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 WHRadjBMIfrom 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 WHRadjBMIand eight previously established loci at P < 5×10−8: seven for BMI, and one for WHRadjBMIin African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMIwhen 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 WHRadjBMIloci 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 WHRadjBMIloci 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 WHRadjBMIincluding 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.
Original language | English |
---|---|
Article number | e1006719 |
Journal | PLoS genetics |
Volume | 13 |
Issue number | 4 |
DOIs | |
State | Published - Apr 2017 |
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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. / The Bone Mineral Density in Childhood Study (BMDCS) Group.
In: PLoS genetics, Vol. 13, No. 4, e1006719, 04.2017.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry
T2 - African ancestry anthropometry genetics consortium
AU - The Bone Mineral Density in Childhood Study (BMDCS) Group
AU - Ng, Maggie C.Y.
AU - Graff, Mariaelisa
AU - Lu, Yingchang
AU - Justice, Anne E.
AU - Mudgal, Poorva
AU - Liu, Ching Ti
AU - Young, Kristin
AU - Yanek, Lisa R.
AU - Feitosa, Mary F.
AU - Wojczynski, Mary K.
AU - Rand, Kristin
AU - Brody, Jennifer A.
AU - Cade, Brian E.
AU - Dimitrov, Latchezar
AU - Duan, Qing
AU - Guo, Xiuqing
AU - Lange, Leslie A.
AU - Nalls, Michael A.
AU - Okut, Hayrettin
AU - Tajuddin, Salman M.
AU - Tayo, Bamidele O.
AU - Vedantam, Sailaja
AU - Bradfield, Jonathan P.
AU - Chen, Guanjie
AU - Chen, Wei Min
AU - Chesi, Alessandra
AU - Irvin, Marguerite R.
AU - Padhukasahasram, Badri
AU - Smith, Jennifer A.
AU - Zheng, Wei
AU - Allison, Matthew A.
AU - Ambrosone, Christine B.
AU - Bandera, Elisa V.
AU - Bartz, Traci M.
AU - Berndt, Sonja I.
AU - Bernstein, Leslie
AU - Blot, William J.
AU - Bottinger, Erwin P.
AU - Carpten, John
AU - Chanock, Stephen J.
AU - Chen, Yii Der Ida
AU - Conti, David V.
AU - Cooper, Richard S.
AU - Fornage, Myriam
AU - Freedman, Barry I.
AU - Garcia, Melissa
AU - Goodman, Phyllis J.
AU - Hsu, Yu Han H.
AU - Hu, Jennifer
AU - Rao, D. C.
N1 - Funding Information: AABC-MEC: 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. AABC-CARE: CARE was supported by National Institute for Child Health and Development contract NO1-HD-3-3175. AABC-WCHS: WCHS is supported by a U.S. Army Medical Research and Material Command (USAMRMC) grant DAMD-17-01-0-0334, National Institutes of Health grant CA100598, and the Breast Cancer Research Foundation. AABC-SFBCS: SFBCS was supported by National Institutes of Health grant CA77305 and United States Army Medical Research Program grant DAMD17-96-6071. AABC-NC-BCFR: The Breast Cancer Family Registry (BCFR) was supported by the National Cancer Institute, National Institutes of Health under RFA CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry and Principal Investigators, including the Cancer Prevention Institute of California (U01 CA69417). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government or the BCFR. AABC-CBCS: CBCS is supported by National Institutes of Health Specialized Program of Research Excellence in Breast Cancer grant CA58223 and Center for Environmental Health and Susceptibility, National Institute of Environmental Health Sciences, National Institutes of Health, grant ES10126. AABC-PLCO: Genotyping of the PLCO samples was funded by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, the National Institutes of Health. The authors thank Drs. Christine Berg and Philip Prorok, Division of Cancer Prevention, National Cancer Institute, the screening center investigators and staff of the PLCO Cancer Screening Trial, Mr. Thomas Riley and staff at Information Management Services, Inc., and Ms. Barbara O’Brien and staff at Westat, Inc. for their contributions to the PLCO Cancer Screening Trial. AABC-NBHS: NBHS is support by National Institutes of Health grant CA100374. NBHS sample preparation was conducted at the Biospecimen Core Lab that is supported in part by the Vanderbilt-Ingram Cancer Center (CA68485). AABC-WFBC: WFBC is supported by National Institutes of Health grant CA73629. AAPC-CPS-II: CPSII is supported by the American Cancer Society. AAPC-KCPCS: KCPCS was supported by National Institutes of Health grants CA056678, CA082664 and CA092579, with additional support from the Fred Hutchinson Cancer Research Center. AAPC-LAAPC: LAAPC was funded by grant 99-00524V-10258 from the Cancer Research Fund, under Interagency Agreement #97-12013 (University of California contract #98-00924V) with the Department of Health Services Cancer Research Program. AAPC-DCPC: DCPC was supported by National Institutes of Health grant S06GM08016 and Department of Defense grants DAMD W81XWH-07-1-0203 and DAMD W81XWH-06-1-0066. AAPC-MEC: The MEC and genotyping of samples for the GWAS of prostate cancer was supported by National Institutes of Health grants CA63464, CA54281, CA164973, CA1326792, CA148085 and HG004726. AAPC-SELECT trial: The SELECT trial is supported by National Cancer Institute grants U10CA37429 and 5UM1CA182883. AAPC-PLCO: See AABC-PLCO. AAPC-GECAP: GECAP was supported by National Institutes of Health grant ES011126. AAPC-SCCS: SCCS is funded by National Institutes of Health grant CA092447. SCCS sample preparation was conducted at the Biospecimen Core Lab that is supported in part by the Vanderbilt-Ingram Cancer Center (CA68485). AAPC-MDA: MDA was support by grants CA68578, ES007784, DAMD W81XWH-07-1-0645, and CA140388. AAPC-CaP Genes: CaP Genes was supported by CA88164 and CA127298. ARIC: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. BioMe: NIH/NHGRI U01HG007417. BMDCS: We thank the investigators Heidi Kalkwarf, Joan Lappe, Sharon Oberfield, Vicente Gilsanz, John Shepherd and Andrea Kelly for their contribution. BMDCS is supported by NIH: R01 HD58886, HD076321, DK094723-01, DK102659-01; NICHD N01-HD-1-3228, -3329, -3330, -3331, -3332, -3333; CTSA program Grant 8 UL1 TR000077. CARDIA: The Coronary Artery Risk Development in Young Adults (CARDIA) study is supported by the NHLBI (contracts HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, and HHSN268200900041C); the Intramural Research Program of the National Institute on Aging (NIA); and an intra-agency agreement between the NIA and the NHLBI (grant AG0005). CFS: The Cleveland Family Study (CFS) is supported by the National Institutes of Health: HL046380, HL113338, RR000080. Dr. Cade has been supported by HL007901. CHOP: This research was financially supported by an Institute Development Award from the Children’s Hospital of Philadelphia, a Research Development Award from the Cotswold Foundation, NIH grant R01 HD056465 and the Daniel B. Burke Endowed Chair for Diabetes Research (SFAG). CHS: This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL085251, R01HL087652, R01HL105756, R01HL103612, R01HL120393 and HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Participants provided informed consent for participation in DNA studies. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. FamHS: NIH/NIDDK R01DK089256, and NIH/NHLBI R01HL117078. GeneSTAR: NIH/NHLBI U01 HL72518; NIH/NHLBI HL087698; NIH/NHLBI 58625-01A1; NIH/NHLBI HL071025-01A1; NIH/NINR NR0224103; NIH/NCRR M01-RR000052. HANDLS: Healthy Aging in Neighborhoods of Diversity across the Life Span Study (HANDLS) was supported by the Intramural Research Program of the NIH, National Institute on Aging and the National Center on Minority Health and Health Disparities (project # Z01-AG000513 and human subjects protocol # 2009-149). HealthABC: Health, Aging, and Body Composition Study (Health ABC Study) was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and 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 HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. HRS: HRS is supported by the National Institute on Aging (NIA U01AG009740). The genotyping was funded separately by the National Institute on Aging (RC2 AG036495, RC4 AG039029), and the analysis was funded in part by R03 AG046389. Our genotyping was conducted by the NIH Center for Inherited Disease Research (CIDR) at Johns Hopkins University. Genotyping quality control and final preparation of the data were performed by the Genetics Coordinating Center at the University of Washington. HUFS: The HUFS (Howard University Family Study) was supported by grants S06GM008016-380111 to AA and S06GM008016-320107 to CR, both from the NIGMS/MBRS/SCORE Program. Participant enrollment for the HUFS was carried out at the Howard University General Clinical Research Center (GCRC), which was supported by grant 2M01RR010284 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). This research was supported in part by the NIH Intramural Research Program in the Center for Research on Genomics and Global Health (CRGGH) with support from the National Human Genome Research Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Center for Information Technology, and the Office of the Director at the National Institutes of Health (Z01HG200362). HyperGEN: The HyperGEN network is funded by cooperative agreements (U10) with NHLBI: HL54471, HL54472, HL54473, HL54495, HL54496, HL54497, HL54509, HL54515, and R01 HL55673 from the National Heart, Lung, and Blood Institute. The study involves: University of Utah: (Network Coordinating Center, Field Center, and Molecular Genetics Lab); Univ. of Alabama at Birmingham: (Field Center and Echo Coordinating and Analysis Center); Medical College of Wisconsin: (Echo Genotyping Lab); Boston University: (Field Center); University of Minnesota: (Field Center and Biochemistry Lab); University of North Carolina: (Field Center); Washington University: (Data Coordinating Center); Weil Cornell Medical College: (Echo Reading Center); National Heart, Lung, & Blood Institute. For a complete list of HyperGEN Investigators: http://www.biostat.wustl.edu/hypergen/Acknowledge.html. JHS: The Jackson Heart Study is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. JGW is supported by U54GM115428 from the National Institute of General Medical Sciences. Maywood: NIH: R37-HL045508, R01-HL074166, R01-HL086718, R01-HG003054; analysis also funded through R01-DK075787. MESA: The Multi-Ethnic Study of Atherosclerosis study (MESA) was supported by the Multi-Ethnic Study of Atherosclerosis (MESA) contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169 and by grants UL1-TR-000040 and UL1-RR-025005 from NCRR. Funding for MESA SHARe genotyping was provided by NHLBI Contract N02-HL-6-4278. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. 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. We gratefully acknowledge the contribution of all participants from the various studies that contributed to this work. Publisher Copyright: © 2017 Public Library of Science. All rights reserved.
PY - 2017/4
Y1 - 2017/4
N2 - 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 WHRadjBMIfrom 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 WHRadjBMIand eight previously established loci at P < 5×10−8: seven for BMI, and one for WHRadjBMIin African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMIwhen 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 WHRadjBMIloci 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 WHRadjBMIloci 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 WHRadjBMIincluding 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.
AB - 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 WHRadjBMIfrom 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 WHRadjBMIand eight previously established loci at P < 5×10−8: seven for BMI, and one for WHRadjBMIin African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMIwhen 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 WHRadjBMIloci 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 WHRadjBMIloci 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 WHRadjBMIincluding 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.
UR - http://www.scopus.com/inward/record.url?scp=85018433032&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1006719
DO - 10.1371/journal.pgen.1006719
M3 - Article
C2 - 28430825
AN - SCOPUS:85018433032
VL - 13
JO - PLoS Genetics
JF - PLoS Genetics
SN - 1553-7390
IS - 4
M1 - e1006719
ER -