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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.

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.

SUBMITTER: Ng MCY

PROVIDER: S-EPMC5419579 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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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.

Ng Maggie C Y MCY Graff Mariaelisa M Lu Yingchang Y Justice Anne E AE Mudgal Poorva P Liu Ching-Ti CT Young Kristin K Yanek Lisa R LR Feitosa Mary F MF Wojczynski Mary K MK Rand Kristin K Brody Jennifer A JA Cade Brian E BE Dimitrov Latchezar L Duan Qing Q Guo Xiuqing X Lange Leslie A LA Nalls Michael A MA Okut Hayrettin H Tajuddin Salman M SM Tayo Bamidele O BO Vedantam Sailaja S Bradfield Jonathan P JP Chen Guanjie G Chen Wei-Min WM Chesi Alessandra A Irvin Marguerite R MR Padhukasahasram Badri B Smith Jennifer A JA Zheng Wei W Allison Matthew A MA Ambrosone Christine B CB Bandera Elisa V EV Bartz Traci M TM Berndt Sonja I SI Bernstein Leslie L Blot William J WJ Bottinger Erwin P EP Carpten John J Chanock Stephen J SJ Chen Yii-Der Ida YI Conti David V DV Cooper Richard S RS Fornage Myriam M Freedman Barry I BI Garcia Melissa M Goodman Phyllis J PJ Hsu Yu-Han H YH Hu Jennifer J Huff Chad D CD Ingles Sue A SA John Esther M EM Kittles Rick R Klein Eric E Li Jin J McKnight Barbara B Nayak Uma U Nemesure Barbara B Ogunniyi Adesola A Olshan Andrew A Press Michael F MF Rohde Rebecca R Rybicki Benjamin A BA Salako Babatunde B Sanderson Maureen M Shao Yaming Y Siscovick David S DS Stanford Janet L JL Stevens Victoria L VL Stram Alex A Strom Sara S SS Vaidya Dhananjay D Witte John S JS Yao Jie J Zhu Xiaofeng X Ziegler Regina G RG Zonderman Alan B AB Adeyemo Adebowale A Ambs Stefan S Cushman Mary M Faul Jessica D JD Hakonarson Hakon H Levin Albert M AM Nathanson Katherine L KL Ware Erin B EB Weir David R DR Zhao Wei W Zhi Degui D Arnett Donna K DK Grant Struan F A SFA Kardia Sharon L R SLR Oloapde Olufunmilayo I OI Rao D C DC Rotimi Charles N CN Sale Michele M MM Williams L Keoki LK Zemel Babette S BS Becker Diane M DM Borecki Ingrid B IB Evans Michele K MK Harris Tamara B TB Hirschhorn Joel N JN Li Yun Y Patel Sanjay R SR Psaty Bruce M BM Rotter Jerome I JI Wilson James G JG Bowden Donald W DW Cupples L Adrienne LA Haiman Christopher A CA Loos Ruth J F RJF North Kari E KE

PLoS genetics 20170421 4

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 i ...[more]

PMID: 28430825

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Project description:BACKGROUND/OBJECTIVES:Central adiposity measures such as waist circumference (WC) and waist-to-hip ratio (WHR) are associated with cardiometabolic disorders independently of body mass index (BMI) and are gaining clinically utility. Several studies report genetic variants associated with central adiposity, but most utilize only European ancestry populations. Understanding whether the genetic associations discovered among mainly European descendants are shared with African ancestry populations will help elucidate the biological underpinnings of abdominal fat deposition. SUBJECTS/METHODS:To identify the underlying functional genetic determinants of body fat distribution, we conducted an array-wide association meta-analysis among persons of African ancestry across seven studies/consortia participating in the Population Architecture using Genomics and Epidemiology (PAGE) consortium. We used the Metabochip array, designed for fine-mapping cardiovascular-associated loci, to explore novel array-wide associations with WC and WHR among 15?945 African descendants using all and sex-stratified groups. We further interrogated 17 known WHR regions for African ancestry-specific variants. RESULTS:Of the 17 WHR loci, eight single-nucleotide polymorphisms (SNPs) located in four loci were replicated in the sex-combined or sex-stratified meta-analyses. Two of these eight independently associated with WHR after conditioning on the known variant in European descendants (rs12096179 in TBX15-WARS2 and rs2059092 in ADAMTS9). In the fine-mapping assessment, the putative functional region was reduced across all four loci but to varying degrees (average 40% drop in number of putative SNPs and 20% drop in genomic region). Similar to previous studies, the significant SNPs in the female-stratified analysis were stronger than the significant SNPs from the sex-combined analysis. No novel associations were detected in the array-wide analyses. CONCLUSIONS:Of 17 previously identified loci, four loci replicated in the African ancestry populations of this study. Utilizing different linkage disequilibrium patterns observed between European and African ancestries, we narrowed the suggestive region containing causative variants for all four loci.

Dataset Information

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.

Publications

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.

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