-
Sonja I Berndt,
Stefan Gustafsson,
Reedik Magi,
Andrea Ganna,
Eleanor Wheeler,
Mary F Feitosa,
Anne E Justice, Keri L Monda,
Damien C Croteau-Chonka,
Felix R Day, [......],
Joel N Hirschhorn,
Cecilia M Lindgren,
Andrew P Morris,
David Meyre,
Andre Scherag,
Mark I McCarthy,
Elizabeth K Speliotes,
Kari E North,
Ruth J F Loos,
Erik Ingelsson
[show abstract]
[hide abstract]
ABSTRACT: Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
Nature Genetics 04/2013; · 35.53 Impact Factor
-
Sonja I Berndt,
Stefan Gustafsson,
Reedik Mägi,
Andrea Ganna,
Eleanor Wheeler,
Mary F Feitosa,
Anne E Justice, Keri L Monda,
Damien C Croteau-Chonka,
Felix R Day, [......],
Joel N Hirschhorn,
Cecilia M Lindgren,
Andrew P Morris,
David Meyre,
André Scherag,
Mark I McCarthy,
Elizabeth K Speliotes,
Kari E North,
Ruth J F Loos,
Erik Ingelsson
[show abstract]
[hide abstract]
ABSTRACT: Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
Nature Genetics 04/2013; · 35.53 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: There is recent interest in characterizing the subset of obese (OB) individuals who have healthy metabolic profiles yet only two studies have examined this group prospectively but not in racially diverse populations.
We analyzed factors associated with the prevalence and incidence of metabolic syndrome (MetSyn) among individuals grouped by BMI categories in a multi-center, community-based cohort of 14,663 African-American and white men and women aged 45-64 years at recruitment in 1987-1989, the Atherosclerosis Risk in Communities (ARIC) Study. Logistic and proportional hazards regression were utilized to estimate odds ratios (ORs) for the prevalence and hazard ratios (HRs) for incidence of MetSyn with 95% confidence intervals (CIs).
At visit 1, MetSyn was positively associated with age, female gender, African-American race, and inversely related to education, associations being more pronounced among normal weight (NW) subjects. Among those without MetSyn at visit 1, OB subjects were more likely to develop MetSyn compared with NW (HR (95% CI): 4.53 (4.09-5.01)). Several factors were associated with incident MetSyn among NW, including older age (per year: 1.05 (1.03-1.06)), female gender (vs. male: 1.29 (1.10-1.52)), heavy alcohol intake (vs. never: 0.75 (0.59-0.94)), and physical activity (tertile 3 vs. tertile 1: 0.71 (0.58-0.86)) but not OB. Weight gain (>5%) was also more highly associated with MetSyn in NW (1.61 (1.28-2.02)) compared with OB (1.01 (0.85-1.20)).
We conclude that lifestyle factors may play a stronger role in the development of MetSyn in NW individuals compared with OB and that metabolically healthy obesity may not be a stable condition.
Obesity 01/2013; 21(1):203-9. · 4.28 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: ABSTRACT OBJECTIVE: To determine whether 4 genetic variants in the fat mass and obesity associated gene (FTO) identified in genome-wide association studies of diabetes and obesity are associated with cognitive change in midlife in the Atherosclerosis Risk in Communities (ARIC) Study. METHODS: ARIC is a prospective cohort study of the development of atherosclerosis in 15,792 individuals aged 45 to 64 years at baseline from 1986 to 1989. FTO is highly expressed in human fetal and adult brain, and a single nucleotide polymorphism in FTO has previously been associated with reduced brain volume in cognitively normal subjects. Since a relationship between brain atrophy and diminished cognitive function has been demonstrated in ARIC participants, general linear models were used to evaluate the association between 6-year change in scores on 3 neuropsychological tests and FTO genotype. RESULTS: In a sample of 8,364 white and 2,083 African American men and women with no clinical history of stroke, significantly greater mean change in performance on the Delayed Word Recall Test was associated with 2 of 4 FTO single nucleotide polymorphisms examined (rs9939609, rs805136, rs17817449, and rs1421085) in whites but not in African Americans (p ≤ 0.002). The association of the FTO polymorphisms with cognitive change was independent of potential confounding clinical and demographic variables including age, gender, education, diabetes, hypertension, and body mass index. CONCLUSIONS: Further studies will be needed to clarify the biological mechanisms and genetic pathways through which variants in FTO can increase susceptibility to decline in verbal memory detectable in middle-aged, community-dwelling adults.
Neurology 11/2012; · 8.31 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: OBJECTIVE: Retinopathy and retinal microvascular abnormalities are common in adult populations, yet few long-term predictors have been identified. We therefore examined the association between systolic blood pressure (SBP) and fasting plasma glucose, assessed over 18 years, with retinopathy and retinal vascular caliber in 2066 Carotid MRI participants, an Atherosclerosis Risk in Communities ancillary study. METHODS: Retinopathy and retinal vascular caliber were assessed by retinal photography. Confounder-adjusted weighted regression models were used to examine exposures defined as cumulative, long-term prospective, concurrent, and 18-year change. RESULTS: Long-term prospective (prevalence odds ratio (POR) per 10 mm Hg: 1.14 (95% CI: 1.01, 1.30)) and cumulative (POR per 10 mm Hg: 1.30 (95% CI: 1.09, 1.56) effects spanning approximately 18 years were found for SBP and retinopathy. The strongest long-term prospective association for plasma glucose and retinopathy was identified at the baseline visit (POR per 10 mg/dl: 1.26 (95% CI: 1.16, 1.38)); sustained glucose elevations over 18 years were also associated with prevalent retinopathy (POR per 10 mg/dl: 1.33 (95% CI: 1.24, 1.43)). Results were robust to the exclusion of participants with diabetes. CONCLUSIONS: Modest and sustained long-term elevations in glucose and blood pressure are associated with retinopathy and retinal vascular caliber.
Atherosclerosis 10/2012; · 3.79 Impact Factor
-
Jian Yang,
Ruth J F Loos,
Joseph E Powell,
Sarah E Medland,
Elizabeth K Speliotes,
Daniel I Chasman,
Lynda M Rose,
Gudmar Thorleifsson,
Valgerdur Steinthorsdottir,
Reedik Mägi, [......],
David P Strachan,
William G Hill,
Harold Snieder,
Paul M Ridker,
Unnur Thorsteinsdottir,
Kari Stefansson,
Timothy M Frayling,
Joel N Hirschhorn,
Michael E Goddard,
Peter M Visscher
[show abstract]
[hide abstract]
ABSTRACT: There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ∼170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ∼0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.
Nature 09/2012; 490(7419):267-72. · 36.28 Impact Factor
-
Tuomas O. Kilpeläinen,
Lu Qi,
Soren Brage,
Stephen J. Sharp,
Emily Sonestedt,
Ellen Demerath,
Tariq Ahmad,
Samia Mora,
Marika Kaakinen,
Camilla Helene Sandholt, [......], Keri L. Monda,
Thomas Illig,
Marjo-Riitta Järvelin,
Nicholas J. Wareham,
Frank B. Hu,
Leif C. Groop,
Marju Orho-Melander,
Ulf Ekelund,
Paul W. Franks,
Ruth J. F. Loos
[show abstract]
[hide abstract]
ABSTRACT: Background
The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268).
Methods and Findings
All studies identified to have data on the FTO rs9939609 variant (or any proxy [r2>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A−) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20–1.26), but PA attenuated this effect (pinteraction = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio = 1.22/allele, 95% CI 1.19–1.25) than in the inactive group (odds ratio = 1.30/allele, 95% CI 1.24–1.36). No such interaction was found in children and adolescents.
Conclusions
The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity.
Please see later in the article for the Editors' Summary
PLoS Medicine 11/2011; 8(11). · 16.27 Impact Factor
-
Tuomas O Kilpeläinen,
Lu Qi,
Soren Brage,
Stephen J Sharp,
Emily Sonestedt,
Ellen Demerath,
Tariq Ahmad,
Samia Mora,
Marika Kaakinen,
Camilla Helene Sandholt, [......], Keri L Monda,
Thomas Illig,
Marjo-Riitta Järvelin,
Nicholas J Wareham,
Frank B Hu,
Leif C Groop,
Marju Orho-Melander,
Ulf Ekelund,
Paul W Franks,
Ruth J F Loos
[show abstract]
[hide abstract]
ABSTRACT: The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268).
All studies identified to have data on the FTO rs9939609 variant (or any proxy [r(2)>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A-) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20-1.26), but PA attenuated this effect (p(interaction) = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio = 1.22/allele, 95% CI 1.19-1.25) than in the inactive group (odds ratio = 1.30/allele, 95% CI 1.24-1.36). No such interaction was found in children and adolescents.
The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity.
PLoS Medicine 11/2011; 8(11):e1001116. · 16.27 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Physical inactivity accentuates the association of variants in the FTO locus with obesity-related traits but evidence is largely lacking in non-European populations. Here we tested the hypothesis that physical activity (PA) modifies the association of the FTO single-nucleotide polymorphism (SNP) rs9939609 with adiposity traits in 2,656 African Americans (AA) (1,626 women and 1,030 men) and 9,867 European Americans (EA) (5,286 women and 4,581 men) aged 45-66 years in the Atherosclerosis Risk in Communities (ARIC) study. Individuals in the lowest quintile of the sport activity index of the Baecke questionnaire were categorized as low PA. Baseline BMI, waist circumference (WC), and skinfold measures were dependent variables in regression models testing the additive effect of the SNP, low PA, and their interaction, adjusting for age, alcohol use, cigarette use, educational attainment, and percent European ancestry in AA adults, stratified by sex and race/ethnicity. rs9939609 was associated with adiposity in all groups other than AA women. The SNP × PA interaction was significant in AA men (P ≤ 0.002 for all traits) and EA men (P ≤ 0.04 for all traits). For each additional copy of the A (risk) allele, WC in AA men was higher in those with low PA (β(lowPA): 5.1 cm, 95% confidence interval (CI): 2.6-7.5) than high PA (β(highPA): 0.7 cm, 95% CI: -0.4 to 1.9); P (interaction) = 0.002). The interaction effect was not observed in EA or AA women. FTO SNP × PA interactions on adiposity were observed for AA as well as EA men. Differences by sex require further examination.
Obesity 05/2011; 19(9):1866-72. · 4.28 Impact Factor
-
Marilyn C Cornelis, Keri L Monda,
Kai Yu,
Nina Paynter,
Elizabeth M Azzato,
Siiri N Bennett,
Sonja I Berndt,
Eric Boerwinkle,
Stephen Chanock,
Nilanjan Chatterjee, [......],
Eric B Rimm,
Lynda M Rose,
Nathaniel Rothman,
Debra Silverman,
Rachael Stolzenberg-Solomon,
Amy Subar,
Meredith Yeager,
Daniel I Chasman,
Rob M van Dam,
Neil E Caporaso
[show abstract]
[hide abstract]
ABSTRACT: We report the first genome-wide association study of habitual caffeine intake. We included 47,341 individuals of European descent based on five population-based studies within the United States. In a meta-analysis adjusted for age, sex, smoking, and eigenvectors of population variation, two loci achieved genome-wide significance: 7p21 (P = 2.4 × 10(-19)), near AHR, and 15q24 (P = 5.2 × 10(-14)), between CYP1A1 and CYP1A2. Both the AHR and CYP1A2 genes are biologically plausible candidates as CYP1A2 metabolizes caffeine and AHR regulates CYP1A2.
PLoS Genetics 04/2011; 7(4):e1002033. · 8.69 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Platelet activation and aggregation play an important role in the pathogenesis of cardiovascular disease. We examined the association of a single nucleotide polymorphism (SNP) in the GPIIIa platelet glycoprotein (Leu33Pro) with carotid artery plaque morphology and with expression of platelet markers using data from the Atherosclerosis Risk in Communities (ARIC) Carotid MRI study.
The study sample consisted of 1202 Caucasian members of the ARIC study cohort recruited in 2004-2005 to participate in the Carotid MRI Substudy under stratified sampling based on maximum carotid artery wall thickness. The Leu33Pro polymorphism was identified as SNP rs5918 in the ITGB3 gene. Plaque visualization was accomplished with contrast enhanced MRI examination of the thickest segment of the carotid artery. Expression of platelet markers was measured using fasting whole blood flow cytometry.
This cross-sectional analysis based on age and gender adjusted weighted linear regression models suggests that those homozygous for the Leu33Pro risk allele (C) have decreased mean and minimum fibrous cap thickness. We did not observe differences in plaque lipid volume or maximum carotid artery wall thickness across SNP rs5918 genotypes. Carriers of the Leu33Pro polymorphism, as compared to major allele homozygotes, had greater percent of platelets expressing P-selectin, a platelet glycoprotein indicating activation status. Prevalent coronary heart disease did not affect estimates of fibrous cap thickness or of platelet activation.
Our results suggest that individuals with Leu33Pro polymorphism of the GPIIIa glycoprotein may be predisposed to increased risk of atherosclerotic plaque rupture.
Atherosclerosis 02/2011; 216(1):151-6. · 3.79 Impact Factor
-
Matthew B Lanktree,
Yiran Guo,
Muhammed Murtaza,
Joseph T Glessner,
Swneke D Bailey,
N Charlotte Onland-Moret,
Guillaume Lettre,
Halit Ongen,
Ramakrishnan Rajagopalan,
Toby Johnson, [......],
Wolfgang Koenig,
Tom R Gaunt,
Sonia S Anand,
Yvonne T van der Schouw,
Nicole Soranzo,
Garret A Fitzgerald,
Alex Reiner,
Robert A Hegele,
Hakon Hakonarson,
Brendan J Keating
[show abstract]
[hide abstract]
ABSTRACT: Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 × 10(-8)). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 × 10(-11)). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait.
The American Journal of Human Genetics 01/2011; 88(1):6-18. · 10.60 Impact Factor
-
Iris M Heid,
Anne U Jackson,
Joshua C Randall,
Thomas W Winkler,
Lu Qi,
Valgerdur Steinthorsdottir,
Gudmar Thorleifsson,
M Carola Zillikens,
Elizabeth K Speliotes,
Reedik Mägi, [......],
Unnur Thorsteinsdottir,
Cornelia M van Duijn,
Kari Stefansson,
L Adrienne Cupples,
Ruth J F Loos,
Inês Barroso,
Mark I McCarthy,
Caroline S Fox,
Karen L Mohlke,
Cecilia M Lindgren
Nature Genetics 01/2011; 43(11):1164. · 35.53 Impact Factor
-
Iris M Heid,
Anne U Jackson,
Joshua C Randall,
Thomas W Winkler,
Lu Qi,
Valgerdur Steinthorsdottir,
Gudmar Thorleifsson,
M Carola Zillikens,
Elizabeth K Speliotes,
Reedik Mägi, [......],
Unnur Thorsteinsdottir,
Cornelia M van Duijn,
Kari Stefansson,
L Adrienne Cupples,
Ruth J F Loos,
Inês Barroso,
Mark I McCarthy,
Caroline S Fox,
Karen L Mohlke,
Cecilia M Lindgren
[show abstract]
[hide abstract]
ABSTRACT: Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
Nature Genetics 10/2010; 42(11):949-60. · 35.53 Impact Factor
-
Elizabeth K Speliotes,
Cristen J Willer,
Sonja I Berndt, Keri L Monda,
Gudmar Thorleifsson,
Anne U Jackson,
Hana Lango Allen,
Cecilia M Lindgren,
Jian'an Luan,
Reedik Mägi, [......],
Unnur Thorsteinsdottir,
Gonçalo R Abecasis,
Inês Barroso,
Michael Boehnke,
Kari Stefansson,
Kari E North,
Mark I McCarthy,
Joel N Hirschhorn,
Erik Ingelsson,
Ruth J F Loos
[show abstract]
[hide abstract]
ABSTRACT: Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
Nature Genetics 10/2010; 42(11):937-48. · 35.53 Impact Factor
-
Hana Lango Allen,
Karol Estrada,
Guillaume Lettre,
Sonja I Berndt,
Michael N Weedon,
Fernando Rivadeneira,
Cristen J Willer,
Anne U Jackson,
Sailaja Vedantam,
Soumya Raychaudhuri, [......],
Nilanjan Chatterjee,
Ruth J F Loos,
Michael Boehnke,
Mark I McCarthy,
Erik Ingelsson,
Cecilia M Lindgren,
Gonçalo R Abecasis,
Kari Stefansson,
Timothy M Frayling,
Joel N Hirschhorn
[show abstract]
[hide abstract]
ABSTRACT: Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
Nature 09/2010; 467(7317):832-8. · 36.28 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In this review, we discuss the genetic architecture of obesity and the metabolic syndrome, highlighting recent advances in identifying genetic variants and loci responsible for a portion of the variation in components of the metabolic syndrome, namely, adiposity traits, serum HDL and triglycerides, blood pressure, and glycemic traits. We focus particularly on recent progress from large-scale genome-wide association studies (GWAS), by detailing their successes and how lessons learned can pave the way for future discovery. Results from recent GWAS coalesce with earlier work suggesting numerous interconnections between obesity and the metabolic syndrome, developed through several potentially pleiotropic effects. We detail recent work by way of a case study on the cadherin 13 gene and its relation with adiponectin in the HyperGEN and the Framingham Heart Studies, and its association with obesity and the metabolic syndrome. We provide also a gene network analysis of recent variants related to obesity and metabolic syndrome discovered through genome-wide association studies, and 4 gene networks based on searching the NCBI database.
Endocrine, metabolic & immune disorders drug targets. 06/2010; 10(2):86-108.
-
[show abstract]
[hide abstract]
ABSTRACT: In this review, we discuss the genetic architecture of obesity and the metabolic syndrome, highlighting recent advances in identifying genetic variants and loci responsible for a portion of the variation in components of the metabolic syndrome, namely, adiposity traits, serum HDL and triglycerides, blood pressure, and glycemic traits. We focus particularly on recent progress from large-scale genome-wide association studies (GWAS), by detailing their successes and how lessons learned can pave the way for future discovery. Results from recent GWAS coalesce with earlier work suggesting numerous interconnections between obesity and the metabolic syndrome, developed through several potentially pleiotropic effects. We detail recent work by way of a case study on the cadherin 13 gene and its relation with adiponectin in the HyperGEN and the Framingham Heart Studies, and its association with obesity and the metabolic syndrome. We provide also a gene network analysis of recent variants related to obesity and metabolic syndrome discovered through genome- wide association studies, and 4 gene networks based on searching the NCBI database.
Endocrine Metabolic & Immune Disorders - Drug Targets(Formerly Current Drug Targets - Immune Endocrine & Metabolic Disorders) 05/2010; 10(2):86-108.
-
[show abstract]
[hide abstract]
ABSTRACT: We examined the association of variation in the type 2 diabetes risk-conferring TCF7L2 gene with the risk of incident coronary heart disease (CHD) among the lean, overweight, and obese members of the Atherosclerosis Risk in Communities (ARIC) Study cohort. Cox proportional hazard regression analyses were performed using a general model, with the major homozygote as the reference category. For 9,865 whites, a significant increase in the risk of CHD was seen only among lean ( BMI < 25 kg/m(2)) individuals homozygous for the T allele of the TCF7L2 rs7903146 gene risk variant (hazard ratio 1.42; 95% CI 1.03,1.97; P = .01). No association was found among 3,631 blacks, regardless of BMI status. An attenuated hazard ratio was observed among the nondiabetic ARIC cohort members. This study suggests that body mass modifies the association of the TCF7L2 rs7903146 T allele with CHD risk.
Journal of obesity 01/2010; 2010.
-
Nancy L Heard-Costa,
M Carola Zillikens, Keri L Monda,
Asa Johansson,
Tamara B Harris,
Mao Fu,
Talin Haritunians,
Mary F Feitosa,
Thor Aspelund,
Gudny Eiriksdottir, [......],
Jacqueline C M Witteman,
Ben A Oostra,
Robert C Kaplan,
Vilmundur Gudnason,
Jeffrey R O'Connell,
Ingrid B Borecki,
Cornelia M van Duijn,
L Adrienne Cupples,
Caroline S Fox,
Kari E North
[show abstract]
[hide abstract]
ABSTRACT: Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4x10(-7))]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3x10(-8) for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4x10(-6), 0.024 z-score units (0.10 kg/m(2)) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07-1.19; p = 3.2x10(-5) per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.
PLoS Genetics 07/2009; 5(6):e1000539. · 8.69 Impact Factor
