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  • Title: 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.
    Author: Ng MCY, Graff M, Lu Y, Justice AE, Mudgal P, Liu CT, Young K, Yanek LR, Feitosa MF, Wojczynski MK, Rand K, Brody JA, Cade BE, Dimitrov L, Duan Q, Guo X, Lange LA, Nalls MA, Okut H, Tajuddin SM, Tayo BO, Vedantam S, Bradfield JP, Chen G, Chen WM, Chesi A, Irvin MR, Padhukasahasram B, Smith JA, Zheng W, Allison MA, Ambrosone CB, Bandera EV, Bartz TM, Berndt SI, Bernstein L, Blot WJ, Bottinger EP, Carpten J, Chanock SJ, Chen YI, Conti DV, Cooper RS, Fornage M, Freedman BI, Garcia M, Goodman PJ, Hsu YH, Hu J, Huff CD, Ingles SA, John EM, Kittles R, Klein E, Li J, McKnight B, Nayak U, Nemesure B, Ogunniyi A, Olshan A, Press MF, Rohde R, Rybicki BA, Salako B, Sanderson M, Shao Y, Siscovick DS, Stanford JL, Stevens VL, Stram A, Strom SS, Vaidya D, Witte JS, Yao J, Zhu X, Ziegler RG, Zonderman AB, Adeyemo A, Ambs S, Cushman M, Faul JD, Hakonarson H, Levin AM, Nathanson KL, Ware EB, Weir DR, Zhao W, Zhi D, Bone Mineral Density in Childhood Study (BMDCS) Group, Arnett DK, Grant SFA, Kardia SLR, Oloapde OI, Rao DC, Rotimi CN, Sale MM, Williams LK, Zemel BS, Becker DM, Borecki IB, Evans MK, Harris TB, Hirschhorn JN, Li Y, Patel SR, Psaty BM, Rotter JI, Wilson JG, Bowden DW, Cupples LA, Haiman CA, Loos RJF, North KE.
    Journal: PLoS Genet; 2017 Apr; 13(4):e1006719. PubMed ID: 28430825.
    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.
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