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

TitleProtein-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, Dube, 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, Lehtimäki, 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, Lyytikäinen, 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
JournalNat Genet
Volume51
Issue3
Pagination452-469
Date Published2019 Mar
ISSN1546-1718
KeywordsAnimals, Body Fat Distribution, Body Mass Index, Case-Control Studies, Drosophila, Exome, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Homeostasis, Humans, Lipids, Male, Proteins, Risk Factors, Waist-Hip Ratio
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.
DOI10.1038/s41588-018-0334-2
Alternate JournalNat Genet
PubMed ID30778226
PubMed Central IDPMC6560635
Grant ListR01 DK106621 / DK / NIDDK NIH HHS / United States
RG/13/13/30194 / BHF_ / British Heart Foundation / United Kingdom
R01 DK110113 / DK / NIDDK NIH HHS / United States
MR/S003746/1 / MRC_ / Medical Research Council / United Kingdom
16565 / CRUK_ / Cancer Research UK / United Kingdom
G9521010 / MRC_ / Medical Research Council / United Kingdom
P30 DK056336 / DK / NIDDK NIH HHS / United States
R21 HL121422 / HL / NHLBI NIH HHS / United States
MC_PC_14089 / MRC_ / Medical Research Council / United Kingdom
R01 DK093757 / DK / NIDDK NIH HHS / United States
FS/12/82/29736 / BHF_ / British Heart Foundation / United Kingdom
U01 HG007417 / HG / NHGRI NIH HHS / United States
16563 / CRUK_ / Cancer Research UK / United Kingdom
K99 HL130580 / HL / NHLBI NIH HHS / United States
U01 HG007416 / HG / NHGRI NIH HHS / United States
R01 GM126479 / GM / NIGMS NIH HHS / United States
MC_UU_12015/1 / MRC_ / Medical Research Council / United Kingdom
R21 DA040177 / DA / NIDA NIH HHS / United States
212945/Z/18/Z / WT_ / Wellcome Trust / United Kingdom
KL2 TR001109 / TR / NCATS NIH HHS / United States
MC_EX_MR/M009203/1 / MRC_ / Medical Research Council / United Kingdom
R01 DK072193 / DK / NIDDK NIH HHS / United States
R00 HL130580 / HL / NHLBI NIH HHS / United States
P30 DK079626 / DK / NIDDK NIH HHS / United States
R01 DK107786 / DK / NIDDK NIH HHS / United States
MR/L01341X/1 / MRC_ / Medical Research Council / United Kingdom
R01 DK075787 / DK / NIDDK NIH HHS / United States
R01 HL119443 / HL / NHLBI NIH HHS / United States
R01 DK062370 / DK / NIDDK NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
MC_UU_12015/2 / MRC_ / Medical Research Council / United Kingdom
R01 HG008983 / HG / NHGRI NIH HHS / United States
RG/08/014/24067 / BHF_ / British Heart Foundation / United Kingdom
RG/14/5/30893 / BHF_ / British Heart Foundation / United Kingdom
MR/L01632X/1 / MRC_ / Medical Research Council / United Kingdom
MR/M009203/1 / MRC_ / Medical Research Council / United Kingdom
K12 HD043483 / HD / NICHD NIH HHS / United States
MC_UU_00007/10 / MRC_ / Medical Research Council / United Kingdom
U01 DK062370 / DK / NIDDK NIH HHS / United States
R01 DK107904 / DK / NIDDK NIH HHS / United States
R01 DK089256 / DK / NIDDK NIH HHS / United States
P30 DK020572 / DK / NIDDK NIH HHS / United States
R01 HD057194 / HD / NICHD NIH HHS / United States
T32 HL007055 / HL / NHLBI NIH HHS / United States
RG/18/13/33946 / BHF_ / British Heart Foundation / United Kingdom

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