Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African Ancestry Anthropometry Genetics Consortium.

PLoS Genet
Authors
Keywords
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, 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.

Year of Publication
2017
Journal
PLoS Genet
Volume
13
Issue
4
Pages
e1006719
Date Published
2017 Apr
ISSN
1553-7404
DOI
10.1371/journal.pgen.1006719
PubMed ID
28430825
PubMed Central ID
PMC5419579
Links
Grant list
U01 HG007417 / HG / NHGRI NIH HHS / United States
K99 HL130580 / HL / NHLBI NIH HHS / United States
P30 ES010126 / ES / NIEHS NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
U10 CA037429 / CA / NCI NIH HHS / United States
U01 AG009740 / AG / NIA NIH HHS / United States
R01 DK113003 / DK / NIDDK NIH HHS / United States
U01 HL130114 / HL / NHLBI NIH HHS / United States
U01 CA127298 / CA / NCI NIH HHS / United States
UG1 CA189974 / CA / NCI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
R01 HD056465 / HD / NICHD NIH HHS / United States
P30 DK020541 / DK / NIDDK NIH HHS / United States
R01 CA088164 / CA / NCI NIH HHS / United States
UM1 CA182883 / CA / NCI NIH HHS / United States