Dataset Information

Identification, replication, and fine-mapping of Loci associated with adult height in individuals of african ancestry.

ABSTRACT: Adult height is a classic polygenic trait of high heritability (h(2) approximately 0.8). More than 180 single nucleotide polymorphisms (SNPs), identified mostly in populations of European descent, are associated with height. These variants convey modest effects and explain approximately10% of the variance in height. Discovery efforts in other populations, while limited, have revealed loci for height not previously implicated in individuals of European ancestry. Here, we performed a meta-analysis of genome-wide association (GWA) results for adult height in 20,427 individuals of African ancestry with replication in up to 16,436 African Americans. We found two novel height loci (Xp22-rs12393627, P?=?3.4×10(-12) and 2p14-rs4315565, P?=?1.2×10(-8)). As a group, height associations discovered in European-ancestry samples replicate in individuals of African ancestry (P?=?1.7×10(-4) for overall replication). Fine-mapping of the European height loci in African-ancestry individuals showed an enrichment of SNPs that are associated with expression of nearby genes when compared to the index European height SNPs (P<0.01). Our results highlight the utility of genetic studies in non-European populations to understand the etiology of complex human diseases and traits.

SUBMITTER: N'Diaye A

PROVIDER: S-EPMC3188544 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Identification, replication, and fine-mapping of Loci associated with adult height in individuals of african ancestry.

N'Diaye Amidou A Chen Gary K GK Palmer Cameron D CD Ge Bing B Tayo Bamidele B Mathias Rasika A RA Ding Jingzhong J Nalls Michael A MA Adeyemo Adebowale A Adoue Véronique V Ambrosone Christine B CB Atwood Larry L Bandera Elisa V EV Becker Lewis C LC Berndt Sonja I SI Bernstein Leslie L Blot William J WJ Boerwinkle Eric E Britton Angela A Casey Graham G Chanock Stephen J SJ Demerath Ellen E Deming Sandra L SL Diver W Ryan WR Fox Caroline C Harris Tamara B TB Hernandez Dena G DG Hu Jennifer J JJ Ingles Sue A SA John Esther M EM Johnson Craig C Keating Brendan B Kittles Rick A RA Kolonel Laurence N LN Kritchevsky Stephen B SB Le Marchand Loic L Lohman Kurt K Liu Jiankang J Millikan Robert C RC Murphy Adam A Musani Solomon S Neslund-Dudas Christine C North Kari E KE Nyante Sarah S Ogunniyi Adesola A Ostrander Elaine A EA Papanicolaou George G Patel Sanjay S Pettaway Curtis A CA Press Michael F MF Redline Susan S Rodriguez-Gil Jorge L JL Rotimi Charles C Rybicki Benjamin A BA Salako Babatunde B Schreiner Pamela J PJ Signorello Lisa B LB Singleton Andrew B AB Stanford Janet L JL Stram Alex H AH Stram Daniel O DO Strom Sara S SS Suktitipat Bhoom B Thun Michael J MJ Witte John S JS Yanek Lisa R LR Ziegler Regina G RG Zheng Wei W Zhu Xiaofeng X Zmuda Joseph M JM Zonderman Alan B AB Evans Michele K MK Liu Yongmei Y Becker Diane M DM Cooper Richard S RS Pastinen Tomi T Henderson Brian E BE Hirschhorn Joel N JN Lettre Guillaume G Haiman Christopher A CA

PLoS genetics 20111006 10

Adult height is a classic polygenic trait of high heritability (h(2) approximately 0.8). More than 180 single nucleotide polymorphisms (SNPs), identified mostly in populations of European descent, are associated with height. These variants convey modest effects and explain approximately10% of the variance in height. Discovery efforts in other populations, while limited, have revealed loci for height not previously implicated in individuals of European ancestry. Here, we performed a meta-analysis ...[more]

PMID: 21998595

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Project description:Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ≤ 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.

Project description:BACKGROUND/OBJECTIVES:Central adiposity measures such as waist circumference (WC) and waist-to-hip ratio (WHR) are associated with cardiometabolic disorders independently of body mass index (BMI) and are gaining clinically utility. Several studies report genetic variants associated with central adiposity, but most utilize only European ancestry populations. Understanding whether the genetic associations discovered among mainly European descendants are shared with African ancestry populations will help elucidate the biological underpinnings of abdominal fat deposition. SUBJECTS/METHODS:To identify the underlying functional genetic determinants of body fat distribution, we conducted an array-wide association meta-analysis among persons of African ancestry across seven studies/consortia participating in the Population Architecture using Genomics and Epidemiology (PAGE) consortium. We used the Metabochip array, designed for fine-mapping cardiovascular-associated loci, to explore novel array-wide associations with WC and WHR among 15?945 African descendants using all and sex-stratified groups. We further interrogated 17 known WHR regions for African ancestry-specific variants. RESULTS:Of the 17 WHR loci, eight single-nucleotide polymorphisms (SNPs) located in four loci were replicated in the sex-combined or sex-stratified meta-analyses. Two of these eight independently associated with WHR after conditioning on the known variant in European descendants (rs12096179 in TBX15-WARS2 and rs2059092 in ADAMTS9). In the fine-mapping assessment, the putative functional region was reduced across all four loci but to varying degrees (average 40% drop in number of putative SNPs and 20% drop in genomic region). Similar to previous studies, the significant SNPs in the female-stratified analysis were stronger than the significant SNPs from the sex-combined analysis. No novel associations were detected in the array-wide analyses. CONCLUSIONS:Of 17 previously identified loci, four loci replicated in the African ancestry populations of this study. Utilizing different linkage disequilibrium patterns observed between European and African ancestries, we narrowed the suggestive region containing causative variants for all four loci.

Project description:The discovery of expression quantitative trait loci ("eQTLs") can help to unravel genetic contributions to complex traits. We identified genetic determinants of human liver gene expression variation using two independent collections of primary tissue profiled with Agilent (n?=?206) and Illumina (n?=?60) expression arrays and Illumina SNP genotyping (550K), and we also incorporated data from a published study (n?=?266). We found that ?30% of SNP-expression correlations in one study failed to replicate in either of the others, even at thresholds yielding high reproducibility in simulations, and we quantified numerous factors affecting reproducibility. Our data suggest that drug exposure, clinical descriptors, and unknown factors associated with tissue ascertainment and analysis have substantial effects on gene expression and that controlling for hidden confounding variables significantly increases replication rate. Furthermore, we found that reproducible eQTL SNPs were heavily enriched near gene starts and ends, and subsequently resequenced the promoters and 3'UTRs for 14 genes and tested the identified haplotypes using luciferase assays. For three genes, significant haplotype-specific in vitro functional differences correlated directly with expression levels, suggesting that many bona fide eQTLs result from functional variants that can be mechanistically isolated in a high-throughput fashion. Finally, given our study design, we were able to discover and validate hundreds of liver eQTLs. Many of these relate directly to complex traits for which liver-specific analyses are likely to be relevant, and we identified dozens of potential connections with disease-associated loci. These included previously characterized eQTL contributors to diabetes, drug response, and lipid levels, and they suggest novel candidates such as a role for NOD2 expression in leprosy risk and C2orf43 in prostate cancer. In general, the work presented here will be valuable for future efforts to precisely identify and functionally characterize genetic contributions to a variety of complex traits.

Dataset Information

Identification, replication, and fine-mapping of Loci associated with adult height in individuals of african ancestry.

Publications

Identification, replication, and fine-mapping of Loci associated with adult height in individuals of african ancestry.

Similar Datasets

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