title: Generalization and fine mapping of European ancestry-based central adiposity variants in African ancestry populations.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: S
authors.initials: S
authors.lastname: Yoneyama
authors.affiliation: Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Yao
authors.affiliation: Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: L
authors.initials: L
authors.lastname: Fernandez-Rhodes
authors.affiliation: Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
authors.forename: U
authors.initials: U
authors.lastname: Lim
authors.affiliation: Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Boston
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Buzková
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Carlson
authors.affiliation: Cancer Prevention Institute of California, Fremont, CA, USA.
authors.forename: I
authors.initials: I
authors.lastname: Cheng
authors.affiliation: Baylor College of Medicine, Houston, TX, USA.|Division of Cardiology, Geneva University Hospital, Genève, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Cochran
authors.affiliation: Department of Public Health Sciences, Loyola University, Chicago, IL, USA.
authors.forename: R
authors.initials: R
authors.lastname: Cooper
authors.affiliation: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: G
authors.initials: G
authors.lastname: Ehret
authors.affiliation: The Human Genetics Center and Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Fornage
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Gong
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
authors.forename: M
authors.initials: M
authors.lastname: Gross
authors.affiliation: Department of Biostatistics, Washington University, St Louis, MO, USA.
authors.forename: C C
authors.initials: CC
authors.lastname: Gu
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Haessler
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Haiman
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Henderson
authors.affiliation: Division of Genomic Medicine, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Hindorff
authors.affiliation: Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: D
authors.initials: D
authors.lastname: Houston
authors.affiliation: Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Irvin
authors.affiliation: Department of Internal Medicine, Ohio State Medical Center, Columbus, OH, USA.
authors.forename: R
authors.initials: R
authors.lastname: Jackson
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Kuller
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
authors.forename: M
authors.initials: M
authors.lastname: Leppert
authors.affiliation: Department of Medicine, University of Alabama, Birmingham, AL, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: Lewis
authors.affiliation: Division of Genomic Medicine, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: R
authors.initials: R
authors.lastname: Li
authors.affiliation: Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
authors.forename: L
authors.initials: L
authors.lastname: Le Marchand
authors.affiliation: Department of Genetics, Rutgers University, Piscataway, NJ, USA.
authors.forename: T C
authors.initials: TC
authors.lastname: Matise
authors.affiliation: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: K-Dh
authors.initials: KD
authors.lastname: Nguyen
authors.affiliation: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Chakravarti
authors.affiliation: Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Pankow
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
authors.forename: N
authors.initials: N
authors.lastname: Pankratz
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Pooler
authors.affiliation: Department of Biochemistry and Molecular Biology, Pennsylvania State University, State College, PA, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Ritchie
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Bien
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Colchester, VT, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Wassel
authors.affiliation: Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
authors.forename: Y-D I
authors.initials: YI
authors.lastname: Chen
authors.affiliation: Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
authors.forename: K D
authors.initials: KD
authors.lastname: Taylor
authors.affiliation: Department of Preventive Medicine, School of Medicine, University of California San Diego, San Diego, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Allison
authors.affiliation: Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
authors.forename: J I
authors.initials: JI
authors.lastname: Rotter
authors.affiliation: Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Schreiner
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: F
authors.initials: F
authors.lastname: Schumacher
authors.affiliation: Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
authors.forename: L
authors.initials: L
authors.lastname: Wilkens
authors.affiliation: The Human Genetics Center and Institute of Molecular Medicine, Houston, TX, USA.|Department of Statistics and Biostatistics, Rutgers University, Piscataway, NJ, USA.
authors.forename: E
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Kooperberg
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: U
authors.initials: U
authors.lastname: Peters
authors.affiliation: Department of Genetics, Rutgers University, Piscataway, NJ, USA.
authors.forename: S
authors.initials: S
authors.lastname: Buyske
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: M
authors.initials: M
authors.lastname: Graff
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.|Carolina Center for Genome Sciences, Chapel Hill, NC, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: North
mesh_terms: D050154:Adiposity / Q000235:genetics*; D000328:Adult; D044383:Black People / Q000235:genetics*; D050218:Body Fat Distribution; D005260:Female; D020022:Genetic Predisposition to Disease / Q000208:ethnology; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D056128:Obesity, Abdominal / Q000208:ethnology / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D049629:Waist-Hip Ratio; D044465:White People / Q000235:genetics*