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.
abstract: 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/m2) 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.
authors.affiliation: 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.
authors.forename: Lindsay
authors.identifier: 0000-0001-6985-423X
authors.initials: L
authors.lastname: Fernández-Rhodes
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Gong
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Haessler
authors.affiliation: Department of Epidemiology, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Nora
authors.initials: N
authors.lastname: Franceschini
authors.affiliation: Department of Epidemiology, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Mariaelisa
authors.initials: M
authors.lastname: Graff
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Nishimura
authors.affiliation: Department of Epidemiology, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Epidemiology, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Highland
authors.affiliation: Department of Epidemiology, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Yoneyama
authors.affiliation: Department of Epidemiology and Biostatistics, Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: William S
authors.initials: WS
authors.lastname: Bush
authors.affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Goodloe
authors.affiliation: Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, USA.
authors.forename: Marylyn D
authors.initials: MD
authors.lastname: Ritchie
authors.affiliation: Department of Epidemiology and Biostatistics, Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Dana
authors.initials: D
authors.lastname: Crawford
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Myron
authors.initials: M
authors.lastname: Gross
authors.affiliation: Center for Human Genetics, The University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Myriam
authors.initials: M
authors.lastname: Fornage
authors.affiliation: Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA, USA.
authors.forename: Petra
authors.initials: P
authors.lastname: Buzkova
authors.affiliation: Department of Biostatistics, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Ran
authors.initials: R
authors.lastname: Tao
authors.affiliation: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Carmen
authors.initials: C
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authors.affiliation: National Heart Lung, and Blood Institute, Bethesda, MA, USA.
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authors.initials: L
authors.lastname: Avilés-Santa
authors.affiliation: Insitute of Minority Health Research, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Martha
authors.initials: M
authors.lastname: Daviglus
authors.affiliation: Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Rachel H
authors.initials: RH
authors.lastname: Mackey
authors.affiliation: Geriatrics and Gerontology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Denise
authors.initials: D
authors.lastname: Houston
authors.affiliation: Division of Biostatistics, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
authors.forename: C Charles
authors.initials: CC
authors.lastname: Gu
authors.affiliation: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.|Division of Cardiology, Geneva University Hospital, Geneva, OH, Switzerland.
authors.forename: Georg
authors.initials: G
authors.lastname: Ehret
authors.affiliation: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Khanh-Dung H
authors.initials: KH
authors.lastname: Nguyen
authors.affiliation: Department of Medicine, University of Alabama, Birmingham, AL, USA.
authors.forename: Cora E
authors.initials: CE
authors.lastname: Lewis
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Leppert
authors.affiliation: Department of Biostatistics, University of Alabama, Birmingham, AL, USA.
authors.forename: Marguerite R
authors.initials: MR
authors.lastname: Irvin
authors.affiliation: Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
authors.forename: Unhee
authors.initials: U
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authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Haiman
authors.affiliation: Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
authors.forename: Loic
authors.initials: L
authors.lastname: Le Marchand
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Fredrick
authors.initials: F
authors.lastname: Schumacher
authors.affiliation: Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
authors.forename: Lynne
authors.initials: L
authors.lastname: Wilkens
authors.affiliation: Charles R. Bronfman Instituted for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Yingchang
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Charles R. Bronfman Instituted for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Erwin P
authors.initials: EP
authors.lastname: Bottinger
authors.affiliation: Charles R. Bronfman Instituted for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Ruth J L
authors.initials: RJL
authors.lastname: Loos
authors.affiliation: Division of Endocrine and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.|School of Medicine, National Defense Medical Center, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Wayne H-H
authors.initials: WH
authors.lastname: Sheu
authors.affiliation: Department of Pediatrics, Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Wen-Jane
authors.initials: WJ
authors.lastname: Lee
authors.affiliation: Department of Pediatrics, Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Hai
authors.affiliation: Division of Endocrinology and Metabolism, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Yi-Jen
authors.initials: YJ
authors.lastname: Hung
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
authors.forename: Devin
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authors.lastname: Absher
authors.affiliation: Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Zhunan Town, Taiwan.
authors.forename: I-Chien
authors.initials: IC
authors.lastname: Wu
authors.affiliation: Department of Pediatrics, Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
authors.forename: Kent D
authors.initials: KD
authors.lastname: Taylor
authors.affiliation: Division of Endocrine and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.|School of Medicine, National Defense Medical Center, National Yang-Ming University, Taipei, Taiwan.
authors.forename: I-Te
authors.initials: IT
authors.lastname: Lee
authors.affiliation: Department of Pediatrics, Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
authors.forename: Yeheng
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Cardiovascular Center, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Tzung-Dau
authors.initials: TD
authors.lastname: Wang
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Thomas
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authors.lastname: Quertermous
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Cardiovascular Center, National Taiwan University Hospital, Taipei, Taiwan.
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authors.initials: JJ
authors.lastname: Juang
authors.affiliation: Department of Pediatrics, Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
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authors.initials: JI
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authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Themistocles
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authors.affiliation: Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Zhunan Town, Taiwan.
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authors.affiliation: Department of Pediatrics, Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
authors.forename: Yii-Der Ida
authors.initials: YI
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authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
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authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
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authors.initials: LH
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authors.affiliation: Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
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authors.initials: JE
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authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
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authors.affiliation: School of Social Welfare, The University of Kansas, Lawrence, KS, USA.
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authors.affiliation: Department of Epidemiology, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Whitney R
authors.initials: WR
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authors.affiliation: Department of Nutrition, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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authors.lastname: Gordon-Larsen
authors.affiliation: Division of Genomic Medicine, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
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authors.affiliation: Division of Genomic Medicine, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
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authors.affiliation: Department of Statistics and Biostatistics, Rutgers University, Piscataway, NJ, USA.
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authors.affiliation: Department of Genetics, Rutgers University, Piscataway, NJ, USA.
authors.forename: Tara C
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authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Ulrike
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authors.affiliation: Department of Epidemiology, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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mesh_terms: D015992:Body Mass Index; D005006:Ethnicity / Q000235:genetics*; D005828:Genetics, Population; D006801:Humans; D009765:Obesity / Q000453:epidemiology / Q000235:genetics