Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.

TitreProtein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.
Publication TypeJournal Article
Year of Publication2019
AuthorsJustice, AE, Karaderi, T, Highland, HM, Young, KL, Graff, M, Lu, Y, Turcot, V, Auer, PL, Fine, RS, Guo, X, Schurmann, C, Lempradl, A, Marouli, E, Mahajan, A, Winkler, TW, Locke, AE, Medina-Gomez, C, Esko, T, Vedantam, S, Giri, A, Lo, KSin, Alfred, T, Mudgal, P, C Y Ng, M, Heard-Costa, NL, Feitosa, MF, Manning, AK, Willems, SM, Sivapalaratnam, S, Abecasis, G, Alam, DS, Allison, M, Amouyel, P, Arzumanyan, Z, Balkau, B, Bastarache, L, Bergmann, S, Bielak, LF, Blüher, M, Boehnke, M, Boeing, H, Boerwinkle, E, Böger, CA, Bork-Jensen, J, Bottinger, EP, Bowden, DW, Brandslund, I, Broer, L, Burt, AA, Butterworth, AS, Caulfield, MJ, Cesana, G, Chambers, JC, Chasman, DI, Chen, Y-DIda, Chowdhury, iv, R, Christensen, C, Chu, AY, Collins, FS, Cook, JP, Cox, AJ, Crosslin, DS, Danesh, J, de Bakker, PIW, de Denus, S, de Mutsert, R, Dedoussis, G, Demerath, EW, Dennis, JG, Denny, JC, Di Angelantonio, E, Dörr, M, Drenos, F, Dubé, M-P, Dunning, AM, Easton, DF, Elliott, P, Evangelou, E, Farmaki, A-E, Feng, S, Ferrannini, E, Ferrieres, J, Florez, JC, Fornage, M, Fox, CS, Franks, PW, Friedrich, N, Gan, W, Gandin, I, Gasparini, P, Giedraitis, V, Girotto, G, Gorski, M, Grallert, H, Grarup, N, Grove, ML, Gustafsson, S, Haessler, J, Hansen, T, Hattersley, AT, Hayward, C, Heid, IM, Holmen, OL, G Hovingh, K, Howson, JMM, Hu, Y, Hung, Y-J, Hveem, K, M Ikram, A, Ingelsson, E, Jackson, AU, Jarvik, GP, Jia, Y, Jørgensen, T, Jousilahti, P, Justesen, JM, Kahali, B, Karaleftheri, M, Kardia, SLR, Karpe, F, Kee, F, Kitajima, H, Komulainen, P, Kooner, JS, Kovacs, P, Krämer, BK, Kuulasmaa, K, Kuusisto, J, Laakso, M, Lakka, TA, Lamparter, D, Lange, LA, Langenberg, C, Larson, EB, Lee, NR, Lee, W-J, Lehtimaki, T, Lewis, CE, Li, H, Li, J, Li-Gao, R, Lin, L-A, Lin, X, Lind, L, Lindström, J, Linneberg, A, Liu, C-T, Liu, DJ, Luan, J'an, Lyytikainen, L-P, Macgregor, S, Mägi, R, Männistö, S, Marenne, G, Marten, J, Masca, NGD, McCarthy, MI, Meidtner, K, Mihailov, E, Moilanen, L, Moitry, M, Mook-Kanamori, DO, Morgan, A, Morris, AP, Müller-Nurasyid, M, Munroe, PB, Narisu, N, Nelson, CP, Neville, M, Ntalla, I, O'Connell, JR, Owen, KR, Pedersen, O, Peloso, GM, Pennell, CE, Perola, M, Perry, JA, Perry, JRB, Pers, TH, Ewing, A, Polasek, O, Raitakari, OT, Rasheed, A, Raulerson, CK, Rauramaa, R, Reilly, DF, Reiner, AP, Ridker, PM, Rivas, MA, Robertson, NR, Robino, A, Rudan, I, Ruth, KS, Saleheen, D, Salomaa, V, Samani, NJ, Schreiner, PJ, Schulze, MB, Scott, RA, Segura-Lepe, M, Sim, X, Slater, AJ, Small, KS, Smith, BH, Smith, JA, Southam, L, Spector, TD, Speliotes, EK, Stefansson, K, Steinthorsdottir, V, Stirrups, KE, Strauch, K, Stringham, HM, Stumvoll, M, Sun, L, Surendran, P, Swart, KMA, Tardif, J-C, Taylor, KD, Teumer, A, Thompson, DJ, Thorleifsson, G, Thorsteinsdottir, U, Thuesen, BH, Tonjes, A, Torres, M, Tsafantakis, E, Tuomilehto, J, Uitterlinden, AG, Uusitupa, M, van Duijn, CM, Vanhala, M, Varma, R, Vermeulen, SH, Vestergaard, H, Vitart, V, Vogt, TF, Vuckovic, D, Wagenknecht, LE, Walker, M, Wallentin, L, Wang, F, Wang, CA, Wang, S, Wareham, NJ, Warren, HR, Waterworth, DM, Wessel, J, White, HD, Willer, CJ, Wilson, JG, Wood, AR, Wu, Y, Yaghootkar, H, Yao, J, Yerges-Armstrong, LM, Young, R, Zeggini, E, Zhan, X, Zhang, W, Zhao, JHua, Zhao, W, Zheng, H, Zhou, W, M Zillikens, C, Rivadeneira, F, Borecki, IB, J Pospisilik, A, Deloukas, P, Frayling, TM, Lettre, G, Mohlke, KL, Rotter, JI, Kutalik, Z, Hirschhorn, JN, L Cupples, A, Loos, RJF, North, KE, Lindgren, CM
Corporate AuthorsCHD 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
JournalNature genetics
Volume51
Issue3
Pagination452-469
Date Published03/2019
DOI10.1038/s41588-018-0334-2
ISSN1546-1718
Abstract

Body-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.

Alternate URL

http://www.ncbi.nlm.nih.gov/pubmed/30778226?dopt=Abstract

WOS ID (UT)

000459947200014

Alternate JournalNat. Genet.
Citation Key / SERVAL ID9396
Peer reviewRefereed
PubMed ID30778226
Grant ListT32 HL007055 / HL / NHLBI NIH HHS / United States
                         

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