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Justice, A.E., Karaderi, T., Highland, H.M., Young, K.L., Graff, M., Lu, Y., Turcot, V., Auer, P.L., Fine, R.S., Guo, X., Schurmann, C., Lempradl, A., Marouli, E., Mahajan, A., Winkler, T.W., Locke, A.E., Medina-Gomez, C., Esko, T., Vedantam, S., Giri, A., Lo, K.S., Alfred, T., Mudgal, P., Ng, M.C.Y., Heard-Costa, N.L., Feitosa, M.F., Manning, A.K., Willems, S.M., Sivapalaratnam, S., Abecasis, G., Alam, D.S., Allison, M., Amouyel, P., Arzumanyan, Z., Balkau, B., Bastarache, L., Bergmann, S., Bielak, L.F., Blüher, M., Boehnke, M., Boeing, H., Boerwinkle, E., Böger, C.A., Bork-Jensen, J., Bottinger, E.P., Bowden, D.W., Brandslund, I., Broer, L., Burt, A.A., Butterworth, A.S., Caulfield, M.J., Cesana, G., Chambers, J.C., Chasman, D.I., Chen, Y.I., Chowdhury, R., Christensen, C., Chu, A.Y., Collins, F.S., Cook, J.P., Cox, A.J., Crosslin, D.S., Danesh, J., de Bakker, P.I.W., Denus, S., Mutsert, R., Dedoussis, G., Demerath, E.W., Dennis, J.G., Denny, J.C., Angelantonio, E.D., Dörr, M., Drenos, F., Dubé, M.P., Dunning, A.M., Easton, D.F., Elliott, P., Evangelou, E., Farmaki, A.E., Feng, S., Ferrannini, E., Ferrieres, J., Florez, J.C., Fornage, M., Fox, C.S., Franks, P.W., Friedrich, N., Gan, W., Gandin, I., Gasparini, P., Giedraitis, V., Girotto, G., Gorski, M., Grallert, H., Grarup, N., Grove, M.L., Gustafsson, S., Haessler, J., Hansen, T., Hattersley, A.T., Hayward, C., Heid, I.M., Holmen, O.L., Hovingh, G.K., Howson, J.M.M., Hu, Y., Hung, Y.J., Hveem, K., Ikram, M.A., Ingelsson, E., Jackson, A.U., Jarvik, G.P., Jia, Y., Jørgensen, T., Jousilahti, P., Justesen, J.M., Kahali, B., Karaleftheri, M., Kardia, S.L.R., Karpe, F., Kee, F., Kitajima, H., Komulainen, P., Kooner, J.S., Kovacs, P., Krämer, B.K., Kuulasmaa, K., Kuusisto, J., Laakso, M., Lakka, T.A., Lamparter, D., Lange, L.A., Langenberg, C., Larson, E.B., Lee, N.R., Lee, W.J., Lehtimäki, T., Lewis, C.E., Li, H., Li, J., Li-Gao, R., Lin, L.A., Lin, X., Lind, L., Lindström, J., Linneberg, A., Liu, C.T., Liu, D.J., Luan, J., Lyytikäinen, L.P., MacGregor, S., Mägi, R., Männistö, S., Marenne, G., Marten, J., Masca, N.G.D., McCarthy, M.I., Meidtner, K., Mihailov, E., Moilanen, L., Moitry, M., Mook-Kanamori, D.O., Morgan, A., Morris, A.P., Müller-Nurasyid, M., Munroe, P.B., Narisu, N., Nelson, C.P., Neville, M., Ntalla, I., O'Connell, J.R., Owen, K.R., Pedersen, O., Peloso, G.M., Pennell, C.E., Perola, M., Perry, J.A., Perry, J.R.B., Pers, T.H., Ewing, A., Polasek, O., Raitakari, O.T., Rasheed, A., Raulerson, C.K., Rauramaa, R., Reilly, D.F., Reiner, A.P., Ridker, P.M., Rivas, M.A., Robertson, N.R., Robino, A., Rudan, I., Ruth, K.S., Saleheen, D., Salomaa, V., Samani, N.J., Schreiner, P.J., Schulze, M.B., Scott, R.A., Segura-Lepe, M., Sim, X., Slater, A.J., Small, K.S., Smith, B.H., Smith, J.A., Southam, L., Spector, T.D., Speliotes, E.K., Stefansson, K., Steinthorsdottir, V., Stirrups, K.E., Strauch, K., Stringham, H.M., Stumvoll, M., Sun, L., Surendran, P., Swart, K.M.A., Tardif, J.C., Taylor, K.D., Teumer, A., Thompson, D.J., Thorleifsson, G., Thorsteinsdottir, U., Thuesen, B.H., Tönjes, A., Torres, M., Tsafantakis, E., Tuomilehto, J., Uitterlinden, A.G., Uusitupa, M., van Duijn, C.M., Vanhala, M., Varma, R., Vermeulen, S.H., Vestergaard, H., Vitart, V., Vogt, T.F., Vuckovic, D., Wagenknecht, L.E., Walker, M., Wallentin, L., Wang, F., Wang, C.A., Wang, S., Wareham, N.J., Warren, H.R., Waterworth, D.M., Wessel, J., White, H.D., Willer, C.J., Wilson, J.G., Wood, A.R., Wu, Y., Yaghootkar, H., Yao, J., Yerges-Armstrong, L.M., Young, R., Zeggini, E., Zhan, X., Zhang, W., Zhao, J.H., Zhao, W., Zheng, H., Zhou, W., Zillikens, M.C., 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, , Rivadeneira, F., Borecki, I.B., Pospisilik, J.A., Deloukas, P., Frayling, T.M., Lettre, G., Mohlke, K.L., Rotter, J.I., Kutalik, Z., Hirschhorn, J.N., Cupples, L.A., Loos, R.J.F., North, K.E., Lindgren, C.M. (2019). Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.  Nat. Genet. 51(3): 452--469.
FlyBase ID
FBrf0241652
Publication Type
Research paper
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.

PubMed ID
PubMed Central ID
PMC6560635 (PMC) (EuropePMC)
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    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Nat. Genet.
    Title
    Nature Genetics
    Publication Year
    1992-
    ISBN/ISSN
    1061-4036 1546-1718
    Data From Reference
    Alleles (4)
    Genes (3)
    Human Disease Models (3)
    Natural transposons (1)
    Experimental Tools (1)
    Transgenic Constructs (4)