title: Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation.
abstract: Variation in body fat distribution contributes to the metabolic sequelae of obesity. The genetic determinants of body fat distribution are poorly understood. The goal of this study was to gain new insights into the underlying genetics of body fat distribution by conducting sample-size-weighted fixed-effects genome-wide association meta-analyses in up to 9,594 women and 8,738 men of European, African, Hispanic and Chinese ancestry, with and without sex stratification, for six traits associated with ectopic fat (hereinafter referred to as ectopic-fat traits). In total, we identified seven new loci associated with ectopic-fat traits (ATXN1, UBE2E2, EBF1, RREB1, GSDMB, GRAMD3 and ENSA; P < 5 × 10-8; false discovery rate < 1%). Functional analysis of these genes showed that loss of function of either Atxn1 or Ube2e2 in primary mouse adipose progenitor cells impaired adipocyte differentiation, suggesting physiological roles for ATXN1 and UBE2E2 in adipogenesis. Future studies are necessary to further explore the mechanisms by which these genes affect adipocyte biology and how their perturbations contribute to systemic metabolic disease.
authors.affiliation: NHLBI's Framingham Heart Study, Framingham, Massachusetts, USA.|Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Audrey Y
authors.initials: AY
authors.lastname: Chu
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
authors.forename: Xuan
authors.initials: X
authors.lastname: Deng
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
authors.forename: Virginia A
authors.initials: VA
authors.lastname: Fisher
authors.affiliation: Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Drong
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Genetics, Washington University, St. Louis, Missouri, USA.
authors.forename: Mary F
authors.initials: MF
authors.lastname: Feitosa
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
authors.forename: Ching-Ti
authors.initials: CT
authors.lastname: Liu
authors.affiliation: Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Olivia
authors.initials: O
authors.lastname: Weeks
authors.affiliation: Division of Epidemiology and Biostatistics, Department of Population and Public Health Sciences, Wright State University Boonshoft School of Medicine, Dayton, Ohio, USA.
authors.forename: Audrey C
authors.initials: AC
authors.lastname: Choh
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Duan
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Health Science Center at San Antonio &University of Texas of the Rio Grande Valley, Brownsville, Texas, USA.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Dyer
authors.affiliation: NHLBI's Framingham Heart Study, Framingham, Massachusetts, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Eicher
authors.affiliation: Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, California, USA.
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
authors.forename: Nancy L
authors.identifier: 0000-0001-9730-0306
authors.initials: NL
authors.lastname: Heard-Costa
authors.affiliation: Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.|German Center for Cardiovascular Research (DZHK), Greifswald, Germany.
authors.forename: Tim
authors.identifier: 0000-0002-5393-2413
authors.initials: T
authors.lastname: Kacprowski
authors.affiliation: TOPS Nutrition and Obesity Research Center, Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, USA.
authors.forename: Jack W
authors.initials: JW
authors.lastname: Kent
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Lange
authors.affiliation: University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Xinggang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.|Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Kurt
authors.initials: K
authors.lastname: Lohman
authors.affiliation: Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Lingyi
authors.initials: L
authors.lastname: Lu
authors.affiliation: Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Anubha
authors.initials: A
authors.lastname: Mahajan
authors.affiliation: University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: O'Connell
authors.affiliation: University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Ankita
authors.initials: A
authors.lastname: Parihar
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Health Science Center at San Antonio &University of Texas of the Rio Grande Valley, Brownsville, Texas, USA.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Peralta
authors.affiliation: Icelandic Heart Association, Kopavogur, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Albert V
authors.identifier: 0000-0003-1942-5845
authors.initials: AV
authors.lastname: Smith
authors.affiliation: TOPS Obesity and Metabolic Research Center, Biotechnology and Bioengineering Center, Department of Physiology at the Medical College of Wisconsin, Wisconsin, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Homuth
authors.affiliation: TOPS Obesity and Metabolic Research Center, Biotechnology and Bioengineering Center, Department of Physiology at the Medical College of Wisconsin, Wisconsin, USA.
authors.forename: Ahmed H
authors.initials: AH
authors.lastname: Kissebah
authors.affiliation: Department of Surgical Sciences, Section of Radiology, Uppsala University, Uppsala, Sweden.
authors.forename: Joel
authors.initials: J
authors.lastname: Kullberg
authors.affiliation: Department of Neuroradiology, University Hospital Berne, Berne, Switzerland.
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authors.affiliation: National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, Maryland, USA.
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authors.initials: LJ
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authors.affiliation: German Center for Cardiovascular Research (DZHK), Greifswald, Germany.|Institute for Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Nauck
authors.affiliation: TOPS Nutrition and Obesity Research Center, Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, USA.|TOPS Obesity and Metabolic Research Center, Biotechnology and Bioengineering Center, Department of Physiology at the Medical College of Wisconsin, Wisconsin, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Olivier
authors.affiliation: Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Peyser
authors.affiliation: Department of Radiology and Radiologic Sciences, Department of Cardiovascular Medicine and Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: Terry
authors.affiliation: Department of Genetics, Washington University, St. Louis, Missouri, USA.
authors.forename: Mary K
authors.initials: MK
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authors.affiliation: Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, California, USA.
authors.forename: Jie
authors.initials: J
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authors.affiliation: Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Lawrence F
authors.initials: LF
authors.lastname: Bielak
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Health Science Center at San Antonio &University of Texas of the Rio Grande Valley, Brownsville, Texas, USA.
authors.forename: John
authors.initials: J
authors.lastname: Blangero
authors.affiliation: Department of Genetics, Washington University, St. Louis, Missouri, USA.
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Borecki
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA.|Department of Biochemistry, Center for Diabetes Research, and Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
authors.affiliation: Department of Radiology and Radiologic Sciences, Department of Cardiovascular Medicine and Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: John Jeffrey
authors.identifier: 0000-0002-4398-8237
authors.initials: JJ
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authors.affiliation: Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas Health Science Center (UTHealth) School of Public Health Brownsville Campus, Brownsville, Texas, USA.
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Czerwinski
authors.affiliation: Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.|Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Jingzhong
authors.initials: J
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authors.affiliation: German Center for Cardiovascular Research (DZHK), Greifswald, Germany.|Institute for Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Nele
authors.initials: N
authors.lastname: Friedrich
authors.affiliation: Icelandic Heart Association, Kopavogur, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Vilmunder
authors.initials: V
authors.lastname: Gudnason
authors.affiliation: National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Tamara B
authors.initials: TB
authors.lastname: Harris
authors.affiliation: Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.|Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Ingelsson
authors.affiliation: NHLBI's Framingham Heart Study, Framingham, Massachusetts, USA.
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authors.initials: AD
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authors.affiliation: Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.
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authors.affiliation: Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
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authors.initials: CD
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authors.affiliation: Department of Surgical Sciences, Section of Radiology, Uppsala University, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
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authors.affiliation: Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.|Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
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authors.affiliation: University of Maryland School of Medicine, Baltimore, Maryland, USA.|Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, Maryland, USA.
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authors.initials: BD
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authors.affiliation: Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, UK.|Department of Biostatistics, University of Liverpool, Liverpool, UK.
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authors.initials: AP
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authors.affiliation: University of Mississippi Medical Center, Jackson, Mississippi, USA.
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authors.initials: TH
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authors.initials: JI
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authors.affiliation: University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Alan R
authors.initials: AR
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authors.affiliation: Division of Epidemiology and Biostatistics, Department of Population and Public Health Sciences, Wright State University Boonshoft School of Medicine, Dayton, Ohio, USA.
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authors.initials: B
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authors.affiliation: German Center for Cardiovascular Research (DZHK), Greifswald, Germany.|Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.|German Center for Diabetes Research (DZD), Greifswald, Germany.
authors.forename: Henry
authors.initials: H
authors.lastname: Völzke
authors.affiliation: Institute for Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
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authors.initials: H
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authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
authors.forename: James G
authors.initials: JG
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authors.affiliation: Division of Preventive Medicine, Department of Family Medicine and Public Health, University of California San Diego School of Medicine, San Diego, California, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Allison
authors.affiliation: Li Ka Shing Center for Health Information and Discovery, Big Data Institute, University of Oxford, Oxford, UK.
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Lindgren
authors.affiliation: Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.|Gastroenterology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Wolfram
authors.identifier: 0000-0001-9972-1569
authors.initials: W
authors.lastname: Goessling
authors.affiliation: NHLBI's Framingham Heart Study, Framingham, Massachusetts, USA.|Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
authors.forename: L Adrienne
authors.initials: LA
authors.lastname: Cupples
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Steinhauser
authors.affiliation: NHLBI's Framingham Heart Study, Framingham, Massachusetts, USA.|Division of Endocrinology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Fox
mesh_terms: D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D050218:Body Fat Distribution; D002454:Cell Differentiation; D015331:Cohort Studies; D005006:Ethnicity / Q000235:genetics; D005260:Female; D056426:Genetic Loci / Q000235:genetics*; D005819:Genetic Markers / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D005819:Genetic Markers