| Title: |
Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. |
| 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; Ng, MCY; Reiner, AP; Vedantam, S; Willems, SM; Winkler, TW; Abecasis, G; Aben, KK; Alam, DS; Alharthi, SE; Allison, M; 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; Corominas Galbany, J; 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; Ruijter, HM; 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; Farooqi, IS; Faul, JD; Fauser, S; Feng, S; Ferrannini, E; Ferrieres, 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, P; 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, KM; 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; Hovingh, GK; Howson, JMM; Hu, Y; Huang, PL; Huffman, JE; Ikram, MA; Ingelsson, E; Jackson, AU; Jansson, J-H; Jarvik, GP; Jensen, GB; Jia, Y; Johansson, S; Jørgensen, ME; Jørgensen, T; Jukema, JW; 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, E; 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, KS; Lophatananon, A; Lotery, AJ; Loukola, A; Luan, J; 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; Olde Loohuis, LM; 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; Renström, 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, AV; 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; Velez Edwards, DR; 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, JH; Zhao, W; Zhou, W; Zondervan, KT; 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, JI; Pospisilik, JA; Rivadeneira, F; Borecki, IB; Deloukas, P; Frayling, TM; Lettre, G; North, KE; Lindgren, CM; Hirschhorn, JN; Loos, RJF |
| Publisher Information: |
Nature Publishing Group |
| Publication Year: |
2017 |
| Collection: |
University of Exeter: Open Research Exeter (ORE) |
| Subject Terms: |
Genome-wide association studies; Obesity |
| Description: |
This is the author accepted manuscript. The final version is available from Nature Publishing Group via the DOI in this record. ; 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. ; .P.R. was supported by R01DK089256. A.W.H. is supported by an NHMRC Practitioner Fellowship (APP1103329). A.K.M. received funding from NIH/NIDDK K01DK107836. A.T.H. is a Wellcome Trust Senior Investigator (WT098395) and an NIH Research Senior Investigator. A.P.M. is a Wellcome Trust Senior Fellow in Basic Biomedical Science (WT098017). A.R.W. is supported by the European Research Council (SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC). A.U.J. is supported by the American Heart Association (13POST16500011) and the NIH (R01DK089256, R01DK101855, K99HL130580). B.K. and E.K.S. were supported by the Doris Duke Medical Foundation, the NIH (R01DK106621), the University of Michigan Internal Medicine ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
https://www.ncbi.nlm.nih.gov/pubmed/29273807; http://hdl.handle.net/10871/31715; Nature Genetics |
| DOI: |
10.1038/s41588-017-0011-x |
| Availability: |
http://hdl.handle.net/10871/31715; https://doi.org/10.1038/s41588-017-0011-x |
| Rights: |
© 2017 Nature America Inc., part of Springer Nature. All rights reserved. ; 2018-06-23 ; Under embargo until 23 June 2018 in compliance with publisher policy. |
| Accession Number: |
edsbas.DC2DDE0B |
| Database: |
BASE |