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Turcot, V., Lu, Y., Highland, H.M., Schurmann, C., Justice, A.E., Fine, R.S., Bradfield, J.P., Esko, T., Giri, A., Graff, M., Guo, X., Hendricks, A.E., Karaderi, T., Lempradl, A., Locke, A.E., Mahajan, A., Marouli, E., Sivapalaratnam, S., Young, K.L., Alfred, T., Feitosa, M.F., Masca, N.G.D., Manning, A.K., Medina-Gomez, C., Mudgal, P., Ng, M.C.Y., Reiner, A.P., Vedantam, S., Willems, S.M., Winkler, T.W., Abecasis, G., Aben, K.K., Alam, D.S., Alharthi, S.E., Allison, M., Amouyel, P., Asselbergs, F.W., Auer, P.L., Balkau, B., Bang, L.E., Barroso, I., Bastarache, L., Benn, M., Bergmann, S., Bielak, L.F., Blüher, M., Boehnke, M., Boeing, H., Boerwinkle, E., Böger, C.A., Bork-Jensen, J., Bots, M.L., Bottinger, E.P., Bowden, D.W., Brandslund, I., Breen, G., Brilliant, M.H., Broer, L., Brumat, M., Burt, A.A., Butterworth, A.S., Campbell, P.T., Cappellani, S., Carey, D.J., Catamo, E., Caulfield, M.J., Chambers, J.C., Chasman, D.I., Chen, Y.I., Chowdhury, R., Christensen, C., Chu, A.Y., Cocca, M., Collins, F.S., Cook, J.P., Corley, J., Corominas Galbany, J., Cox, A.J., Crosslin, D.S., Cuellar-Partida, G., D'Eustacchio, A., Danesh, J., Davies, G., Bakker, P.I.W., Groot, M.C.H., Mutsert, R., Deary, I.J., Dedoussis, G., Demerath, E.W., Heijer, M., Hollander, A.I., Ruijter, H.M., Dennis, J.G., Denny, J.C., Di Angelantonio, E., Drenos, F., Du, M., Dubé, M.P., Dunning, A.M., Easton, D.F., Edwards, T.L., Ellinghaus, D., Ellinor, P.T., Elliott, P., Evangelou, E., Farmaki, A.E., Farooqi, I.S., Faul, J.D., Fauser, S., Feng, S., Ferrannini, E., Ferrieres, J., Florez, J.C., Ford, I., Fornage, M., Franco, O.H., Franke, A., Franks, P.W., Friedrich, N., Frikke-Schmidt, R., Galesloot, T.E., Gan, W., Gandin, I., Gasparini, P., Gibson, J., Giedraitis, V., Gjesing, A.P., Gordon-Larsen, P., Gorski, M., Grabe, H.J., Grant, S.F.A., Grarup, N., Griffiths, H.L., Grove, M.L., Gudnason, V., Gustafsson, S., Haessler, J., Hakonarson, H., Hammerschlag, A.R., Hansen, T., Harris, K.M., Harris, T.B., Hattersley, A.T., Have, C.T., Hayward, C., He, L., Heard-Costa, N.L., Heath, A.C., Heid, I.M., Helgeland, Ø., Hernesniemi, J., Hewitt, A.W., Holmen, O.L., Hovingh, G.K., Howson, J.M.M., Hu, Y., Huang, P.L., Huffman, J.E., Ikram, M.A., Ingelsson, E., Jackson, A.U., Jansson, J.H., Jarvik, G.P., Jensen, G.B., Jia, Y., Johansson, S., Jørgensen, M.E., Jørgensen, T., Jukema, J.W., Kahali, B., Kahn, R.S., Kähönen, M., Kamstrup, P.R., Kanoni, S., Kaprio, J., Karaleftheri, M., Kardia, S.L.R., Karpe, F., Kathiresan, S., Kee, F., Kiemeney, L.A., Kim, E., Kitajima, H., Komulainen, P., Kooner, J.S., Kooperberg, C., Korhonen, T., Kovacs, P., Kuivaniemi, H., Kutalik, Z., Kuulasmaa, K., Kuusisto, J., Laakso, M., Lakka, T.A., Lamparter, D., Lange, E.M., Lange, L.A., Langenberg, C., Larson, E.B., Lee, N.R., Lehtimäki, T., Lewis, C.E., Li, H., Li, J., Li-Gao, R., Lin, H., Lin, K.H., Lin, L.A., Lin, X., Lind, L., Lindström, J., Linneberg, A., Liu, C.T., Liu, D.J., Liu, Y., Lo, K.S., Lophatananon, A., Lotery, A.J., Loukola, A., Luan, J., Lubitz, S.A., Lyytikäinen, L.P., Männistö, S., Marenne, G., Mazul, A.L., McCarthy, M.I., McKean-Cowdin, R., Medland, S.E., Meidtner, K., Milani, L., Mistry, V., Mitchell, P., Mohlke, K.L., Moilanen, L., Moitry, M., Montgomery, G.W., Mook-Kanamori, D.O., Moore, C., Mori, T.A., Morris, A.D., Morris, A.P., Müller-Nurasyid, M., Munroe, P.B., Nalls, M.A., Narisu, N., Nelson, C.P., Neville, M., Nielsen, S.F., Nikus, K., Njølstad, P.R., Nordestgaard, B.G., Nyholt, D.R., O'Connel, J.R., O'Donoghue, M.L., Olde Loohuis, L.M., Ophoff, R.A., Owen, K.R., Packard, C.J., Padmanabhan, S., Palmer, C.N.A., Palmer, N.D., Pasterkamp, G., Patel, A.P., Pattie, A., Pedersen, O., Peissig, P.L., Peloso, G.M., Pennell, C.E., Perola, M., Perry, J.A., Perry, J.R.B., Pers, T.H., Person, T.N., Peters, A., Petersen, E.R.B., Peyser, P.A., Pirie, A., Polasek, O., Polderman, T.J., Puolijoki, H., Raitakari, O.T., Rasheed, A., Rauramaa, R., Reilly, D.F., Renström, F., Rheinberger, M., Ridker, P.M., Rioux, J.D., Rivas, M.A., Roberts, D.J., Robertson, N.R., Robino, A., Rolandsson, O., Rudan, I., Ruth, K.S., Saleheen, D., Salomaa, V., Samani, N.J., Sapkota, Y., Sattar, N., Schoen, R.E., Schreiner, P.J., Schulze, M.B., Scott, R.A., Segura-Lepe, M.P., Shah, S.H., Sheu, W.H., Sim, X., Slater, A.J., Small, K.S., Smith, A.V., Southam, L., Spector, T.D., Speliotes, E.K., Starr, J.M., Stefansson, K., Steinthorsdottir, V., Stirrups, K.E., Strauch, K., Stringham, H.M., Stumvoll, M., Sun, L., Surendran, P., Swift, A.J., Tada, H., Tansey, K.E., Tardif, J.C., Taylor, K.D., Teumer, A., Thompson, D.J., Thorleifsson, G., Thorsteinsdottir, U., Thuesen, B.H., Tönjes, A., Tromp, G., Trompet, S., Tsafantakis, E., Tuomilehto, J., Tybjaerg-Hansen, A., Tyrer, J.P., Uher, R., Uitterlinden, A.G., Uusitupa, M., Laan, S.W., Duijn, C.M., Leeuwen, N., van Setten, J., Vanhala, M., Varbo, A., Varga, T.V., Varma, R., Velez Edwards, D.R., Vermeulen, S.H., Veronesi, G., Vestergaard, H., Vitart, V., Vogt, T.F., Völker, U., Vuckovic, D., Wagenknecht, L.E., Walker, M., Wallentin, L., Wang, F., Wang, C.A., Wang, S., Wang, Y., Ware, E.B., Wareham, N.J., Warren, H.R., Waterworth, D.M., Wessel, J., White, H.D., Willer, C.J., Wilson, J.G., Witte, D.R., Wood, A.R., Wu, Y., Yaghootkar, H., Yao, J., Yao, P., Yerges-Armstrong, L.M., Young, R., Zeggini, E., Zhan, X., Zhang, W., Zhao, J.H., Zhao, W., Zhao, W., Zhou, W., Zondervan, K.T., CHD Exome+ Consortium, , EPIC-CVD Consortium, , ExomeBP Consortium, , Global Lipids Genetic Consortium, , GoT2D Genes Consortium, , EPIC InterAct Consortium, , INTERVAL Study, , ReproGen Consortium, , T2D-Genes Consortium, , MAGIC Investigators, , Understanding Society Scientific Group, , Rotter, J.I., Pospisilik, J.A., Rivadeneira, F., Borecki, I.B., Deloukas, P., Frayling, T.M., Lettre, G., North, K.E., Lindgren, C.M., Hirschhorn, J.N., Loos, R.J.F. (2018). Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.  Nat. Genet. 50(1): 26--41.
FlyBase ID
FBrf0250468
Publication Type
Research paper
Abstract
Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
PubMed ID
PubMed Central ID
PMC5945951 (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
    Genes (9)