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.; 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; Oloapde, Olufunmilayo I.

2017

Download

Formats

Format
BibTeX
MARCXML
TextMARC
MARC
DataCite
DublinCore
EndNote
NLM
RefWorks
RIS

Add to Basket

Files

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.

Details

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

Author

Ng, Maggie C. Y. : Wake Forest University : (http://orcid.org/0000-0002-4133-2007)
Graff, Mariaelisa : University of North Carolina
Lu, Yingchang : Mount Sinai
Justice, Anne E. : University of North Carolina
Mudgal, Poorva : Wake Forest University
Liu, Ching-Ti : Boston University
Young, Kristin : University of North Carolina
Yanek, Lisa R. : Johns Hopkins University : (http://orcid.org/0000-0001-7117-1075)
Feitosa, Mary F. : Washington University
Wojczynski, Mary K. : Washington University : (http://orcid.org/0000-0002-2420-162X)
Rand, Kristin : University of Southern California
Brody, Jennifer A. : University of Washington : (http://orcid.org/0000-0001-8509-148X)
Cade, Brian E. : Harvard University : (http://orcid.org/0000-0003-1424-0673)
Dimitrov, Latchezar : Wake Forest University
Duan, Qing : University of North Carolina
Guo, Xiuqing : University of California Los Angeles
Lange, Leslie A. : University of North Carolina
Nalls, Michael A. : National Institute on Aging
Okut, Hayrettin : Wake Forest University
Oloapde, Olufunmilayo I. : University of Chicago

Content Type

Article

Published in

PLOS Genetics

Identifier(s)

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

Data availability statement

All relevant data are within the paper and its Supporting Information files. Summary association statistics from meta-analyses are available from dbGAP at accession number phs000930.

Funding Information

National Institutes of Health, CA63464
National Institutes of Health, CA54281
National Institutes of Health, CA164973
National Institutes of Health, CA1326792
National Institutes of Health, CA148085
National Institutes of Health, HG004726
Department of Defense, Breast Cancer Research Program Era of Hope Scholar Award, W81XWH-08-1-0383
Norris Foundation
National Institute for Child Health and Development, NO1-HD-3-3175
U.S. Army Medical Research and Material Command, DAMD-17-01-0-0334
National Institutes of Health, CA100598
Breast Cancer Research Foundation
National Institutes of Health, CA77305
United States Army, Medical Research Program, DAMD17-96-6071
National Cancer Institute, RFA CA-06-503
Cancer Prevention Institute of California, U01 CA69417
National Institutes of Health, Specialized Program of Research Excellence in Breast Cancer, CA58223
National Institute of Environmental Health Sciences, ES10126
National Cancer Institute, Intramural Research Program
National Institutes of Health, CA100374
Vanderbilt-Ingram Cancer Center, CA68485
National Institutes of Health, CA73629
American Cancer Society
National Institutes of Health, CA056678
National Institutes of Health, CA082664
National Institutes of Health, CA092579
Fred Hutchinson Cancer Research Center
Department of Health Services, Cancer Research Program, 99-00524V-10258
National Institutes of Health, S06GM08016
Department of Defense, DAMD W81XWH-07-1-0203
Department of Defense, DAMD W81XWH-06-1-0066
National Institutes of Health, CA63464
National Institutes of Health, CA54281
National Institutes of Health, CA164973
National Institutes of Health, CA1326792
National Institutes of Health, CA148085
National Institutes of Health, HG004726
National Cancer Institute, U10CA37429
National Cancer Institute, 5UM1CA182883
National Institutes of Health, ES011126
National Institutes of Health, CA092447
Vanderbilt-Ingram Cancer Center, CA68485
CA68578
ES007784
DAMD W81XWH-07-1-0645
CA140388
CA88164
CA127298
National Heart, Lung, and Blood Institute, HHSN268201100005C
National Heart, Lung, and Blood Institute, HHSN268201100006C
National Heart, Lung, and Blood Institute, HHSN268201100007C
National Heart, Lung, and Blood Institute, HHSN268201100008C
National Heart, Lung, and Blood Institute, HHSN268201100009C
National Heart, Lung, and Blood Institute, HHSN268201100010C
National Heart, Lung, and Blood Institute, HHSN268201100011C
National Heart, Lung, and Blood Institute, HHSN268201100012C
National Heart, Lung, and Blood Institute, R01HL087641
National Heart, Lung, and Blood Institute, R01HL59367
National Heart, Lung, and Blood Institute, R01HL086694
National Human Genome Research Institute, U01HG004402
National Institutes of Health, HHSN268200625226C
National Institutes of Health, UL1RR025005
National Institutes of Health, U01HG007417
National Institutes of Health, HD58886
National Institutes of Health, HD076321
National Institutes of Health, DK094723-01
National Institutes of Health, DK102659-01
National Institutes of Health, N01-HD-1-3228
National Institutes of Health, N01-HD-1-3329
National Institutes of Health, N01-HD-1-3330
National Institutes of Health, N01-HD-1-3331
National Institutes of Health, N01-HD-1-3332
National Institutes of Health, N01-HD-1-3333
CTSA, Grant 8, UL1 TR000077
NHLBI, HHSN268201300025C
NHLBI, HHSN268201300026C
NHLBI, HHSN268201300027C
NHLBI, HHSN268201300028C
NHLBI, HHSN268201300029C
NHLBI, HHSN268200900041C
National Institute on Aging, Intramural Research Program
NIA/NHLBI, AG0005
National Institutes of Health, HL046380
National Institutes of Health, HL113338
National Institutes of Health, RR000080
National Institutes of Health, HL007901
Children’s Hospital of Philadelphia, Institute Development Award
Cotswold Foundation, Research Development Award
National Institutes of Health, R01 HD056465
SFAG, Daniel B. Burke Endowed Chair for Diabetes Research
NHLBI, HHSN268201200036C
NHLBI, HHSN268200800007C
NHLBI, N01HC55222
NHLBI, N01HC85079
NHLBI, N01HC85080
NHLBI, N01HC85081
NHLBI, N01HC85082
NHLBI, N01HC85083
NHLBI, N01HC85086
NHLBI, U01HL080295
NHLBI, R01HL085251
NHLBI, R01HL087652
NHLBI, R01HL105756
NHLBI, R01HL103612
NHLBI, R01HL120393
NHLBI, HL130114
National Institute of Neurological Disorders and Stroke
National Institute on Aging, R01AG023629
National Center for Advancing Translational Sciences, UL1TR000124
National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center, DK063491
National Institutes of Health, R37-HL045508
National Institutes of Health, R01-HL053353
National Institutes of Health, R01-DK075787
National Institutes of Health, U01-HL054512
National Institutes of Health, R01-DK075787
National Institutes of Health, R01-CA142996
National Institutes of Health, P50-CA125183
National Institutes of Health, R01-CA89085
National Institutes of Health, U01-CA161032
American Cancer Society, MRSG-13-063-01-TBG
American Cancer Society, CRP-10-119-01-CCE
NHLBI, R01HL118267
NIAID, R01AI079139
NIDDK, R01DK064695
NIDDK, R01 DK113003
American Asthma Foundation
R01 DK084350
National Institute of Neurological Disorders and Stroke, U01 NS041588
National Institutes of Health, HHSC268200782096C
National Institutes of Health, R01 DK087914
National Institutes of Health, R01 DK066358
National Institutes of Health, R01 DK053591
National Institutes of Health, R01 HL56266
National Institutes of Health, R01 DK070941
Wake Forest University, M01 RR07122
Wake Forest University, Venture Fund, 20543
NHGRI, U01HG004790
National Heart, Lung, and Blood Institute, N01WH22110
U.S. Department of Health and Human Services, 24152
U.S. Department of Health and Human Services, 32100-2
U.S. Department of Health and Human Services, 32105-6
U.S. Department of Health and Human Services, 32108-9
U.S. Department of Health and Human Services, 32111-13
U.S. Department of Health and Human Services, 32115
U.S. Department of Health and Human Services, 32118-32119
U.S. Department of Health and Human Services, 32122
U.S. Department of Health and Human Services, 42107-26
U.S. Department of Health and Human Services, 42129-32
U.S. Department of Health and Human Services, 44221
R01 DK101855-01
R01 DK089256
R01 DK089256
R01 DK101855-01
15GRNT25880008
KL2TR001109
R01 DK089256
R01 DK101855-01
R01HG006292
R01HL129132

Publication Date

2017-04-21

Language

English

Copyright Statement

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.

Acknowledgments/ Other Resources

Nigeria: NIH: R37-HL045508, R01-HL053353, R01-DK075787 and U01-HL054512; analysis also funded through R01-DK075787. ROOT: NIH: R01-CA142996, P50-CA125183, R01-CA89085, and U01-CA161032. American Cancer Society: MRSG-13-063-01-TBG and CRP-10-119-01-CCE. SAPPHIRE: NIH/NHLBI R01HL118267; NIH/NIAID R01AI079139; NIH/NIDDK R01DK064695 and R01 DK113003; American Asthma Foundation. SIGNET-REGARDS: The Sea Islands Genetics Network (SIGNET) was supported by R01 DK084350 (MM Sale). The authors thank the other investigators, the staff, and the participants of the REGARDS study for their valuable contributions. A full list of participating REGARDS investigators and institutions can be found at http://www.regardsstudy.org. This study (REGARDS) was supported by a cooperative agreement U01 NS041588 from the National Institute of Neurological Disorders and Stroke (NINDS). WFSM: Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSC268200782096C. This work was supported by National Institutes of Health grants R01 DK087914, R01 DK066358, R01 DK053591, R01 HL56266, R01 DK070941 and by the Wake Forest School of Medicine grant M01 RR07122 and Venture Fund 20543. WHI: Funding support for the “Epidemiology of putative genetic variants: The Women’s Health Initiative” study is provided through the NHGRI PAGE program (U01HG004790 and its NHGRI ARRA supplement). The WHI program is funded by the National Heart, Lung, and Blood Institute; NIH; and U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: http://www.whiscience.org/publications/ WHI_investigators_shortlist.pdf. CAH: R01 DK101855-01. CL: R01 DK089256. KEN: R01 DK089256, R01 DK101855-01, 15GRNT25880008. KLY: KL2TR001109. LAC: R01 DK089256. RJFL: R01 DK101855-01. YLi: R01HG006292 and R01HL129132. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Record Appears in

Centers and Institutes > Center for Clinical Cancer Genetics and Global Health
Biological Sciences Division > Human Genetics
Biological Sciences Division > Medicine
All

Record Created

2023-07-17

Actions

Preview

Statistics

Download Full History