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Discovery and fine-mapping of adiposity loci using high density imputation of genomewide association studies in individuals of African ancestry: African Ancestry Anthropometry Genetics Consortium.
- Source :
- PLoS Genetics; 4/21/2017, Vol. 13 Issue 4, p1-25, 25p, 2 Charts, 2 Graphs
- Publication Year :
- 2017
-
Abstract
- 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, WHR<subscript>adjBMI</subscript>), 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 WHR<subscript>adjBMI</subscript> 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 WHR<subscript>adjBMI</subscript> and eight previously established loci at P < 5×10<superscript>−8</superscript>: seven for BMI, and one for WHR<subscript>adjBMI</subscript> in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHR<subscript>adjBMI</subscript> 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 WHR<subscript>adjBMI</subscript> (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 WHR<subscript>adjBMI</subscript> 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 WHR<subscript>adjBMI</subscript> 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 WHR<subscript>adjBMI</subscript> 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 15537390
- Volume :
- 13
- Issue :
- 4
- Database :
- Complementary Index
- Journal :
- PLoS Genetics
- Publication Type :
- Academic Journal
- Accession number :
- 126891395
- Full Text :
- https://doi.org/10.1371/journal.pgen.1006719