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

Maggie C. Y. Ng, Mariaelisa Graff, Yingchang Lu, Anne E. Justice, Poorva Mudgal, Ching-Ti Liu, Kristin Young, Lisa R. Yanek, Mary F. Feitosa, Mary K. Wojczynski, Kristin Rand, Jennifer A. Brody, Brian E. Cade, Latchezar Dimitrov, Qing Duan, Xiuqing Guo, Leslie A. Lange, Michael A. Nalls, Hayrettin Okut, Salman M. Tajuddin, Bamidele O. Tayo, Sailaja Vedantam, Jonathan P. Bradfield, Guanjie Chen, Wei-Min Chen, Alessandra Chesi, Marguerite R. Irvin, Badri Padhukasahasram, Jennifer A. Smith, Wei Zheng, Matthew A. Allison, Christine B. Ambrosone, Elisa V. Bandera, Traci M. Bartz, Sonja I. Berndt, Leslie Bernstein, William J. Blot, Erwin P. Bottinger, John Carpten, Stephen J. Chanock, Yii-Der Ida Chen, David V. Conti, Richard S. Cooper, Myriam Fornage, Barry I. Freedman, Melissa Garcia, Phyllis J. Goodman, Yu-Han H. Hsu, Jennifer Hu, Chad D. Huff, Sue A. Ingles, Esther M. John, Rick Kittles, Eric Klein, Jin Li, Barbara McKnight, Uma Nayak, Barbara Nemesure, Adesola Ogunniyi, Andrew Olshan, Michael F. Press, Rebecca Rohde, Benjamin A. Rybicki, Babatunde Salako, Maureen Sanderson, Yaming Shao, David S. Siscovick, Janet L. Stanford, Victoria L. Stevens, Alex Stram, Sara S. Strom, Dhananjay Vaidya, John S. Witte, Jie Yao, Xiaofeng Zhu, Regina G. Ziegler, Alan B. Zonderman, Adebowale Adeyemo, Stefan Ambs, Mary Cushman, Jessica D. Faul, Hakon Hakonarson, Albert M. Levin, Katherine L. Nathanson, Erin B. Ware, David R. Weir, Wei Zhao, Degui Zhi, Donna K. Arnett, Struan F. A. Grant, Sharon L. R. Kardia, Olufunmilayo I. Oloapde, D. C. Rao, Charles N. Rotimi, Michele M. Sale, L. Keoki Williams, Babette S. Zemel, Diane M. Becker, Ingrid B. Borecki, Michele K. Evans, Tamara B. Harris, Joel N. Hirschhorn, Yun Li, Sanjay R. Patel, Bruce M. Psaty, Jerome I. Rotter, James G. Wilson, Donald W. Bowden, L. Adrienne Cupples, Christopher A. Haiman, Ruth J. F. Loos, Kari E. North

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.