0.00055) received marginal support in our study. CONCLUSIONS: Two genes/chromosome regions reached genome-wide association significance (P < 1 × 10(-7) , 550K SNPs) in our GWAS: SLC2A9, the chromosome 2 60.1 Mb region (rs6723995), and the DIP2C gene region. Five other genes (F5, PXDNL, FRAS1, LCORL, and MICAL2) yielded P < 1 × 10(-5) . Four previous reported associations were replicated in our study, including SLC2A9, ABCG2, RREB, and SLC17A1.
Obesity 01/2013; · 4.28 Impact Factor
-
Sandra Deliard,
Saarene Panossian,
Frank D Mentch,
Cecilia E Kim,
Cuiping Hou,
Edward C Frackelton,
Jonathan P Bradfield,
Joseph T Glessner,
Haitao Zhang,
Kai Wang,
Patrick M A Sleiman,
Rosetta M Chiavacci,
Robert I Berkowitz,
Hakon Hakonarson,
Jianhua Zhao, Struan F A Grant
[show abstract]
[hide abstract]
ABSTRACT: Common variation at the loci harboring fat mass and obesity (FTO), melanocortin receptor 4 (MC4R), and transmembrane protein 18 (TMEM18) is consistently reported as being statistically most strongly associated with obesity. Investigations if these loci also harbor rarer missense variants that confer substantially higher risk of common childhood obesity in African American (AA) children were conducted.
The exons of FTO, MC4R, and TMEM18 in an initial subset of our cohort were sequenced, that is, 200 obese (BMI≥95th percentile) and 200 lean AA children (BMI≤5th percentile). Any missense exonic variants that were uncovered went on to be further genotyped in a further 768 obese and 768 lean (BMI≤50th percentile) children of the same ethnicity.
A number of exonic variants were observed from our sequencing effort: seven in FTO, of which four were non-synonymous (A163T, G182A, M400V, and A405V), thirteen in MC4R, of which six were non-synonymous (V103I, N123S, S136A, F202L, N240S, and I251L), and four in TMEM18, of which two were non-synonymous (P2S and V113L). Follow-up genotyping of these missense variants revealed only one significant difference in allele frequency between cases and controls, namely with N240S in MC4R (Fisher's exact P = 0.0001).
In summary, moderately rare missense variants within the FTO, MC4R, and TMEM18 genes observed in our study did not confer risk of common childhood obesity in African Americans except for a degree of evidence for one known loss-of-function variant in MC4R.
Obesity 01/2013; 21(1):159-63. · 4.28 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: ChIP-sequencing (ChIP-seq) methods directly offer whole-genome coverage, where combining chromatin immunoprecipitation (ChIP) and massively parallel sequencing can be utilized to identify the repertoire of mammalian DNA sequences bound by transcription factors in vivo. "Next-generation" genome sequencing technologies provide 1-2 orders of magnitude increase in the amount of sequence that can be cost-effectively generated over older technologies thus allowing for ChIP-seq methods to directly provide whole-genome coverage for effective profiling of mammalian protein-DNA interactions. For successful ChIP-seq approaches, one must generate high quality ChIP DNA template to obtain the best sequencing outcomes. The description is based around experience with the protein product of the gene most strongly implicated in the pathogenesis of type 2 diabetes, namely the transcription factor transcription factor 7-like 2 (TCF7L2). This factor has also been implicated in various cancers. Outlined is how to generate high quality ChIP DNA template derived from the colorectal carcinoma cell line, HCT116, in order to build a high-resolution map through sequencing to determine the genes bound by TCF7L2, giving further insight in to its key role in the pathogenesis of complex traits.
Journal of Visualized Experiments 01/2013;
-
Joseph T Glessner,
Albert Vernon Smith,
Saarene Panossian,
Cecilia E Kim,
Nagahide Takahashi,
Kelly A Thomas,
Fengxiang Wang,
Kallyn Seidler,
Tamara B Harris,
Lenore J Launer,
Brendan Keating,
John Connolly,
Patrick M A Sleiman,
Joseph D Buxbaum, Struan F A Grant,
Vilmundur Gudnason,
Hakon Hakonarson
[show abstract]
[hide abstract]
ABSTRACT: Longevity has a strong genetic component evidenced by family-based studies. Lipoprotein metabolism, FOXO proteins, and insulin/IGF-1 signaling pathways in model systems have shown polygenic variations predisposing to shorter lifespan. To test the hypothesis that rare variants could influence lifespan, we compared the rates of CNVs in healthy children (0-18 years of age) with individuals 67 years or older. CNVs at a significantly higher frequency in the pediatric cohort were considered risk variants impacting lifespan, while those enriched in the geriatric cohort were considered longevity protective variants. We performed a whole-genome CNV analysis on 7,313 children and 2,701 adults of European ancestry genotyped with 302,108 SNP probes. Positive findings were evaluated in an independent cohort of 2,079 pediatric and 4,692 geriatric subjects. We detected 8 deletions and 10 duplications that were enriched in the pediatric group (P = 3.33×10(-8)-1.6×10(-2) unadjusted), while only one duplication was enriched in the geriatric cohort (P = 6.3×10(-4)). Population stratification correction resulted in 5 deletions and 3 duplications remaining significant (P = 5.16×10(-5)-4.26×10(-2)) in the replication cohort. Three deletions and four duplications were significant combined (combined P = 3.7×10(-4)-3.9×10(-2)). All associated loci were experimentally validated using qPCR. Evaluation of these genes for pathway enrichment demonstrated ∼50% are involved in alternative splicing (P = 0.0077 Benjamini and Hochberg corrected). We conclude that genetic variations disrupting RNA splicing could have long-term biological effects impacting lifespan.
PLoS ONE 01/2013; 8(1):e53846. · 4.09 Impact Factor
-
Jin Li,
Joseph T Glessner,
Haitao Zhang,
Cuiping Hou,
Zhi Wei,
Jonathan P Bradfield,
Frank D Mentch,
Yiran Guo,
Cecilia Kim,
Qianghua Xia,
Rosetta M Chiavacci,
Kelly A Thomas,
Haijun Qiu, Struan F A Grant,
Susan L Furth,
Hakon Hakonarson,
Patrick M A Sleiman
[show abstract]
[hide abstract]
ABSTRACT: Hematological traits are important clinical indicators, the genetic determinants of which have not been fully investigated. Common measures of hematological traits include red blood cell count (RBC), hemoglobin concentration (HGB), hematocrit (HCT), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV) and platelet count (PLT) and white blood cell count (WBC). We carried out a GWA study of the eight common hematological traits among 7,943 African American children and 6,234 Caucasian children. In African Americans, we report five novel associations of HBE1 variants with HCT and MCHC, the alpha globin gene cluster variants with RBC and MCHC, and a variant at the ARHGEF3 locus with PLT, as well as replication of four previously reported loci at genome wide significance. In Caucasians, we report a novel association of variants at the COPZ1 locus with PLT as well as replication of four previously reported loci at genome-wide significance. Extended analysis of an association observed between MCH and the alpha globin gene cluster variants demonstrated independent effects and epistatic interaction at the locus, impacting the risk of iron deficiency anemia in African Americans with specific genotype states. In summary, we extend understanding of genetic variants underlying hematological traits based on analyses in African American children.
Human Molecular Genetics 12/2012; · 7.64 Impact Factor
-
Mario Capasso,
Marcella Devoto,
Cuiping Hou,
Shahab Asgharzadeh,
Joseph T Glessner,
Edward F Attiyeh,
Yael P Mosse,
Cecilia Kim,
Sharon J Diskin,
Kristina A Cole, [......],
Maria Garris,
Carmel McConville,
Wendy B London,
Robert C Seeger, Struan F A Grant,
Hongzhe Li,
Nazneen Rahman,
Eric Rappaport,
Hakon Hakonarson,
John M Maris
-
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, [......],
Debbie A Lawlor,
George Davey Smith,
Timothy M Frayling,
Mark I McCarthy, Struan F A Grant,
Vincent W V Jaddoe,
Marjo-Riitta Jarvelin,
Nicholas J Timpson,
Inga Prokopenko,
Rachel M Freathy
[show abstract]
[hide abstract]
ABSTRACT: 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.
Nature Genetics 12/2012; · 35.53 Impact Factor
-
Maggie C Y Ng,
Richa Saxena,
Jiang Li,
Nicholette D Palmer,
Latchezar Dimitrov,
Jianzhao Xu,
Laura J Rasmussen-Torvik,
Joseph M Zmuda,
David S Siscovick,
Sanjay R Patel, [......], Struan F A Grant,
Josée Dupuis,
James B Meigs,
Bruce M Psaty,
James S Pankow,
Carl D Langefeld,
Barry I Freedman,
Jerome I Rotter,
James G Wilson,
Donald W Bowden
[show abstract]
[hide abstract]
ABSTRACT: Type 2 diabetes (T2D) disproportionally affects African Americans (AfA) but, to date, genetic variants identified from genome-wide association studies (GWAS) are primarily from European and Asian populations. We examined the single nucleotide polymorphism (SNP) and locus transferability of 40 reported T2D loci in six AfA GWAS consisting of 2,806 T2D case subjects with or without end-stage renal disease and 4,265 control subjects from the Candidate Gene Association Resource Plus Study. Our results revealed that seven index SNPs at the TCF7L2, KLF14, KCNQ1, ADCY5, CDKAL1, JAZF1, and GCKR loci were significantly associated with T2D (P < 0.05). The strongest association was observed at TCF7L2 rs7903146 (odds ratio [OR] 1.30; P = 6.86 × 10(-8)). Locus-wide analysis demonstrated significant associations (P(emp) < 0.05) at regional best SNPs in the TCF7L2, KLF14, and HMGA2 loci as well as suggestive signals in KCNQ1 after correction for the effective number of SNPs at each locus. Of these loci, the regional best SNPs were in differential linkage disequilibrium (LD) with the index and adjacent SNPs. Our findings suggest that some loci discovered in prior reports affect T2D susceptibility in AfA with similar effect sizes. The reduced and differential LD pattern in AfA compared with European and Asian populations may facilitate fine mapping of causal variants at loci shared across populations.
Diabetes 11/2012; · 8.29 Impact Factor
-
M Arfan Ikram,
Myriam Fornage,
Albert V Smith,
Sudha Seshadri,
Reinhold Schmidt,
Stéphanie Debette,
Henri A Vrooman,
Sigurdur Sigurdsson,
Stefan Ropele,
H Rob Taal, [......],
Vincent W V Jaddoe,
Vilmundur Gudnason,
B Gwen Windham,
Philip A Wolf,
Cornelia M van Duijn,
Thomas H Mosley,
Helena Schmidt,
Lenore J Launer,
Monique M B Breteler,
Charles DeCarli
[show abstract]
[hide abstract]
ABSTRACT: During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 × 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 × 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 × 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 × 10(-3) for 6q22 and 1.2 × 10(-3) for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.
Nature Genetics 04/2012; 44(5):539-44. · 35.53 Impact Factor
-
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, [......],
Andrew T Hattersley,
Mads Melbye,
Hans Bisgaard,
Craig E Pennell,
Elisabeth Widen,
Hakon Hakonarson,
George Davey Smith,
Joachim Heinrich,
Marjo-Riitta Jarvelin,
Vincent W V Jaddoe
[show abstract]
[hide abstract]
ABSTRACT: 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, Parkinson's 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.
Nature Genetics 04/2012; 44(5):532-8. · 35.53 Impact Factor
-
H Rob Taal,
Beate St Pourcain,
Elisabeth Thiering,
Shikta Das,
Dennis O Mook-Kanamori,
Nicole M Warrington,
Marika Kaakinen,
Eskil,
Jonathan P Bradfield,
Rachel M Freathy, [......],
Mads Melbye,
Hans Bisgaard,
Craig E Pennell,
Elisabeth Widen,
Hakon Hakonarson,
George Davey Smith,
Joachim Heinrich,
Marjo-Riitta Jarvelin,
Vincent W V Jaddoe,
Early Growth Genetics (EGG) Consortium
Nature Genetics 04/2012; 44(5):532-538. · 35.53 Impact Factor
-
Jonathan P Bradfield,
H Rob Taal,
Nicholas J Timpson,
André Scherag,
Cecile Lecoeur,
Nicole M Warrington,
Elina Hypponen,
Claus Holst,
Beatriz Valcarcel,
Elisabeth Thiering, [......],
I Sadaf Farooqi,
Mark I McCarthy,
Philippe Froguel,
David Meyre,
Johannes Hebebrand,
Marjo-Riitta Jarvelin,
Vincent W V Jaddoe,
George Davey Smith,
Hakon Hakonarson, Struan F A Grant
[show abstract]
[hide abstract]
ABSTRACT: 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).
Nature Genetics 04/2012; 44(5):526-31. · 35.53 Impact Factor
-
Richa Saxena,
Clara C Elbers,
Yiran Guo,
Inga Peter,
Tom R Gaunt,
Jessica L Mega,
Matthew B Lanktree,
Archana Tare,
Berta Almoguera Castillo,
Yun R Li, [......],
Paul I W de Bakker,
Jeanne McCaffery,
Cisca Wijmenga,
Marc S Sabatine,
James G Wilson,
Alex Reiner,
Donald W Bowden,
Hakon Hakonarson,
David S Siscovick,
Brendan J Keating
[show abstract]
[hide abstract]
ABSTRACT: To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with ∼2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 × 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p < 2.4 × 10(-6)). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 × 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 × 10(-15)). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 × 10(-8)). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups.
The American Journal of Human Genetics 02/2012; 90(3):410-25. · 10.60 Impact Factor
-
PLoS ONE 01/2012; 7(2). · 4.09 Impact Factor
-
M Arfan Ikram,
Myriam Fornage,
Albert V Smith,
Sudha Seshadri,
Reinhold Schmidt,
Stéphanie Debette,
Henri A Vrooman,
Sigurdur Sigurdsson,
Stefan Ropele,
H Rob Taal, [......],
Vincent W V Jaddoe,
Vilmundur Gudnason,
B Gwen Windham,
Philip A Wolf,
Cornelia M van Duijn,
Thomas H Mosley,
Helena Schmidt,
Lenore J Launer,
Monique M B Breteler,
Charles Decarli
Nature Genetics 01/2012; 44(6):732. · 35.53 Impact Factor
-
Josephine Elia,
Joseph T Glessner,
Kai Wang,
Nagahide Takahashi,
Corina J Shtir,
Dexter Hadley,
Patrick M A Sleiman,
Haitao Zhang,
Cecilia E Kim,
Reid Robison, [......],
Philip Shaw,
Marcella Devoto,
Peter S White, Struan F A Grant,
Joseph D Buxbaum,
Judith L Rapoport,
Nigel M Williams,
Stanley F Nelson,
Stephen V Faraone,
Hakon Hakonarson
[show abstract]
[hide abstract]
ABSTRACT: Attention deficit hyperactivity disorder (ADHD) is a common, heritable neuropsychiatric disorder of unknown etiology. We performed a whole-genome copy number variation (CNV) study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs. We evaluated statistically significant findings in multiple independent cohorts, with a total of 2,493 cases with ADHD and 9,222 controls of European ancestry, using matched platforms. CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10(-9)). We saw GRM5 (encoding glutamate receptor, metabotropic 5) deletions in ten cases and one control (P = 1.36 × 10(-6)). We saw GRM7 deletions in six cases, and we saw GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. We experimentally validated the observed variants using quantitative RT-PCR. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in ∼10% of the cases (P = 4.38 × 10(-10)) after correction for occurrence in the controls. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts.
Nature Genetics 12/2011; 44(1):78-84. · 35.53 Impact Factor
