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Meta-Analysis
. 2017 Jan;49(1):125-130.
doi: 10.1038/ng.3738. Epub 2016 Dec 5.

Multiethnic Genome-Wide Meta-Analysis of Ectopic Fat Depots Identifies Loci Associated With Adipocyte Development and Differentiation

Audrey Y Chu  1   2 Xuan Deng  3 Virginia A Fisher  3 Alexander Drong  4 Yang Zhang  5   6 Mary F Feitosa  7 Ching-Ti Liu  3 Olivia Weeks  6 Audrey C Choh  8 Qing Duan  9 Thomas D Dyer  10 John D Eicher  1 Xiuqing Guo  11 Nancy L Heard-Costa  3 Tim Kacprowski  12   13 Jack W Kent Jr  14 Leslie A Lange  9 Xinggang Liu  15 Kurt Lohman  16   17 Lingyi Lu  17 Anubha Mahajan  4 Jeffrey R O'Connell  15 Ankita Parihar  15 Juan M Peralta  10 Albert V Smith  18   19 Yi Zhang  20 Georg Homuth  12 Ahmed H Kissebah  20 Joel Kullberg  21 René Laqua  22 Lenore J Launer  23 Matthias Nauck  13   24 Michael Olivier  14   20 Patricia A Peyser  25 James G Terry  26 Mary K Wojczynski  7 Jie Yao  11 Lawrence F Bielak  25 John Blangero  10 Ingrid B Borecki  7 Donald W Bowden  27   28 John Jeffrey Carr  26 Stefan A Czerwinski  29 Jingzhong Ding  16   30 Nele Friedrich  13   24 Vilmunder Gudnason  18   19 Tamara B Harris  23 Erik Ingelsson  31   32 Andrew D Johnson  1 Sharon L R Kardia  25 Carl D Langefeld  17 Lars Lind  21 Yongmei Liu  16   33 Braxton D Mitchell  15   34 Andrew P Morris  4   35 Thomas H Mosley Jr  36 Jerome I Rotter  11 Alan R Shuldiner  15 Bradford Towne  8 Henry Völzke  13   37   38 Henri Wallaschofski  24 James G Wilson  39 Matthew Allison  40 Cecilia M Lindgren  41 Wolfram Goessling  6   42   43   44   45 L Adrienne Cupples  1   3 Matthew L Steinhauser  5   6   45   46 Caroline S Fox  1   47
Affiliations
Free PMC article
Meta-Analysis

Multiethnic Genome-Wide Meta-Analysis of Ectopic Fat Depots Identifies Loci Associated With Adipocyte Development and Differentiation

Audrey Y Chu et al. Nat Genet. .
Free PMC article

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.

Figures

Figure 1
Figure 1. Functional characterization of Atxn1, Ebf1, Rreb1 and Ube2e2
(a,b,e) Data is displayed as box/whisker plots where the center line represents the median, box limits contain the 25th–75th percentiles, and whiskers span max/min values. (a) Gene expression measured by qPCR in murine subcutaneous (SAT), perigonadal visceral (VAT), and pericardial (PAT) adipose tissues (n=6 mice). Statistical significance was assessed using ANOVA and Sidak’s correction for multiple comparisons. (b) Gene expression measured by qPCR in murine adipose tissues after 8 weeks of high fat feeding compared to normal chow fed controls (n=5 mice per group). Statistical significance was assigned using a two-sided T-test. (c) Gene expression measured by qPCR in cultured adipocyte progenitors isolated from the subcutaneous (SAT) or perigonadal visceral (VAT) depots (n=4 replicates). Cells were expanded to confluence and then collected at intervals after induction of adipogenic differentiation. Data displayed as mean, error bar=s.e.m. Statistical significance was assessed using ANOVA and Sidak’s correction for multiple comparisons to time 0. (d) Oil-red-o staining of progenitors isolated from subcutaneous adipose and exposed to retroviral delivery of shRNA constructs during ex vivo expansion and induction of adipogenesis. Relative to control vector carrying a scramble sequence, shRNA constructs specific for Atxn1 and Ube2e2 impaired adipogenic differentiation. Scale=1mm. (e) Oil-red-o stain was alcohol extracted and quantified at OD520 (n=9 technical replicates). Statistical significance was assessed using ANOVA and Sidak’s correction for multiple comparisons to control (Scramble). Data representative of 3 independent experiments.

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