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Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation

Nature Genetics volume 49, pages 125130 (2017) | Download Citation

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.

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Acknowledgements

The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute, the National Institutes of Health, or the US Department of Health and Human Services. Please see the Supplementary Note for acknowledgments and funding sources.

Author information

Author notes

    • Audrey Y Chu
    •  & Caroline S Fox

    Present address: Merck Research Laboratories, Boston, Massachusetts, USA.

    • Ahmed H Kissebah

    Deceased.

    • Audrey Y Chu
    • , Xuan Deng
    •  & Virginia A Fisher

    These authors contributed equally to this work.

    • L Adrienne Cupples
    • , Matthew L Steinhauser
    •  & Caroline S Fox

    These authors jointly supervised this work.

Affiliations

  1. NHLBI's Framingham Heart Study, Framingham, Massachusetts, USA.

    • Audrey Y Chu
    • , John D Eicher
    • , Andrew D Johnson
    • , L Adrienne Cupples
    •  & Caroline S Fox
  2. Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Audrey Y Chu
  3. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.

    • Xuan Deng
    • , Virginia A Fisher
    • , Ching-Ti Liu
    • , Nancy L Heard-Costa
    •  & L Adrienne Cupples
  4. Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, UK.

    • Alexander Drong
    • , Anubha Mahajan
    •  & Andrew P Morris
  5. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Yang Zhang
    •  & Matthew L Steinhauser
  6. Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Yang Zhang
    • , Olivia Weeks
    • , Wolfram Goessling
    •  & Matthew L Steinhauser
  7. Department of Genetics, Washington University, St. Louis, Missouri, USA.

    • Mary F Feitosa
    • , Mary K Wojczynski
    •  & Ingrid B Borecki
  8. Division of Epidemiology and Biostatistics, Department of Population and Public Health Sciences, Wright State University Boonshoft School of Medicine, Dayton, Ohio, USA.

    • Audrey C Choh
    •  & Bradford Towne
  9. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Qing Duan
    •  & Leslie A Lange
  10. 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.

    • Thomas D Dyer
    • , Juan M Peralta
    •  & John Blangero
  11. Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor–UCLA Medical Center, Torrance, California, USA.

    • Xiuqing Guo
    • , Jie Yao
    •  & Jerome I Rotter
  12. Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.

    • Tim Kacprowski
    •  & Georg Homuth
  13. German Center for Cardiovascular Research (DZHK), Greifswald, Germany.

    • Tim Kacprowski
    • , Matthias Nauck
    • , Nele Friedrich
    •  & Henry Völzke
  14. TOPS Nutrition and Obesity Research Center, Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, USA.

    • Jack W Kent Jr
    •  & Michael Olivier
  15. University of Maryland School of Medicine, Baltimore, Maryland, USA.

    • Xinggang Liu
    • , Jeffrey R O'Connell
    • , Ankita Parihar
    • , Braxton D Mitchell
    •  & Alan R Shuldiner
  16. Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

    • Kurt Lohman
    • , Jingzhong Ding
    •  & Yongmei Liu
  17. Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

    • Kurt Lohman
    • , Lingyi Lu
    •  & Carl D Langefeld
  18. Icelandic Heart Association, Kopavogur, Iceland.

    • Albert V Smith
    •  & Vilmunder Gudnason
  19. Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

    • Albert V Smith
    •  & Vilmunder Gudnason
  20. TOPS Obesity and Metabolic Research Center, Biotechnology and Bioengineering Center, Department of Physiology at the Medical College of Wisconsin, Wisconsin, USA.

    • Yi Zhang
    • , Ahmed H Kissebah
    •  & Michael Olivier
  21. Department of Surgical Sciences, Section of Radiology, Uppsala University, Uppsala, Sweden.

    • Joel Kullberg
    •  & Lars Lind
  22. Department of Neuroradiology, University Hospital Berne, Berne, Switzerland.

    • René Laqua
  23. National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, Maryland, USA.

    • Lenore J Launer
    •  & Tamara B Harris
  24. Institute for Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.

    • Matthias Nauck
    • , Nele Friedrich
    •  & Henri Wallaschofski
  25. Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.

    • Patricia A Peyser
    • , Lawrence F Bielak
    •  & Sharon L R Kardia
  26. Department of Radiology and Radiologic Sciences, Department of Cardiovascular Medicine and Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

    • James G Terry
    •  & John Jeffrey Carr
  27. Center for Genomics and Personalized Medicine Research, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA.

    • Donald W Bowden
  28. Department of Biochemistry, Center for Diabetes Research, and Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.

    • Donald W Bowden
  29. Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas Health Science Center (UTHealth) School of Public Health Brownsville Campus, Brownsville, Texas, USA.

    • Stefan A Czerwinski
  30. Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

    • Jingzhong Ding
  31. Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

    • Erik Ingelsson
  32. Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.

    • Erik Ingelsson
  33. Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

    • Yongmei Liu
  34. Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, Maryland, USA.

    • Braxton D Mitchell
  35. Department of Biostatistics, University of Liverpool, Liverpool, UK.

    • Andrew P Morris
  36. University of Mississippi Medical Center, Jackson, Mississippi, USA.

    • Thomas H Mosley Jr
  37. Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.

    • Henry Völzke
  38. German Center for Diabetes Research (DZD), Greifswald, Germany.

    • Henry Völzke
  39. Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.

    • James G Wilson
  40. Division of Preventive Medicine, Department of Family Medicine and Public Health, University of California San Diego School of Medicine, San Diego, California, USA.

    • Matthew Allison
  41. Li Ka Shing Center for Health Information and Discovery, Big Data Institute, University of Oxford, Oxford, UK.

    • Cecilia M Lindgren
  42. Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.

    • Wolfram Goessling
  43. Gastroenterology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Wolfram Goessling
  44. Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Wolfram Goessling
  45. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Wolfram Goessling
    •  & Matthew L Steinhauser
  46. Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Matthew L Steinhauser
  47. Division of Endocrinology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Caroline S Fox

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Contributions

X.G., A.H.K., J.K., L.J.L., M.O., P.A.P., I.B.B., D.W.B., S.A.C., J.D., V.G., T.B.H., C.D.L., L. Lind, Y.L., J.I.R., B.T. and M.A. contributed to the study design; Yi Zhang, L.J.L., M.O., P.A.P., J.G.T., I.B.B., D.W.B., J.J.C., S.A.C., V.G., T.B.H., L. Lind, B.D.M., T.H.M., J.I.R., A.R.S., H.V., J.G.W. and M.A. contributed to study management; A.H.K., J.K., M.K.W., D.W.B., S.A.C., V.G., L. Lind, B.D.M., T.H.M., A.R.S., B.T. and H.V. recruited subjects; A.Y.C., X.D., V.A.F., Yang Zhang, M.F.F., C.-T.L., O.W., A.C.C., Q.D., X.G., N.L.H.-C., X.L., L. Lu, J.R.O., A.P., A.V.S., Yi Zhang, A.H.K., M.O., P.A.P., J.G.T., M.K.W., L.F.B., I.B.B., D.W.B., J.J.C., S.A.C., J.D., N.F., S.L.R.K., C.D.L., Y.L., B.D.M., J.I.R., A.R.S., B.T., H.W., M.A., C.M.L., W.G., L.A.C., M.L.S. and C.S.F. interpreted results; A.Y.C., Yang Zhang, M.F.F., X.G., J.W.K., Yi Zhang, A.H.K., M.K.W., I.B.B., C.M.L., M.L.S. and C.S.F. drafted the manuscript; A.Y.C., X.D., V.A.F., M.F.F., C.-T.L., O.W., A.C.C., X.G., N.L.H.-C., J.W.K., X.L., L. Lu, A.M., J.R.O., A.P., Yi Zhang, G.H., A.H.K., J.K., M.N., M.O., P.A.P., J.G.T., L.F.B., J.B., I.B.B., D.W.B., J.J.C., S.A.C., J.D., N.F., E.I., S.L.R.K., C.D.L., L. Lind, Y.L., B.D.M., A.P.M., T.H.M., J.I.R., A.R.S., B.T., H.V., H.W., M.A., C.M.L., W.G., L.A.C., M.L.S. and C.S.F. performed critical review; A.Y.C., X.D., V.A.F., A.D., Yang Zhang, M.F.F., A.C.C., Q.D., T.D.D., J.D.E., X.G., N.L.H.-C., T.K., J.W.K., L.A.L., X.L., K.L., L. Lu, A.M., J.R.O., A.P., J.M.P., A.V.S., J.Y., L.F.B., J.D., C.D.L., Y.L., B.D.M., A.P.M., C.M.L. contributed to statistical methods and analysis; Yi Zhang, G.H., M.O., D.W.B., S.A.C., E.I., S.L.R.K., Y.L., A.P.M., J.I.R., A.R.S., B.T. and C.M.L. performed genotyping; A.Y.C., X.D., V.A.F., M.F.F., C.-T.L., A.C.C., J.D.E., A.D.J., T.K., A.V.S. and Yi Zhang contributed to bioinformatics; Yang Zhang, O.W., R.L., N.F., W.G. and M.L.S. worked on data collection; and Yang Zhang and M.L.S. contributed to animal work and functional data.

Competing interests

C.S.F. and A.Y.C. are currently employed by Merck Research Laboratories.

Corresponding authors

Correspondence to Audrey Y Chu or Matthew L Steinhauser or Caroline S Fox.

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DOI

https://doi.org/10.1038/ng.3738

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