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

Audrey Y. Chu, Xuan Deng, Virginia A. Fisher, Alexander Drong, Yang Zhang, Mary F. Feitosa, Ching Ti Liu, Olivia Weeks, Audrey C. Choh, Qing Duan, Thomas D. Dyer, John D. Eicher, Xiuqing Guo, Nancy L. Heard-Costa, Tim Kacprowski, Jack W. Kent, Leslie A. Lange, Xinggang Liu, Kurt Lohman, Lingyi Lu & 48 others Anubha Mahajan, Jeffrey R. O'Connell, Ankita Parihar, Juan M. Peralta, Albert V. Smith, Yi Zhang, Georg Homuth, Ahmed H. Kissebah, Joel Kullberg, René Laqua, Lenore J. Launer, Matthias Nauck, Michael Olivier, Patricia A. Peyser, James G. Terry, Mary K. Wojczynski, Jie Yao, Lawrence F. Bielak, John Blangero, Ingrid B. Borecki, Donald W. Bowden, John Jeffrey Carr, Stefan A. Czerwinski, Jingzhong Ding, Nele Friedrich, Vilmunder Gudnason, Tamara B. Harris, Erik Ingelsson, Andrew D. Johnson, Sharon L R Kardia, Carl D. Langefeld, Lars Lind, Yongmei Liu, Braxton D. Mitchell, Andrew P. Morris, Thomas H. Mosley, Jerome I. Rotter, Alan R. Shuldiner, Bradford Towne, Henry Völzke, Henri Wallaschofski, James G. Wilson, Matthew Allison, Cecilia M. Lindgren, Wolfram Goessling, L. Adrienne Cupples, Matthew L. Steinhauser, Caroline S. Fox

    Research output: Contribution to journalArticle

    40 Citations (Scopus)

    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.

    Original languageEnglish (US)
    Pages (from-to)125-130
    Number of pages6
    JournalNature Genetics
    Volume49
    Issue number1
    DOIs
    StatePublished - Jan 1 2017

    Fingerprint

    Body Fat Distribution
    Adipocytes
    Meta-Analysis
    Fats
    Genome
    Adipogenesis
    Genome-Wide Association Study
    Metabolic Diseases
    Hispanic Americans
    Sample Size
    Genes
    Stem Cells
    Obesity

    ASJC Scopus subject areas

    • Genetics

    Cite this

    Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation. / Chu, Audrey Y.; Deng, Xuan; Fisher, Virginia A.; Drong, Alexander; Zhang, Yang; Feitosa, Mary F.; Liu, Ching Ti; Weeks, Olivia; Choh, Audrey C.; Duan, Qing; Dyer, Thomas D.; Eicher, John D.; Guo, Xiuqing; Heard-Costa, Nancy L.; Kacprowski, Tim; Kent, Jack W.; Lange, Leslie A.; Liu, Xinggang; Lohman, Kurt; Lu, Lingyi; Mahajan, Anubha; O'Connell, Jeffrey R.; Parihar, Ankita; Peralta, Juan M.; Smith, Albert V.; Zhang, Yi; Homuth, Georg; Kissebah, Ahmed H.; Kullberg, Joel; Laqua, René; Launer, Lenore J.; Nauck, Matthias; Olivier, Michael; Peyser, Patricia A.; Terry, James G.; Wojczynski, Mary K.; Yao, Jie; Bielak, Lawrence F.; Blangero, John; Borecki, Ingrid B.; Bowden, Donald W.; Carr, John Jeffrey; Czerwinski, Stefan A.; Ding, Jingzhong; Friedrich, Nele; Gudnason, Vilmunder; Harris, Tamara B.; Ingelsson, Erik; Johnson, Andrew D.; Kardia, Sharon L R; Langefeld, Carl D.; Lind, Lars; Liu, Yongmei; Mitchell, Braxton D.; Morris, Andrew P.; Mosley, Thomas H.; Rotter, Jerome I.; Shuldiner, Alan R.; Towne, Bradford; Völzke, Henry; Wallaschofski, Henri; Wilson, James G.; Allison, Matthew; Lindgren, Cecilia M.; Goessling, Wolfram; Cupples, L. Adrienne; Steinhauser, Matthew L.; Fox, Caroline S.

    In: Nature Genetics, Vol. 49, No. 1, 01.01.2017, p. 125-130.

    Research output: Contribution to journalArticle

    Chu, AY, Deng, X, Fisher, VA, Drong, A, Zhang, Y, Feitosa, MF, Liu, CT, Weeks, O, Choh, AC, Duan, Q, Dyer, TD, Eicher, JD, Guo, X, Heard-Costa, NL, Kacprowski, T, Kent, JW, Lange, LA, Liu, X, Lohman, K, Lu, L, Mahajan, A, O'Connell, JR, Parihar, A, Peralta, JM, Smith, AV, Zhang, Y, Homuth, G, Kissebah, AH, Kullberg, J, Laqua, R, Launer, LJ, Nauck, M, Olivier, M, Peyser, PA, Terry, JG, Wojczynski, MK, Yao, J, Bielak, LF, Blangero, J, Borecki, IB, Bowden, DW, Carr, JJ, Czerwinski, SA, Ding, J, Friedrich, N, Gudnason, V, Harris, TB, Ingelsson, E, Johnson, AD, Kardia, SLR, Langefeld, CD, Lind, L, Liu, Y, Mitchell, BD, Morris, AP, Mosley, TH, Rotter, JI, Shuldiner, AR, Towne, B, Völzke, H, Wallaschofski, H, Wilson, JG, Allison, M, Lindgren, CM, Goessling, W, Cupples, LA, Steinhauser, ML & Fox, CS 2017, 'Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation', Nature Genetics, vol. 49, no. 1, pp. 125-130. https://doi.org/10.1038/ng.3738
    Chu, Audrey Y. ; Deng, Xuan ; Fisher, Virginia A. ; Drong, Alexander ; Zhang, Yang ; Feitosa, Mary F. ; Liu, Ching Ti ; Weeks, Olivia ; Choh, Audrey C. ; Duan, Qing ; Dyer, Thomas D. ; Eicher, John D. ; Guo, Xiuqing ; Heard-Costa, Nancy L. ; Kacprowski, Tim ; Kent, Jack W. ; Lange, Leslie A. ; Liu, Xinggang ; Lohman, Kurt ; Lu, Lingyi ; Mahajan, Anubha ; O'Connell, Jeffrey R. ; Parihar, Ankita ; Peralta, Juan M. ; Smith, Albert V. ; Zhang, Yi ; Homuth, Georg ; Kissebah, Ahmed H. ; Kullberg, Joel ; Laqua, René ; Launer, Lenore J. ; Nauck, Matthias ; Olivier, Michael ; Peyser, Patricia A. ; Terry, James G. ; Wojczynski, Mary K. ; Yao, Jie ; Bielak, Lawrence F. ; Blangero, John ; Borecki, Ingrid B. ; Bowden, Donald W. ; Carr, John Jeffrey ; Czerwinski, Stefan A. ; Ding, Jingzhong ; Friedrich, Nele ; Gudnason, Vilmunder ; Harris, Tamara B. ; Ingelsson, Erik ; Johnson, Andrew D. ; Kardia, Sharon L R ; Langefeld, Carl D. ; Lind, Lars ; Liu, Yongmei ; Mitchell, Braxton D. ; Morris, Andrew P. ; Mosley, Thomas H. ; Rotter, Jerome I. ; Shuldiner, Alan R. ; Towne, Bradford ; Völzke, Henry ; Wallaschofski, Henri ; Wilson, James G. ; Allison, Matthew ; Lindgren, Cecilia M. ; Goessling, Wolfram ; Cupples, L. Adrienne ; Steinhauser, Matthew L. ; Fox, Caroline S. / Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation. In: Nature Genetics. 2017 ; Vol. 49, No. 1. pp. 125-130.
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    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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    AU - Deng, Xuan

    AU - Fisher, Virginia A.

    AU - Drong, Alexander

    AU - Zhang, Yang

    AU - Feitosa, Mary F.

    AU - Liu, Ching Ti

    AU - Weeks, Olivia

    AU - Choh, Audrey C.

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    AU - Lu, Lingyi

    AU - Mahajan, Anubha

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    AU - Czerwinski, Stefan A.

    AU - Ding, Jingzhong

    AU - Friedrich, Nele

    AU - Gudnason, Vilmunder

    AU - Harris, Tamara B.

    AU - Ingelsson, Erik

    AU - Johnson, Andrew D.

    AU - Kardia, Sharon L R

    AU - Langefeld, Carl D.

    AU - Lind, Lars

    AU - Liu, Yongmei

    AU - Mitchell, Braxton D.

    AU - Morris, Andrew P.

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    AU - Towne, Bradford

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    AU - Wallaschofski, Henri

    AU - Wilson, James G.

    AU - Allison, Matthew

    AU - Lindgren, Cecilia M.

    AU - Goessling, Wolfram

    AU - Cupples, L. Adrienne

    AU - Steinhauser, Matthew L.

    AU - Fox, Caroline S.

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    N2 - 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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