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.

Authors:
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

PLoS Genet 2017 Apr 21;13(4):e1006719. Epub 2017 Apr 21.

Department of Epidemiology, University of North Carolina, Chapel Hill, NC, United States of America.

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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Source
http://dx.doi.org/10.1371/journal.pgen.1006719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5419579PMC
April 2017
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