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.

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, Henry Ford Health System
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, Henry Ford Health Sciences CenterFollow
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, Henry Ford Health SystemFollow
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
Keoki L. Williams, Henry Ford Health SystemFollow
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

Document Type

Article

Publication Date

4-1-2017

Publication Title

PLoS Genet

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.

Medical Subject Headings

Adiposity; African Continental Ancestry Group; Anthropometry; Body Mass Index; Chromosome Mapping; European Continental Ancestry Group; Female; Gene Frequency; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Linkage Disequilibrium; Male; Obesity; Polymorphism, Single Nucleotide; Serine Endopeptidases; Transcription Factor 7-Like 2 Protein; Waist-Hip Ratio

PubMed ID

28430825

Volume

13

Issue

4

First Page

1006719

Last Page

1006719

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