Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

TitleProtein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.
Publication TypeJournal Article
Year of Publication2018
AuthorsTurcot, 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 AuthorsCHD 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
JournalNat Genet
Volume50
Issue1
Pagination26-41
Date Published2018 Jan
ISSN Number1546-1718
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.

DOI10.1038/s41588-017-0011-x
User Guide Notes

http://www.ncbi.nlm.nih.gov/pubmed/29273807?dopt=Abstract

Alternate JournalNat. Genet.
Citation Key9526
PubMed ID29273807
PubMed Central IDPMC5945951
Grant ListMR/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