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, Wake Forest University
Mariaelisa Graff, University of North Carolina at Chapel Hill
Yingchang Lu, Icachn School of Medicine at Mount Sinai
Anne E. Justice, University of North Carolina at Chapel Hill
Poorva Mudgal, Wake Forest University
Ching-Ti Liu, Boston University
Kristin Young, University of North Carolina at Chapel Hill
Lisa R. Yanek, Johns Hopkins University
Mary F. Feitosa, Washington University in St. Louis
Mary K. Wojczynski, Washington University in St. Louis
Kristin Rand, University of Southern California
Jennifer A. Brody, University of Washington
Brian E. Cade, Brigham and Women’s Hospital
Latchezar Dimitrov, Wake Forest University
Qing Duan, University of North Carolina at Chapel Hill
Xiuqing Guo, Harbor-UCLA Medical Center
Leslie A. Lange, University of North Carolina at Chapel Hill
Michael A. Nalls, National Institutes of Health
Hayrettin Okut, Wake Forest University
Salman M. Tajuddin, National Institutes of Health
Bamidele O. Tayo, Loyola University Chicago
Sailaja Vedantam, Boston Children's Hospital
Jonathan P. Bradfield, The Children’s Hospital of Philadelphia
Guanjie Chen, National Institutes of Health
Wei-Min Chen, University of Virginia
Alessandra Chesi, The Children’s Hospital of Philadelphia
Marguerite R. Irvin, The University of Alabama at Birmingham
Badri Padhukasahasram, Henry Ford Health System
Jennifer A. Smith, University of Michigan - Ann Arbor
Wei Zheng, Vanderbilt University
Donna K. Arnett, University of KentuckyFollow

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, WHR_adjBMI), 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 WHR_adjBMI 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 WHR_adjBMI and eight previously established loci at P < 5×10⁻⁸: seven for BMI, and one for WHR_adjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHR_adjBMI 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 WHR_adjBMI (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 WHR_adjBMI 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 WHR_adjBMI 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 WHR_adjBMI 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.

Document Type

Article

Publication Date

4-21-2017

Notes/Citation Information

Published in PLOS Genetics, v. 13, 4, e1006719, p. 1-25.

This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Due to the large number of authors, only the first 30 and the authors affiliated with the University of Kentucky are listed in the author section above. For the complete list of authors, please download this article.

Digital Object Identifier (DOI)

https://doi.org/10.1371/journal.pgen.1006719

Funding Information

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.

Related Content

Summary association statistics from meta-analyses are available from dbGAP at accession number phs000930.

Repository Citation

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 and Environmental Health Faculty Publications. 20.
https://uknowledge.uky.edu/epidemiology_facpub/20