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.
Digital Object Identifier (DOI)
The MEC and genotyping of samples for the GWAS of breast and prostate cancer was supported by National Institutes of Health grants CA63464, CA54281, CA164973, CA1326792, CA148085, HG004726 and a Department of Defense Breast Cancer Research Program Era of Hope Scholar Award to CAH (W81XWH-08-1-0383) and the Norris Foundation.
Due to the large number of funding sources, only the first few are listed in this section. For the complete list of funding sources, please download this article.
Summary association statistics from meta-analyses are available from dbGAP at accession number phs000930.
Ng, Maggie C. Y.; Graff, Mariaelisa; Lu, Yingchang; Justice, Anne E.; Mudgal, Poorva; Liu, Ching-Ti; Young, Kristin; Yanek, Lisa R.; Feitosa, Mary F.; Wojczynski, Mary K.; Rand, Kristin; Brody, Jennifer A.; Cade, Brian E.; Dimitrov, Latchezar; Duan, Qing; Guo, Xiuqing; Lange, Leslie A.; Nalls, Michael A.; Okut, Hayrettin; Tajuddin, Salman M.; Tayo, Bamidele O.; Vedantam, Sailaja; Bradfield, Jonathan P.; Chen, Guanjie; Chen, Wei-Min; Chesi, Alessandra; Irvin, Marguerite R.; Padhukasahasram, Badri; Smith, Jennifer A.; Zheng, Wei; and Arnett, Donna K., "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" (2017). Epidemiology Faculty Publications. 20.
S1 Fig. Study design of GWAS meta-analyses and replications for BMI and WHRadjBMI.
journal.pgen.1006719.s002.pdf (232 kB)
S2 Fig. Quantile-quantile plot of 1000 genomes phase 1 imputed discovery results and their associations to adult BMI in men and women of African ancestry using all variants and only variants outside of known GWAS loci.
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S3 Fig. Quantile-quantile plot of 1000 genomes phase 1 imputed discovery results and their associations to adult BMI in women only and men only of African ancestry using all variants and only variants outside of known GWAS loci.
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S4 Fig. Quantile-quantile plot of 1000 genomes phase 1 imputed discovery results and their associations to adult waist-to-hip ratio adjusted for BMI (WHRadjBMI) in men and women of African ancestry using all variants and only variants outside of known GWAS loci.
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S5 Fig. Quantile-quantile plot of 1000 genomes phase 1 imputed discovery results and their associations to adult waist-to-hip ratio adjusted for BMI (WHRadjBMI) in women only and men only of African ancestry using all variants and only variants outside of known GWAS loci.
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S6 Fig. Manhattan plot of 1000 genomes phase 1 imputed discovery results and their associations to adult BMI in men and women of African ancestry.
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S7 Fig. Manhattan plot of 1000 genomes phase 1 imputed discovery results and their associations to waist-to-hip ratio adjusted for BMI (WHRadjBMI) in men and women of African ancestry.
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S8 Fig. Miami plot of 1000 genomes phase 1 imputed discovery results and their associations to adult BMI in women only (top) and men only (bottom) of African ancestry.
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S9 Fig. Miami plot of 1000 genomes phase 1 imputed discovery results and their associations to adult waist-to-hip ratio adjusted for BMI (WHRadjBMI) in women only (top) and men only (bottom) of African ancestry.
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S1 Table. Study design and sample quality control of discovery and replication studies.
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S2 Table. Study-specific descriptive statistics of discovery and replication studies.
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S3 Table. Genotyping methods, quality control of variants, imputation, and statistical analysis in discovery and replication studies.
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S4 Table. Comparison of coverage of variants using the 1000 Genomes and HapMap reference panels for imputation in the Women's Health Initiative study.
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S5 Table. Comparison of lead variants between 1000 Genomes and HapMap imputed meta-analysis in AA in previously identified BMI loci in discovery and replication studies.
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S6 Table. Associations of lead variants from novel and previously identified BMI and WHRadjBMI loci in combined and sex-stratified analyses of African ancestry discovery and replication samples.
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S7 Table. Association of African Ancestry sex-combined genome-wide significant variants in children of African ancestry.
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S8 Table. Putative coding or regulatory variants in linkage disequilibrium (r2 > 0.7) with WHRadjBMI loci.
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S9 Table. Previously-reported associations of novel BMI and WHRadjBMI loci with other traits in the GRASP Catalog.
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S10 Table. Conditional analysis of African ancestry primary and secondary lead SNPs with European lead SNPs in previously identified BMI and WHRadjBMI loci.
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S11 Table. SNP transferability of BMI and WHRadjBMI lead SNPs from European sex combined and sex stratified GWAS in African ancestry individuals.
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S12 Table. Locus transferability and conditional analyses of European BMI and WHRadjBMI loci in African ancestry individuals.
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S13 Table. Fine mapping of novel loci and previously identified loci with locus-wide significance in African ancestry individuals using 1000 Genomes imputed results from African, European and combined ancestries.
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S14 Table. Functional characterization of variants in tractable credible sets in meta-analysis of African and European ancestry GWAS.
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S1 Text. Supplementary note.
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S2 Text. Members of the BMDCS Group.