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Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.
journal contribution
posted on 2019-04-24, 11:25 authored by AE Justice, T Karaderi, HM Highland, KL Young, M Graff, Y Lu, V Turcot, PL Auer, RS Fine, X Guo, C Schurmann, A Lempradl, E Marouli, A Mahajan, TW Winkler, AE Locke, C Medina-Gomez, T Esko, S Vedantam, A Giri, KS Lo, T Alfred, P Mudgal, MCY Ng, NL Heard-Costa, MF Feitosa, AK Manning, SM Willems, S Sivapalaratnam, G Abecasis, DS Alam, M Allison, P Amouyel, Z Arzumanyan, B Balkau, L Bastarache, S Bergmann, LF Bielak, M Blüher, M Boehnke, H Boeing, E Boerwinkle, CA Böger, J Bork-Jensen, EP Bottinger, DW Bowden, I Brandslund, L Broer, AA Burt, AS Butterworth, MJ Caulfield, G Cesana, JC Chambers, DI Chasman, Y-DI Chen, R Chowdhury, C Christensen, AY Chu, FS Collins, JP Cook, AJ Cox, DS Crosslin, J Danesh, PIW de Bakker, SD Denus, RD Mutsert, G Dedoussis, EW Demerath, JG Dennis, JC Denny, ED Angelantonio, M Dörr, F Drenos, M-P Dubé, AM Dunning, DF Easton, P Elliott, E Evangelou, A-E Farmaki, S Feng, E Ferrannini, J Ferrieres, JC Florez, M Fornage, CS Fox, PW Franks, N Friedrich, W Gan, I Gandin, P Gasparini, V Giedraitis, G Girotto, M Gorski, H Grallert, N Grarup, ML Grove, S Gustafsson, J Haessler, T Hansen, AT Hattersley, C Hayward, IM Heid, OL Holmen, GK Hovingh, JMM Howson, Y Hu, Y-J Hung, K Hveem, MA Ikram, E Ingelsson, AU Jackson, GP Jarvik, Y Jia, T Jørgensen, P Jousilahti, JM Justesen, B Kahali, M Karaleftheri, SLR Kardia, F Karpe, F Kee, H Kitajima, P Komulainen, JS Kooner, P Kovacs, BK Krämer, K Kuulasmaa, J Kuusisto, M Laakso, TA Lakka, D Lamparter, LA Lange, C Langenberg, EB Larson, NR Lee, W-J Lee, T Lehtimäki, CE Lewis, H Li, J Li, R Li-Gao, L-A Lin, X Lin, L Lind, J Lindström, A Linneberg, C-T Liu, DJ Liu, J Luan, L-P Lyytikäinen, S MacGregor, R Mägi, S Männistö, G Marenne, J Marten, NGD Masca, MI McCarthy, K Meidtner, E Mihailov, L Moilanen, M Moitry, DO Mook-Kanamori, A Morgan, AP Morris, M Müller-Nurasyid, PB Munroe, N Narisu, CP Nelson, M Neville, I Ntalla, JR O'Connell, KR Owen, O Pedersen, GM Peloso, CE Pennell, M Perola, JA Perry, JRB Perry, TH Pers, A Ewing, O Polasek, OT Raitakari, A Rasheed, CK Raulerson, R Rauramaa, DF Reilly, AP Reiner, PM Ridker, MA Rivas, NR Robertson, A Robino, I Rudan, KS Ruth, D Saleheen, V Salomaa, NJ Samani, PJ Schreiner, MB Schulze, RA Scott, M Segura-Lepe, X Sim, AJ Slater, KS Small, BH Smith, JA Smith, L Southam, TD Spector, EK Speliotes, K Stefansson, V Steinthorsdottir, KE Stirrups, K Strauch, HM Stringham, M Stumvoll, L Sun, P Surendran, KMA Swart, J-C Tardif, KD Taylor, A Teumer, DJ Thompson, G Thorleifsson, U Thorsteinsdottir, BH Thuesen, A Tönjes, M Torres, E Tsafantakis, J Tuomilehto, AG Uitterlinden, M Uusitupa, CM van Duijn, M Vanhala, R Varma, SH Vermeulen, H Vestergaard, V Vitart, TF Vogt, D Vuckovic, LE Wagenknecht, M Walker, L Wallentin, F Wang, CA Wang, S Wang, NJ Wareham, HR Warren, DM Waterworth, J Wessel, HD White, CJ Willer, JG Wilson, AR Wood, Y Wu, H Yaghootkar, J Yao, LM Yerges-Armstrong, R Young, E Zeggini, X Zhan, W Zhang, JH Zhao, W Zhao, H Zheng, W Zhou, MC Zillikens, CHD Exome+ Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, InterAct, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, F Rivadeneira, IB Borecki, JA Pospisilik, P Deloukas, TM Frayling, G Lettre, KL Mohlke, JI Rotter, Z Kutalik, JN Hirschhorn, LA Cupples, RJF Loos, KE North, CM LindgrenBody-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
Funding
This work was primarily supported through funding from the National Institute of Health (NIH): 1K99HL130580, R01-DK089256, 2R01HD057194, U01HG007416, R01DK101855, T32 HL007055, KL2TR001109; and the American Heart Association (AHA): 13POST16500011 and 13GRNT16490017. Co-author Y. Jia recently passed away while this work was in process. This study was completed as part of the Genetic Investigation of ANtropometric Traits (GIANT) Consortium. This research has been conducted using the UK Biobank resource. A full list of acknowledgements is provided in the Supplementary Data 18.
History
Citation
Nature Genetics, 2019, 51 (3), pp. 452-469Author affiliation
/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Cardiovascular SciencesVersion
- AM (Accepted Manuscript)
Published in
Nature GeneticsPublisher
Nature Research (part of Springer Nature)eissn
1546-1718Acceptance date
2018-12-17Copyright date
2019Available date
2019-08-18Publisher DOI
Publisher version
https://www.nature.com/articles/s41588-018-0334-2Notes
The file associated with this record is under embargo until 6 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above.Language
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