Trans-ethnic fine-mapping of genetic loci for body mass index in the diverse ancestral populations of the Population Architecture using Genomics and Epidemiology (PAGE) Study reveals evidence for multiple signals at established loci

Lindsay Fernández-Rhodes; Jian Gong; Jeffrey Haessler; Nora Franceschini; Mariaelisa Graff; Katherine K Nishimura; Yujie Wang; Heather M Highland; Sachiko Yoneyama; William S Bush; Robert Goodloe; Marylyn D Ritchie; Dana Crawford; Myron Gross; Myriam Fornage; Petra Buzkova; Ran Tao; Carmen Isasi; Larissa Avilés-Santa; Martha Daviglus; Rachel H Mackey; Denise Houston; C Charles Gu; Georg Ehret; Khanh-Dung H Nguyen; Cora E Lewis; Mark Leppert; Marguerite R Irvin; Unhee Lim; Christopher A Haiman; Loic Le Marchand; Fredrick Schumacher; Lynne Wilkens; Yingchang Lu; Erwin P Bottinger; Ruth J L Loos; Wayne H-H Sheu; Xiuqing Guo; Wen-Jane Lee; Yang Hai; Yi-Jen Hung; Devin Absher; I-Chien Wu; Kent D Taylor; I-Te Lee; Yeheng Liu; Tzung-Dau Wang; Thomas Quertermous; Jyh-Ming J Juang; Jerome I Rotter; Themistocles Assimes; Chao A Hsiung; Yii-Der Ida Chen; Ross Prentice; Lewis H Kuller; JoAnn E Manson; Charles Kooperberg; Paul Smokowski; Whitney R Robinson; Penny Gordon-Larsen; Rongling Li; Lucia Hindorff; Steven Buyske; Tara C Matise; Ulrike Peters; Kari E North

doi:10.1007/s00439-017-1787-6

Back

Trans-ethnic fine-mapping of genetic loci for body mass index in the diverse ancestral populations of the Population Architecture using Genomics and Epidemiology (PAGE) Study reveals evidence for multiple signals at established loci

Journal article

Open access

Peer reviewed

Trans-ethnic fine-mapping of genetic loci for body mass index in the diverse ancestral populations of the Population Architecture using Genomics and Epidemiology (PAGE) Study reveals evidence for multiple signals at established loci

Lindsay Fernández-Rhodes, Jian Gong, Jeffrey Haessler, Nora Franceschini, Mariaelisa Graff, Katherine K Nishimura, Yujie Wang, Heather M Highland, Sachiko Yoneyama, William S Bush, …

Human genetics, Vol.136(6), pp.771-800

06/2017

DOI: https://doi.org/10.1007/s00439-017-1787-6

PMCID: PMC5485655

PMID: 28391526

Abstract

Body Mass Index

Ethnic Groups - genetics

Genetics, Population

Humans

Obesity - epidemiology

Obesity - genetics

Most body mass index (BMI) genetic loci have been identified in studies of primarily European ancestries. The effect of these loci in other racial/ethnic groups is less clear. Thus, we aimed to characterize the generalizability of 170 established BMI variants, or their proxies, to diverse US populations and trans-ethnically fine-map 36 BMI loci using a sample of >102,000 adults of African, Hispanic/Latino, Asian, European and American Indian/Alaskan Native descent from the Population Architecture using Genomics and Epidemiology Study. We performed linear regression of the natural log of BMI (18.5-70 kg/m ) on the additive single nucleotide polymorphisms (SNPs) at BMI loci on the MetaboChip (Illumina, Inc.), adjusting for age, sex, population stratification, study site, or relatedness. We then performed fixed-effect meta-analyses and a Bayesian trans-ethnic meta-analysis to empirically cluster by allele frequency differences. Finally, we approximated conditional and joint associations to test for the presence of secondary signals. We noted directional consistency with the previously reported risk alleles beyond what would have been expected by chance (binomial p < 0.05). Nearly, a quarter of the previously described BMI index SNPs and 29 of 36 densely-genotyped BMI loci on the MetaboChip replicated/generalized in trans-ethnic analyses. We observed multiple signals at nine loci, including the description of seven loci with novel multiple signals. This study supports the generalization of most common genetic loci to diverse ancestral populations and emphasizes the importance of dense multiethnic genomic data in refining the functional variation at genetic loci of interest and describing several loci with multiple underlying genetic variants.

Files and links (1)

url

https://doi.org/10.1007/s00439-017-1787-6View

Version of Record (VoR) Open

Metrics

11 Record Views

26 Times Cited - Web of Science

See more details

Details

Title: Trans-ethnic fine-mapping of genetic loci for body mass index in the diverse ancestral populations of the Population Architecture using Genomics and Epidemiology (PAGE) Study reveals evidence for multiple signals at established loci
Creators: Lindsay Fernández-Rhodes - Department of Epidemiology, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. fernandez-rhodes@unc.edu
Jian Gong - Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Jeffrey Haessler - Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Nora Franceschini - Department of Epidemiology, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Mariaelisa Graff - Department of Epidemiology, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Katherine K Nishimura - Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Yujie Wang - Department of Epidemiology, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Heather M Highland - Department of Epidemiology, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Sachiko Yoneyama - Department of Epidemiology, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
William S Bush - Department of Epidemiology and Biostatistics, Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA
Robert Goodloe - Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA
Marylyn D Ritchie - Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, USA
Dana Crawford - Department of Epidemiology and Biostatistics, Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA
Myron Gross - Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA
Myriam Fornage - Center for Human Genetics, The University of Texas Health Science Center at Houston, Houston, TX, USA
Petra Buzkova - Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA, USA
Ran Tao - Department of Biostatistics, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Carmen Isasi - Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
Larissa Avilés-Santa - National Heart Lung, and Blood Institute, Bethesda, MA, USA
Martha Daviglus - Insitute of Minority Health Research, University of Illinois at Chicago, Chicago, IL, USA
Rachel H Mackey - Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
Denise Houston - Geriatrics and Gerontology, Wake Forest School of Medicine, Winston-Salem, NC, USA
C Charles Gu - Division of Biostatistics, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA
Georg Ehret - Division of Cardiology, Geneva University Hospital, Geneva, OH, Switzerland
Khanh-Dung H Nguyen - Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA
Cora E Lewis - Department of Medicine, University of Alabama, Birmingham, AL, USA
Mark Leppert - Department of Human Genetics, University of Utah, Salt Lake City, UT, USA
Marguerite R Irvin - Department of Biostatistics, University of Alabama, Birmingham, AL, USA
Unhee Lim - Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
Christopher A Haiman - Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
Loic Le Marchand - Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
Fredrick Schumacher - Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
Lynne Wilkens - Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
Yingchang Lu - Charles R. Bronfman Instituted for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Erwin P Bottinger - Charles R. Bronfman Instituted for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Ruth J L Loos - Charles R. Bronfman Instituted for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Wayne H-H Sheu - School of Medicine, National Defense Medical Center, National Yang-Ming University, Taipei, Taiwan
Xiuqing Guo - Department of Pediatrics, Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA
Wen-Jane Lee - Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
Yang Hai - Department of Pediatrics, Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA
Yi-Jen Hung - Division of Endocrinology and Metabolism, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
Devin Absher - HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
I-Chien Wu - Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Zhunan Town, Taiwan
Kent D Taylor - Department of Pediatrics, Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA
I-Te Lee - School of Medicine, National Defense Medical Center, National Yang-Ming University, Taipei, Taiwan
Yeheng Liu - Department of Pediatrics, Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA
Tzung-Dau Wang - Division of Cardiology, Department of Internal Medicine, Cardiovascular Center, National Taiwan University Hospital, Taipei, Taiwan
Thomas Quertermous - Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
Jyh-Ming J Juang - Division of Cardiology, Department of Internal Medicine, Cardiovascular Center, National Taiwan University Hospital, Taipei, Taiwan
Jerome I Rotter - Department of Pediatrics, Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA
Themistocles Assimes - Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
Chao A Hsiung - Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Zhunan Town, Taiwan
Yii-Der Ida Chen - Department of Pediatrics, Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA
Ross Prentice - Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Lewis H Kuller - Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
JoAnn E Manson - Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA
Charles Kooperberg - Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Paul Smokowski - School of Social Welfare, The University of Kansas, Lawrence, KS, USA
Whitney R Robinson - Department of Epidemiology, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Penny Gordon-Larsen - Department of Nutrition, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Rongling Li - Division of Genomic Medicine, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
Lucia Hindorff - Division of Genomic Medicine, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
Steven Buyske - Department of Statistics and Biostatistics, Rutgers University, Piscataway, NJ, USA
Tara C Matise - Department of Genetics, Rutgers University, Piscataway, NJ, USA
Ulrike Peters - Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Kari E North - Department of Epidemiology, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Publication Details: Human genetics, Vol.136(6), pp.771-800
Date published: 06/2017
Grant note: N01HC95095 / NHLBI NIH HHS N01HC65235 / NHLBI NIH HHS U01 HG004803 / NHGRI NIH HHS HHSN268201100007C / NHLBI NIH HHS U01 HG004402 / NHGRI NIH HHS N01HC05187 / NHLBI NIH HHS UL1 TR001881 / NCATS NIH HHS UL1 TR000445 / NCATS NIH HHS HHSN268201100005G / NHLBI NIH HHS R56 AG023629 / NIA NIH HHS N01HC48049 / NHLBI NIH HHS HHSN268201100002C / WHI NIH HHS P30 ES010126 / NIEHS NIH HHS P30 DK020541 / NIDDK NIH HHS N01 HC045133 / NHLBI NIH HHS UM1 CA164973 / NCI NIH HHS HHSN268201100011C / NHLBI NIH HHS HHSN268201100011I / NHLBI NIH HHS HHSN268201100007I / NHLBI NIH HHS R01 HL080295 / NHLBI NIH HHS R01 CA063464 / NCI NIH HHS P2C HD050924 / NICHD NIH HHS R56 AG020098 / NIA NIH HHS HHSN268201100010C / NHLBI NIH HHS UL1 RR025005 / NCRR NIH HHS U01 HG004802 / NHGRI NIH HHS HHSN268201100005C / NHLBI NIH HHS N01HC45205 / NHLBI NIH HHS R01 HL059367 / NHLBI NIH HHS N01HC75150 / NHLBI NIH HHS R01 DK101855 / NIDDK NIH HHS R01 AG020098 / NIA NIH HHS R37 CA054281 / NCI NIH HHS R01 HL055673 / NHLBI NIH HHS HHSN268201100005I / NHLBI NIH HHS U01 HG007416 / NHGRI NIH HHS N01HC65233 / NHLBI NIH HHS T32 HL007055 / NHLBI NIH HHS N01HC65236 / NHLBI NIH HHS P01 CA033619 / NCI NIH HHS U01 HG007376 / NHGRI NIH HHS P30 DK063491 / NIDDK NIH HHS N01HC48050 / NHLBI NIH HHS N01HC85086 / NHLBI NIH HHS U01 HL080295 / NHLBI NIH HHS N01HC48047 / NHLBI NIH HHS UL1 TR001073 / NCATS NIH HHS HHSN268201100012C / NHLBI NIH HHS S10 OD018522 / NIH HHS R25 CA094880 / NCI NIH HHS R01 DK110113 / NIDDK NIH HHS HHSN268201100008I / NHLBI NIH HHS N01HC65237 / NHLBI NIH HHS N01 HC015103 / NHLBI NIH HHS U01 HG004798 / NHGRI NIH HHS R01 AG023629 / NIA NIH HHS N01 HC045134 / NHLBI NIH HHS HHSN268201100006C / NHLBI NIH HHS U01 CA164973 / NCI NIH HHS UL1 TR000124 / NCATS NIH HHS T32 HD007168 / NICHD NIH HHS HHSN268201200036C / NHLBI NIH HHS HHSN268201100002I / NHLBI NIH HHS R01 AG027058 / NIA NIH HHS U01 HL130114 / NHLBI NIH HHS U01 CA098758 / NCI NIH HHS R01 AG015928 / NIA NIH HHS U01 HG007417 / NHGRI NIH HHS S10 OD020069 / NIH HHS HHSN268201100008C / NHLBI NIH HHS N01HC65234 / NHLBI NIH HHS R01 DK089256 / NIDDK NIH HHS R01 HL086694 / NHLBI NIH HHS U01 HG007397 / NHGRI NIH HHS N01 HC035129 / NHLBI NIH HHS U01 HG004790 / NHGRI NIH HHS R01 HD057194 / NICHD NIH HHS N01WH22110 / WHI NIH HHS N01HC48048 / NHLBI NIH HHS N01HC85079 / NHLBI NIH HHS U01 HG004801 / NHGRI NIH HHS
Academic Unit: Statistics (SAS); Genetics (SAS)
Language: English
Resource Type: Journal article
Identifiers: 991031665367004646