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

Justice, AE and Karaderi, T and Highland, HM and Young, KL and Graff, M and Lu, Y and Turcot, V and Auer, PL and Fine, RS and Guo, X and Schurmann, C and Lempradl, A and Marouli, E and Mahajan, A and Winkler, TW and Locke, AE and Medina-Gomez, C and Esko, T and Vedantam, S and Giri, A and Lo, KS and Alfred, T and Mudgal, P and Ng, MCY and Heard-Costa, NL and Feitosa, MF and Manning, AK and Willems, SM and Sivapalaratnam, S and Abecasis, G and Alam, DS and Allison, M and Amouyel, P and Arzumanyan, Z and Balkau, B and Bastarache, L and Bergmann, S and Bielak, LF and Blüher, M and Boehnke, M and Boeing, H and Boerwinkle, E and Böger, CA and Bork-Jensen, J and Bottinger, EP and Bowden, DW and Brandslund, I and Broer, L and Burt, AA and Butterworth, AS and Caulfield, MJ and Cesana, G and Chambers, JC and Chasman, DI and Chen, Y-DI and Chowdhury, R and Christensen, C and Chu, AY and Collins, FS and Cook, JP and Cox, AJ and Crosslin, DS and Danesh, J and de Bakker, PIW and Denus, S and Mutsert, R and Dedoussis, G and Demerath, EW and Dennis, JG and Denny, JC and Angelantonio, ED and Dörr, M and Drenos, F and Dubé, M-P and Dunning, AM and Easton, DF and Elliott, P and Evangelou, E and Farmaki, A-E and Feng, S and Ferrannini, E and Ferrieres, J and Florez, JC and Fornage, M and Fox, CS and Franks, PW and Friedrich, N and Gan, W and Gandin, I and Gasparini, P and Giedraitis, V and Girotto, G and Gorski, M and Grallert, H and Grarup, N and Grove, ML and Gustafsson, S and Haessler, J and Hansen, T and Hattersley, AT and Hayward, C and Heid, IM and Holmen, OL and Hovingh, GK and Howson, JMM and Hu, Y and Hung, Y-J and Hveem, K and Ikram, MA and Ingelsson, E and Jackson, AU and Jarvik, GP and Jia, Y and Jørgensen, T and Jousilahti, P and Justesen, JM and Kahali, B and Karaleftheri, M and Kardia, SLR and Karpe, F and Kee, F and Kitajima, H and Komulainen, P and Kooner, JS and Kovacs, P and Krämer, BK and Kuulasmaa, K and Kuusisto, J and Laakso, M and Lakka, TA and Lamparter, D and Lange, LA and Langenberg, C and Larson, EB and Lee, NR and Lee, W-J and Lehtimäki, T and Lewis, CE and Li, H and Li, J and Li-Gao, R and Lin, L-A and Lin, X and Lind, L and Lindström, J and Linneberg, A and Liu, C-T and Liu, DJ and Luan, J and Lyytikäinen, L-P and MacGregor, S and Mägi, R and Männistö, S and Marenne, G and Marten, J and Masca, NGD and McCarthy, MI and Meidtner, K and Mihailov, E and Moilanen, L and Moitry, M and Mook-Kanamori, DO and Morgan, A and Morris, AP and Müller-Nurasyid, M and Munroe, PB and Narisu, N and Nelson, CP and Neville, M and Ntalla, I and O�Connell, JR and Owen, KR and Pedersen, O and Peloso, GM and Pennell, CE and Perola, M and Perry, JA and Perry, JRB and Pers, TH and Ewing, A and Polasek, O and Raitakari, OT and Rasheed, A and Raulerson, CK and Rauramaa, R and Reilly, DF and Reiner, AP and Ridker, PM and Rivas, MA and Robertson, NR and Robino, A and Rudan, I and Ruth, KS and Saleheen, D and Salomaa, V and Samani, NJ and Schreiner, PJ and Schulze, MB and Scott, RA and Segura-Lepe, M and Sim, X and Slater, AJ and Small, KS and Smith, BH and Smith, JA and Southam, L and Spector, TD and Speliotes, EK and Stefansson, K and Steinthorsdottir, V and Stirrups, KE and Strauch, K and Stringham, HM and Stumvoll, M and Sun, L and Surendran, P and Swart, KMA and Tardif, J-C and Taylor, KD and Teumer, A and Thompson, DJ and Thorleifsson, G and Thorsteinsdottir, U and Thuesen, BH and Tönjes, A and Torres, M and Tsafantakis, E and Tuomilehto, J and Uitterlinden, AG and Uusitupa, M and van Duijn, CM and Vanhala, M and Varma, R and Vermeulen, SH and Vestergaard, H and Vitart, V and Vogt, TF and Vuckovic, D and Wagenknecht, LE and Walker, M and Wallentin, L and Wang, F and Wang, CA and Wang, S and Wareham, NJ and Warren, HR and Waterworth, DM and Wessel, J and White, HD and Willer, CJ and Wilson, JG and Wood, AR and Wu, Y and Yaghootkar, H and Yao, J and Yerges-Armstrong, LM and Young, R and Zeggini, E and Zhan, X and Zhang, W and Zhao, JH and Zhao, W and Zheng, H and Zhou, W and Zillikens, MC and Rivadeneira, F and Borecki, IB and Pospisilik, JA and Deloukas, P and Frayling, TM and Lettre, G and Mohlke, KL and Rotter, JI and Kutalik, Z and Hirschhorn, JN and Cupples, LA and Loos, RJF and North, KE and Lindgren, CM and Consortium, CHD Exome+ and for Heart, Cohorts and in Genomic Epidemiology (CHARGE) Consortium, Aging Research and Consortium, EPIC-CVD and Consortium, ExomeBP and Consortium, Global Lipids Genetic and Consortium, GoT2D Genes and Consortium, ReproGen and Consortium, T2D-Genes and Investigators, The MAGIC (2019) Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution. In: Nature Genetics, 51 (3). pp. 452-469.

nat_gen_ 51-3_ 452 - 469_2019.pdf - Published Version

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Official URL: https://doi.org/10.1038/s41588-018-0334-2


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.

Item Type: Journal Article
Publication: Nature Genetics
Publisher: Nature Publishing Group
Additional Information: The copyright for this article belongs to the Author(s).
Keywords: adiponectin; protein; lipid; protein, ACVR1C gene; adipogenesis; African; angiogenesis; ANGPTL4 gene; Article; bioinformatics; body fat distribution; body mass; bone development; coding; DAGLB gene; DNAH10 gene; Drosophila; East Asian; European; exome; expression quantitative trait locus; FGFR2 gene; gene; gene frequency; gene knockdown; genetic trait; genetic variability; genotype; glucose homeostasis; Hispanic; human; insulin blood level; lipid homeostasis; meta analysis; MLXIPL gene; nonhuman; phenotype; PLXND1 gene; priority journal; RAPGEF3 gene; recessive inheritance; RNA splicing; RREB1 gene; sex difference; South Asian; TBX15 gene; triacylglycerol level; waist hip ratio; white adipose tissue; animal; body fat distribution; case control study; female; genetic predisposition; genetic variation; genetics; genome-wide association study; homeostasis; male; procedures; risk factor, Animals; 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
Department/Centre: Autonomous Societies / Centres > Centre for Brain Research
Date Deposited: 31 Oct 2022 11:22
Last Modified: 31 Oct 2022 11:22
URI: https://eprints.iisc.ac.in/id/eprint/77714

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