| Title | Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. |
| Publication Type | Journal Article |
| Year of Publication | 2018 |
| Authors | Turcot, V, Lu, Y, Highland, HM, Schurmann, C, Justice, AE, Fine, RS, Bradfield, JP, Esko, T, Giri, A, Graff, M, Guo, X, Hendricks, AE, Karaderi, T, Lempradl, A, Locke, AE, Mahajan, A, Marouli, E, Sivapalaratnam, S, Young, KL, Alfred, T, Feitosa, MF, Masca, NGD, Manning, AK, Medina-Gomez, C, Mudgal, P, C Y Ng, M, Reiner, AP, Vedantam, S, Willems, SM, Winkler, TW, Abecasis, GR, Aben, KK, Alam, DS, Alharthi, SE, Allison, MA, Amouyel, P, Asselbergs, FW, Auer, PL, Balkau, B, Bang, LE, Barroso, I, Bastarache, L, Benn, M, Bergmann, S, Bielak, LF, Blüher, M, Boehnke, M, Boeing, H, Boerwinkle, E, Böger, CA, Bork-Jensen, J, Bots, ML, Bottinger, EP, Bowden, DW, Brandslund, I, Breen, G, Brilliant, MH, Broer, L, Brumat, M, Burt, AA, Butterworth, AS, Campbell, PT, Cappellani, S, Carey, DJ, Catamo, E, Caulfield, MJ, Chambers, JC, Chasman, DI, Chen, Y-DI, Chowdhury, R, Christensen, C, Chu, AY, Cocca, M, Collins, FS, Cook, JP, Corley, J, Galbany, JCorominas, Cox, AJ, Crosslin, DS, Cuellar-Partida, G, D'Eustacchio, A, Danesh, J, Davies, G, Bakker, PIW, Groot, MCH, Mutsert, R, Deary, IJ, Dedoussis, G, Demerath, EW, Heijer, M, Hollander, AI den, Ruijter, HM den, Dennis, JG, Denny, JC, Angelantonio, E, Drenos, F, Du, M, Dubé, M-P, Dunning, AM, Easton, DF, Edwards, TL, Ellinghaus, D, Ellinor, PT, Elliott, P, Evangelou, E, Farmaki, A-E, I Farooqi, S, Faul, JD, Fauser, S, Feng, S, Ferrannini, E, Ferrières, J, Florez, JC, Ford, I, Fornage, M, Franco, OH, Franke, A, Franks, PW, Friedrich, N, Frikke-Schmidt, R, Galesloot, TE, Gan, W, Gandin, I, Gasparini, PP, Gibson, J, Giedraitis, V, Gjesing, AP, Gordon-Larsen, P, Gorski, M, Grabe, H-J, Grant, SFA, Grarup, N, Griffiths, HL, Grove, ML, Gudnason, V, Gustafsson, S, Haessler, J, Hakonarson, H, Hammerschlag, AR, Hansen, T, Harris, TB, Hattersley, AT, Have, CT, Hayward, C, He, L, Heard-Costa, NL, Heath, AC, Heid, IM, Helgeland, Ø, Hernesniemi, J, Hewitt, AW, Holmen, OL, G Hovingh, K, Howson, JMM, Hu, Y, Huang, PL, Huffman, JE, Ikram, MArfan, Ingelsson, E, Jackson, AU, Jansson, J-H, Jarvik, GP, Jensen, GB, Jia, Y, Johansson, S, Jørgensen, ME, Jørgensen, T, J Jukema, W, Kahali, B, Kahn, RS, Kähönen, M, Kamstrup, PR, Kanoni, S, Kaprio, J, Karaleftheri, M, Kardia, SLR, Karpe, F, Kathiresan, S, Kee, F, Kiemeney, LA, Kim, ES, Kitajima, H, Komulainen, P, Kooner, JS, Kooperberg, C, Korhonen, T, Kovacs, P, Kuivaniemi, H, Kutalik, Z, Kuulasmaa, K, Kuusisto, J, Laakso, M, Lakka, TA, Lamparter, D, Lange, EM, Lange, LA, Langenberg, C, Larson, EB, Lee, NR, Lehtimäki, T, Lewis, CE, 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, DJ, Liu, Y, Lo, KSin, Lophatananon, A, Lotery, AJ, Loukola, A, Luan, J'an, Lubitz, SA, Lyytikäinen, L-P, Männistö, S, Marenne, G, Mazul, AL, McCarthy, MI, McKean-Cowdin, R, Medland, SE, Meidtner, K, Milani, L, Mistry, V, Mitchell, P, Mohlke, KL, Moilanen, L, Moitry, M, Montgomery, GW, Mook-Kanamori, DO, Moore, C, Mori, TA, Morris, AD, Morris, AP, Müller-Nurasyid, M, Munroe, PB, Nalls, MA, Narisu, N, Nelson, CP, Neville, M, Nielsen, SF, Nikus, K, Njølstad, PR, Nordestgaard, BG, Nyholt, DR, O'Connel, JR, O'Donoghue, ML, Ophoff, RA, Owen, KR, Packard, CJ, Padmanabhan, S, Palmer, CNA, Palmer, ND, Pasterkamp, G, Patel, AP, Pattie, A, Pedersen, O, Peissig, PL, Peloso, GM, Pennell, CE, Perola, M, Perry, JA, Perry, JRB, Pers, TH, Person, TN, Peters, A, Petersen, ERB, Peyser, PA, Pirie, A, Polasek, O, Polderman, TJ, Puolijoki, H, Raitakari, OT, Rasheed, A, Rauramaa, R, Reilly, DF, Renstrom, F, Rheinberger, M, Ridker, PM, Rioux, JD, Rivas, MA, Roberts, DJ, Robertson, NR, Robino, A, Rolandsson, O, Rudan, I, Ruth, KS, Saleheen, D, Salomaa, V, Samani, NJ, Sapkota, Y, Sattar, N, Schoen, RE, Schreiner, PJ, Schulze, MB, Scott, RA, Segura-Lepe, MP, Shah, SH, Sheu, WH-H, Sim, X, Slater, AJ, Small, KS, Smith, AVernon, Southam, L, Spector, TD, Speliotes, EK, Starr, JM, Stefansson, K, Steinthorsdottir, V, Stirrups, KE, Strauch, K, Stringham, HM, Stumvoll, M, Sun, L, Surendran, P, Swift, AJ, Tada, H, Tansey, KE, Tardif, J-C, Taylor, KD, Teumer, A, Thompson, DJ, Thorleifsson, G, Thorsteinsdottir, U, Thuesen, BH, Tönjes, A, Tromp, G, Trompet, S, Tsafantakis, E, Tuomilehto, J, Tybjaerg-Hansen, A, Tyrer, JP, Uher, R, Uitterlinden, AG, Uusitupa, M, Laan, SW, Duijn, CM, Leeuwen, N, van Setten, J, Vanhala, M, Varbo, A, Varga, TV, Varma, R, Edwards, DRVelez, Vermeulen, SH, Veronesi, G, Vestergaard, H, Vitart, V, Vogt, TF, Völker, U, Vuckovic, D, Wagenknecht, LE, Walker, M, Wallentin, L, Wang, F, Wang, CA, Wang, S, Wang, Y, Ware, EB, Wareham, NJ, Warren, HR, Waterworth, DM, Wessel, J, White, HD, Willer, CJ, Wilson, JG, Witte, DR, Wood, AR, Wu, Y, Yaghootkar, H, Yao, J, Yao, P, Yerges-Armstrong, LM, Young, R, Zeggini, E, Zhan, X, Zhang, W, Zhao, W, Zhou, W, Zondervan, KT, Rotter, JI, Pospisilik, JA, Rivadeneira, F, Borecki, IB, Deloukas, P, Frayling, TM, Lettre, G, North, KE, Lindgren, CM, Hirschhron, JN, Loos, RJF |
| Corporate Authors | 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 |
| Journal | Nat Genet |
| Volume | 50 |
| Issue | 1 |
| Pagination | 26-41 |
| Date Published | 2018 Jan |
| ISSN Number | 1546-1718 |
| 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. |
| DOI | 10.1038/s41588-017-0011-x |
| User Guide Notes | |
| Alternate Journal | Nat. Genet. |
| Citation Key | 9526 |
| PubMed ID | 29273807 |
| PubMed Central ID | PMC5945951 |
| Grant List | MR/P013880/1 / MRC_ / Medical Research Council / United Kingdom R01 DK107786 / DK / NIDDK NIH HHS / United States Z01 AG000932-01 / ImNIH / Intramural NIH HHS / United States U01 DK062370 / DK / NIDDK NIH HHS / United States MR/K006584/1 / MRC_ / Medical Research Council / United Kingdom BB/F019394/1 / BB_ / Biotechnology and Biological Sciences Research Council / United Kingdom R21 HL121422 / HL / NHLBI NIH HHS / United States MR/M501633/1 / MRC_ / Medical Research Council / United Kingdom R01 DK093757 / DK / NIDDK NIH HHS / United States U01 HG007417 / HG / NHGRI NIH HHS / United States G9521010 / MRC_ / Medical Research Council / United Kingdom G1001799 / MRC_ / Medical Research Council / United Kingdom K99 HL130580 / HL / NHLBI NIH HHS / United States R01 DK106621 / DK / NIDDK NIH HHS / United States RG/13/13/30194 / BHF_ / British Heart Foundation / United Kingdom K24 HL105780 / HL / NHLBI NIH HHS / United States R01 HL109946 / HL / NHLBI NIH HHS / United States R01 HL057818 / HL / NHLBI NIH HHS / United States R01 DK106236 / DK / NIDDK NIH HHS / United States MR/N01104X/2 / MRC_ / Medical Research Council / United Kingdom R01 HL092577 / HL / NHLBI NIH HHS / United States U01 HG007416 / HG / NHGRI NIH HHS / United States K01 DK107836 / DK / NIDDK NIH HHS / United States R01 GM126479 / GM / NIGMS NIH HHS / United States SP/13/2/30111 / BHF_ / British Heart Foundation / United Kingdom R21 DA040177 / DA / NIDA NIH HHS / United States RG/08/014/24067 / BHF_ / British Heart Foundation / United Kingdom R01 HD073342 / HD / NICHD NIH HHS / United States KL2 TR001109 / TR / NCATS NIH HHS / United States Z99 AG999999 / ImNIH / Intramural NIH HHS / United States R01 DK072193 / DK / NIDDK NIH HHS / United States R00 HL130580 / HL / NHLBI NIH HHS / United States MR/L01632X/1 / MRC_ / Medical Research Council / United Kingdom MC_UU_12015/7 / MRC_ / Medical Research Council / United Kingdom R25 CA094880 / CA / NCI NIH HHS / United States R01 DK110113 / DK / NIDDK NIH HHS / United States R01 DK075787 / DK / NIDDK NIH HHS / United States F31 HG009850 / HG / NHGRI NIH HHS / United States MR/L01341X/1 / MRC_ / Medical Research Council / United Kingdom MR/K026992/1 / MRC_ / Medical Research Council / United Kingdom MR/L003120/1 / MRC_ / Medical Research Council / United Kingdom S10 OD018522 / OD / NIH HHS / United States R01 HL128914 / HL / NHLBI NIH HHS / United States G0601966 / MRC_ / Medical Research Council / United Kingdom MC_UU_12015/1 / MRC_ / Medical Research Council / United Kingdom K99 HL094535 / HL / NHLBI NIH HHS / United States P30 CA008748 / CA / NCI NIH HHS / United States MR/N01104X/1 / MRC_ / Medical Research Council / United Kingdom R01 HG008983 / HG / NHGRI NIH HHS / United States P30 DK063491 / DK / NIDDK NIH HHS / United States MC_UU_12015/2 / MRC_ / Medical Research Council / United Kingdom R01 DK101855 / DK / NIDDK NIH HHS / United States RG/16/4/32218 / BHF_ / British Heart Foundation / United Kingdom R00 HL094535 / HL / NHLBI NIH HHS / United States MC_PC_U127561128 / MRC_ / Medical Research Council / United Kingdom MR/M501633/2 / MRC_ / Medical Research Council / United Kingdom MR/P02811X/1 / MRC_ / Medical Research Council / United Kingdom T32 GM096911 / GM / NIGMS 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 RG/14/5/30893 / BHF_ / British Heart Foundation / United Kingdom MR/K007017/1 / MRC_ / Medical Research Council / United Kingdom / WT_ / Wellcome Trust / United Kingdom 323195 / ERC_ / European Research Council / International R01 HD057194 / HD / NICHD NIH HHS / United States MC_PC_13040 / MRC_ / Medical Research Council / United Kingdom R01 HL117078 / HL / NHLBI NIH HHS / United States UL1 TR001881 / TR / NCATS NIH HHS / United States T32 HL007055 / HL / NHLBI NIH HHS / United States G0600237 / MRC_ / Medical Research Council / United Kingdom 293574 / ERC_ / European Research Council / International R01 NS033335 / NS / NINDS NIH HHS / United States L30 HL140353 / HL / NHLBI NIH HHS / United States K23 HL114724 / HL / NHLBI NIH HHS / United States |
