New genetic loci link adipose and insulin biology to body fat distribution.

Abstract

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Metadata

Authors/Creators:	Shungin, D Winkler, TW Croteau-Chonka, DC Ferreira, T Locke, AE Mägi, R Strawbridge, RJ Pers, TH Fischer, K Justice, AE Workalemahu, T Wu, JM Buchkovich, ML Heard-Costa, NL Roman, TS Drong, AW Song, C Gustafsson, S Day, FR Esko, T Fall, T Kutalik, Z Luan, J Randall, JC Scherag, A Vedantam, S Wood, AR Chen, J Fehrmann, R Karjalainen, J Kahali, B Liu, CT Schmidt, EM Absher, D Amin, N Anderson, D Beekman, M Bragg-Gresham, JL Buyske, S Demirkan, A Ehret, GB Feitosa, MF Goel, A Jackson, AU Johnson, T Kleber, ME Kristiansson, K Mangino, M Mateo Leach, I Medina-Gomez, C Palmer, CD Pasko, D Pechlivanis, S Peters, MJ Prokopenko, I Stančáková, A Ju Sung, Y Tanaka, T Teumer, A Van Vliet-Ostaptchouk, JV Yengo, L Zhang, W Albrecht, E Ärnlöv, J Arscott, GM Bandinelli, S Barrett, A Bellis, C Bennett, AJ Berne, C Blüher, M Böhringer, S Bonnet, F Böttcher, Y Bruinenberg, M Carba, DB Caspersen, IH Clarke, R Daw, EW Deelen, J Deelman, E Delgado, G Doney, AS Eklund, N Erdos, MR Estrada, K Eury, E Friedrich, N Garcia, ME Giedraitis, V Gigante, B Go, AS Golay, A Grallert, H Grammer, TB Gräßler, J Grewal, J Groves, CJ Haller, T Hallmans, G Hartman, CA Hassinen, M Hayward, C Heikkilä, K Herzig, KH Helmer, Q Hillege, HL Holmen, O Hunt, SC Isaacs, A Ittermann, T James, AL Johansson, I Juliusdottir, T Kalafati, IP Kinnunen, L Koenig, W Kooner, IK Kratzer, W Lamina, C Leander, K Lee, NR Lichtner, P Lind, L Lindström, J Lobbens, S Lorentzon, M Mach, F Magnusson, PK Mahajan, A McArdle, WL Menni, C Merger, S Mihailov, E Milani, L Mills, R Moayyeri, A Monda, KL Mooijaart, SP Mühleisen, TW Mulas, A Müller, G Müller-Nurasyid, M Nagaraja, R Nalls, MA Narisu, N Glorioso, N Nolte, IM Olden, M Rayner, NW Renstrom, F Ried, JS Robertson, NR Rose, LM Sanna, S Scharnagl, H Scholtens, S Sennblad, B Seufferlein, T Sitlani, CM Vernon Smith, A Stirrups, K Stringham, HM Sundström, J Swertz, MA Swift, AJ Syvänen, AC Tayo, BO Thorand, B Thorleifsson, G Tomaschitz, A Troffa, C van Oort, FV Verweij, N Vonk, JM Waite, LL Wennauer, R Wilsgaard, T Wojczynski, MK Wong, A Zhang, Q Hua Zhao, J Brennan, EP Choi, M Eriksson, P Folkersen, L Franco-Cereceda, A Gharavi, AG Hedman, ÅK Hivert, MF Huang, J Kanoni, S Karpe, F Keildson, S Kiryluk, K Liang, L Lifton, RP Ma, B McKnight, AJ McPherson, R Metspalu, A Min, JL Moffatt, MF Montgomery, GW Murabito, JM Nicholson, G Nyholt, DR Olsson, C Perry, JR Reinmaa, E Salem, RM Sandholm, N Schadt, EE Scott, RA Stolk, L Vallejo, EE Westra, HJ Zondervan, KT ADIPOGen Consortium CARDIOGRAMplusC4D Consortium CKDGen Consortium GEFOS Consortium GENIE Consortium GLGC ICBP International Endogene Consortium LifeLines Cohort Study MAGIC Investigators MuTHER Consortium PAGE Consortium ReproGen Consortium Amouyel, P Arveiler, D Bakker, SJ Beilby, J Bergman, RN Blangero, J Brown, MJ Burnier, M Campbell, H Chakravarti, A Chines, PS Claudi-Boehm, S Collins, FS Crawford, DC Danesh, J de Faire, U de Geus, EJ Dörr, M Erbel, R Eriksson, JG Farrall, M Ferrannini, E Ferrières, J Forouhi, NG Forrester, T Franco, OH Gansevoort, RT Gieger, C Gudnason, V Haiman, CA Harris, TB Hattersley, AT Heliövaara, M Hicks, AA Hingorani, AD Hoffmann, W Hofman, A Homuth, G Humphries, SE Hyppönen, E Illig, T Jarvelin, MR Johansen, B Jousilahti, P Jula, AM Kaprio, J Kee, F Keinanen-Kiukaanniemi, SM Kooner, JS Kooperberg, C Kovacs, P Kraja, AT Kumari, M Kuulasmaa, K Kuusisto, J Lakka, TA Langenberg, C Le Marchand, L Lehtimäki, T Lyssenko, V Männistö, S Marette, A Matise, TC McKenzie, CA McKnight, B Musk, AW Möhlenkamp, S Morris, AD Nelis, M Ohlsson, C Oldehinkel, AJ Ong, KK Palmer, LJ Penninx, BW Peters, A Pramstaller, PP Raitakari, OT Rankinen, T Rao, DC Rice, TK Ridker, PM Ritchie, MD Rudan, I Salomaa, V Samani, NJ Saramies, J Sarzynski, MA Schwarz, PE Shuldiner, AR Staessen, JA Steinthorsdottir, V Stolk, RP Strauch, K Tönjes, A Tremblay, A Tremoli, E Vohl, MC Völker, U Vollenweider, P Wilson, JF Witteman, JC Adair, LS Bochud, M Boehm, BO Bornstein, SR Bouchard, C Cauchi, S Caulfield, MJ Chambers, JC Chasman, DI Cooper, RS Dedoussis, G Ferrucci, L Froguel, P Grabe, HJ Hamsten, A Hui, J Hveem, K Jöckel, KH Kivimaki, M Kuh, D Laakso, M Liu, Y März, W Munroe, PB Njølstad, I Oostra, BA Palmer, CN Pedersen, NL Perola, M Pérusse, L Peters, U Power, C Quertermous, T Rauramaa, R Rivadeneira, F Saaristo, TE Saleheen, D Sinisalo, J Slagboom, PE Snieder, H Spector, TD Thorsteinsdottir, U Stumvoll, M Tuomilehto, J Uitterlinden, AG Uusitupa, M van der Harst, P Veronesi, G Walker, M Wareham, NJ Watkins, H Wichmann, HE Abecasis, GR Assimes, TL Berndt, SI Boehnke, M Borecki, IB Deloukas, P Franke, L Frayling, TM Groop, LC Hunter, DJ Kaplan, RC O'Connell, JR Qi, L Schlessinger, D Strachan, DP Stefansson, K van Duijn, CM Willer, CJ Visscher, PM Yang, J Hirschhorn, JN Zillikens, MC McCarthy, MI Speliotes, EK North, KE Fox, CS Barroso, I Franks, PW Ingelsson, E Heid, IM Loos, RJ Cupples, LA Morris, AP Lindgren, CM Mohlke, KL
Copyright, Publisher and Additional Information:	© 2015 Nature Publishing Group. This is an author produced version of a paper subsequently published in Nature . Uploaded in accordance with the publisher's self-archiving policy.
Keywords:	Adipocytes; Adipogenesis; Adipose Tissue; Age Factors; Body Fat Distribution; Body Mass Index; Continental Population Groups; Epigenesis, Genetic; Europe; Female; Genome, Human; Genome-Wide Association Study; Humans; Insulin; Insulin Resistance; Male; Models, Biological; Neovascularization, Physiologic; Obesity; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Sex Characteristics; Transcription, Genetic; Waist-Hip Ratio
Dates:	Accepted: 2 December 2014 Published: 12 February 2015
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield) The University of Sheffield > Sheffield Teaching Hospitals
Depositing User:	Symplectic Sheffield
Date Deposited:	09 Dec 2016 16:33
Last Modified:	03 Apr 2018 13:58
Published Version:	https://doi.org/10.1038/nature14132
Status:	Published
Publisher:	Nature Publishing Group
Refereed:	Yes
Identification Number:	https://doi.org/10.1038/nature14132
Related URLs:	Author

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New genetic loci link adipose and insulin biology to body fat distribution.

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