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

Turcot, V; Lu, Y; Highland, HM; Schurmann, C; Justice, AE; Fine, RS; Bradfield, JP; Esko, T; Giri, A; Graff, M; Guo, X; Kim, E; Kitajima, H; Komulainen, P; Kooner, JS; Kooperberg, C; Korhonen, T; Kovacs, P; Kuivaniemi, H; Kutalik, Z; Alfred, T; Edwards, TL; Kuulasmaa, K; Kuusisto, J; Laakso, M; Lakka, TA; Lamparter, D; Lange, EM; Lange, LA; Langenberg, C; Larson, EB; Lee, NR; Ellinghaus, D; Feitosa, MF; Lehtimäki, T; Lewis, CE; Li, H; Li, J; Li-Gao, R; Lin, H; Lin, K-H; Lin, L-A; Lin, X; Ellinor, PT; Lind, L; Masca, NGD; Lindström, J; Linneberg, A; Liu, C-T; Liu, DJ; Liu, Y; Lo, KS; Lophatananon, A; Lotery, AJ; Elliott, P; Loukola, A; Luan, J; Manning, AK; Lubitz, SA; Lyytikäinen, L-P; Männistö, S; Marenne, G; Mazul, AL; McCarthy, MI; McKean-Cowdin, R; Evangelou, E; Medland, SE; Meidtner, K; Milani, L; Medina-Gomez, C; Mistry, V; Mitchell, P; Mohlke, KL; Moilanen, L; Moitry, M; Montgomery, GW; Farmaki, A-E; Mook-Kanamori, DO; Moore, C; Mori, TA; Morris, AD; Mudgal, P; Morris, AP; Müller-Nurasyid, M; Munroe, PB; Nalls, MA; Narisu, N; Farooqi, IS; Nelson, CP; Neville, M; Nielsen, SF; Nikus, K; Njølstad, PR; Ng, MCY; Nordestgaard, BG; Nyholt, DR; O'Connel, JR; O'Donoghue, ML; Faul, JD; Olde Loohuis, LM; Ophoff, RA; Owen, KR; Packard, CJ; Padmanabhan, S; Palmer, CNA; Reiner, AP; Palmer, ND; Pasterkamp, G; Patel, AP; Fauser, S; Pattie, A; Pedersen, O; Peissig, PL; Peloso, GM; Pennell, CE; Perola, M; Perry, JA; Vedantam, S; Perry, JRB; Pers, TH; Feng, S; Person, TN; Peters, A; Petersen, ERB; Peyser, PA; Pirie, A; Polasek, O; Polderman, TJ; Puolijoki, H; Willems, SM; Raitakari, OT; Hendricks, AE; Rasheed, A; Rauramaa, R; Reilly, DF; Renström, F; Rheinberger, M; Ridker, PM; Rioux, JD; Rivas, MA; Roberts, DJ; Winkler, TW; Ferrannini, E; Robertson, NR; Robino, A; Rolandsson, O; Rudan, I; Ruth, KS; Saleheen, D; Salomaa, V; Samani, NJ; Sapkota, Y; Sattar, N; Ferrieres, J; Abecasis, G; Schoen, RE; Schreiner, PJ; Schulze, MB; Scott, RA; Segura-Lepe, MP; Shah, SH; Sheu, WH-H; Sim, X; Slater, AJ; Florez, JC; Small, KS; Aben, KK; Smith, AV; Southam, L; Spector, TD; Speliotes, EK; Starr, JM; Stefansson, K; Steinthorsdottir, V; Stirrups, KE; Ford, I; Strauch, K; Stringham, HM; Alam, DS; Stumvoll, M; Sun, L; Surendran, P; Swift, AJ; Tada, H; Tansey, KE; Tardif, J-C; Fornage, M; Taylor, KD; Teumer, A; Thompson, DJ; Alharthi, SE; Thorleifsson, G; Thorsteinsdottir, U; Thuesen, BH; Tönjes, A; Tromp, G; Trompet, S; Franco, OH; Tsafantakis, E; Tuomilehto, J; Tybjaerg-Hansen, A; Tyrer, JP; Allison, M; Uher, R; Uitterlinden, AG; Uusitupa, M; Laan, SW; Duijn, CM; Franke, A; Leeuwen, N; van Setten, J; Vanhala, M; Varbo, A; Varga, TV; Amouyel, P; Varma, R; Velez Edwards, DR; Vermeulen, SH; Veronesi, G; Franks, PW; Vestergaard, H; Vitart, V; Vogt, TF; Völker, U; Vuckovic, D; Wagenknecht, LE; Asselbergs, FW; Walker, M; Wallentin, L; Wang, F; Friedrich, N; Wang, CA; Wang, S; Wang, Y; Ware, EB; Wareham, NJ; Warren, HR; Waterworth, DM; Auer, PL; Wessel, J; White, HD; Frikke-Schmidt, R; Willer, CJ; Wilson, JG; Witte, DR; Wood, AR; Wu, Y; Yaghootkar, H; Yao, J; Yao, P; Balkau, B; Yerges-Armstrong, LM; Karaderi, T; Young, R; Zeggini, E; Zhan, X; Zhang, W; Zhao, JH; Zhao, W; Zhou, W; Zondervan, KT; Bang, LE; Galesloot, TE; Rotter, JI; Pospisilik, JA; Rivadeneira, F; Borecki, IB; Deloukas, P; Frayling, TM; Lettre, G; North, KE; Lindgren, CM; Hirschhorn, JN; Gan, W; Barroso, I; Loos, RJF; Consortium, CHD Exome+; Consortium, EPIC-CVD; Consortium, ExomeBP; Consortium, Global Lipids Genetic; Consortium, GoT2D Genes; Consortium, EPIC InterAct; Study, INTERVAL; Consortium, ReproGen; Gandin, I; Consortium, T2D-Genes; Bastarache, L; Investigators, MAGIC; Group, Understanding Society Scientific; Benn, M; Bergmann, S; Bielak, LF; Blüher, M; Boehnke, M; Boeing, H; Gasparini, P; Boerwinkle, E; Böger, CA; Bork-Jensen, J; Bots, ML; Bottinger, EP; Bowden, DW; Brandslund, I; Breen, G; Brilliant, MH; Broer, L; Gibson, J; Brumat, M; Burt, AA; Butterworth, AS; Campbell, PT; Cappellani, S; Carey, DJ; Catamo, E; Caulfield, MJ; Chambers, JC; Chasman, DI; Giedraitis, V; Chen, Y-DI; Chowdhury, R; Christensen, C; Chu, AY; Cocca, M; Collins, FS; Cook, JP; Corley, J; Corominas Galbany, J; Cox, AJ; Gjesing, AP; Crosslin, DS; Cuellar-Partida, G; D'Eustacchio, A; Danesh, J; Davies, G; Bakker, PIW; Groot, MCH; Mutsert, R; Deary, IJ; Dedoussis, G; Gordon-Larsen, P; Demerath, EW; Heijer, M; Hollander, AI; Ruijter, HM; Dennis, JG; Denny, JC; Di Angelantonio, E; Drenos, F; Du, M; Dubé, M-P; Gorski, M; Dunning, AM; Easton, DF; Grabe, H-J; Lempradl, A; Grant, SFA; Grarup, N; Griffiths, HL; Grove, ML; Gudnason, V; Gustafsson, S; Haessler, J; Hakonarson, H; Hammerschlag, AR; Hansen, T; Locke, AE; Harris, KM; Harris, TB; Hattersley, AT; Have, CT; Hayward, C; He, L; Heard-Costa, NL; Heath, AC; Heid, IM; Helgeland, Ø; Mahajan, A; Hernesniemi, J; Hewitt, AW; Holmen, OL; Hovingh, GK; Howson, JMM; Hu, Y; Huang, PL; Huffman, JE; Ikram, MA; Ingelsson, E; Marouli, E; Jackson, AU; Jansson, J-H; Jarvik, GP; Jensen, GB; Jia, Y; Johansson, S; Jørgensen, ME; Jørgensen, T; Jukema, JW; Kahali, B; Sivapalaratnam, S; Kahn, RS; Kähönen, M; Kamstrup, PR; Kanoni, S; Kaprio, J; Karaleftheri, M; Kardia, SLR; Karpe, F; Kathiresan, S; Kee, F; Young, KL; Kiemeney, LA

Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.pdf (919.4 kB)

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

journal contribution

posted on 2018-08-07, 11:44 authored by V Turcot, Y Lu, HM Highland, C Schurmann, AE Justice, RS Fine, JP Bradfield, T Esko, A Giri, M Graff, X Guo, E Kim, H Kitajima, P Komulainen, JS Kooner, C Kooperberg, T Korhonen, P Kovacs, H Kuivaniemi, Z Kutalik, T Alfred, TL Edwards, K Kuulasmaa, J Kuusisto, M Laakso, TA Lakka, D Lamparter, EM Lange, LA Lange, C Langenberg, EB Larson, NR Lee, D Ellinghaus, MF Feitosa, T Lehtimäki, CE Lewis, H Li, J Li, R Li-Gao, H Lin, K-H Lin, L-A Lin, X Lin, PT Ellinor, L Lind, NGD Masca, J Lindström, A Linneberg, C-T Liu, DJ Liu, Y Liu, KS Lo, A Lophatananon, AJ Lotery, P Elliott, A Loukola, J Luan, AK Manning, SA Lubitz, L-P Lyytikäinen, S Männistö, G Marenne, AL Mazul, MI McCarthy, R McKean-Cowdin, E Evangelou, SE Medland, K Meidtner, L Milani, C Medina-Gomez, V Mistry, P Mitchell, KL Mohlke, L Moilanen, M Moitry, GW Montgomery, A-E Farmaki, DO Mook-Kanamori, C Moore, TA Mori, AD Morris, P Mudgal, AP Morris, M Müller-Nurasyid, PB Munroe, MA Nalls, N Narisu, IS Farooqi, CP Nelson, M Neville, SF Nielsen, K Nikus, PR Njølstad, MCY Ng, BG Nordestgaard, DR Nyholt, JR O'Connel, ML O'Donoghue, JD Faul, LM Olde Loohuis, RA Ophoff, KR Owen, CJ Packard, S Padmanabhan, CNA Palmer, AP Reiner, ND Palmer, G Pasterkamp, AP Patel, S Fauser, A Pattie, O Pedersen, PL Peissig, GM Peloso, CE Pennell, M Perola, JA Perry, S Vedantam, JRB Perry, TH Pers, S Feng, TN Person, A Peters, ERB Petersen, PA Peyser, A Pirie, O Polasek, TJ Polderman, H Puolijoki, SM Willems, OT Raitakari, AE Hendricks, A Rasheed, R Rauramaa, DF Reilly, F Renström, M Rheinberger, PM Ridker, JD Rioux, MA Rivas, DJ Roberts, TW Winkler, E Ferrannini, NR Robertson, A Robino, O Rolandsson, I Rudan, KS Ruth, D Saleheen, V Salomaa, NJ Samani, Y Sapkota, N Sattar, J Ferrieres, G Abecasis, RE Schoen, PJ Schreiner, MB Schulze, RA Scott, MP Segura-Lepe, SH Shah, WH-H Sheu, X Sim, AJ Slater, JC Florez, KS Small, KK Aben, AV Smith, L Southam, TD Spector, EK Speliotes, JM Starr, K Stefansson, V Steinthorsdottir, KE Stirrups, I Ford, K Strauch, HM Stringham, DS Alam, M Stumvoll, L Sun, P Surendran, AJ Swift, H Tada, KE Tansey, J-C Tardif, M Fornage, KD Taylor, A Teumer, DJ Thompson, SE Alharthi, G Thorleifsson, U Thorsteinsdottir, BH Thuesen, A Tönjes, G Tromp, S Trompet, OH Franco, E Tsafantakis, J Tuomilehto, A Tybjaerg-Hansen, JP Tyrer, M Allison, R Uher, AG Uitterlinden, M Uusitupa, SW Laan, CM Duijn, A Franke, N Leeuwen, J van Setten, M Vanhala, A Varbo, TV Varga, P Amouyel, R Varma, DR Velez Edwards, SH Vermeulen, G Veronesi, PW Franks, H Vestergaard, V Vitart, TF Vogt, U Völker, D Vuckovic, LE Wagenknecht, FW Asselbergs, M Walker, L Wallentin, F Wang, N Friedrich, CA Wang, S Wang, Y Wang, EB Ware, NJ Wareham, HR Warren, DM Waterworth, PL Auer, J Wessel, HD White, R Frikke-Schmidt, CJ Willer, JG Wilson, DR Witte, AR Wood, Y Wu, H Yaghootkar, J Yao, P Yao, B Balkau, LM Yerges-Armstrong, T Karaderi, R Young, E Zeggini, X Zhan, W Zhang, JH Zhao, W Zhao, W Zhou, KT Zondervan, LE Bang, TE Galesloot, JI Rotter, JA Pospisilik, F Rivadeneira, IB Borecki, P Deloukas, TM Frayling, G Lettre, KE North, CM Lindgren, JN Hirschhorn, W Gan, I Barroso, RJF Loos, CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, EPIC InterAct Consortium, INTERVAL Study, ReproGen Consortium, I Gandin, T2D-Genes Consortium, L Bastarache, MAGIC Investigators, Understanding Society Scientific Group, M Benn, S Bergmann, LF Bielak, M Blüher, M Boehnke, H Boeing, P Gasparini, E Boerwinkle, CA Böger, J Bork-Jensen, ML Bots, EP Bottinger, DW Bowden, I Brandslund, G Breen, MH Brilliant, L Broer, J Gibson, M Brumat, AA Burt, AS Butterworth, PT Campbell, S Cappellani, DJ Carey, E Catamo, MJ Caulfield, JC Chambers, DI Chasman, V Giedraitis, Y-DI Chen, R Chowdhury, C Christensen, AY Chu, M Cocca, FS Collins, JP Cook, J Corley, J Corominas Galbany, AJ Cox, AP Gjesing, DS Crosslin, G Cuellar-Partida, A D'Eustacchio, J Danesh, G Davies, PIW Bakker, MCH Groot, R Mutsert, IJ Deary, G Dedoussis, P Gordon-Larsen, EW Demerath, M Heijer, AI Hollander, HM Ruijter, JG Dennis, JC Denny, E Di Angelantonio, F Drenos, M Du, M-P Dubé, M Gorski, AM Dunning, DF Easton, H-J Grabe, A Lempradl, SFA Grant, N Grarup, HL Griffiths, ML Grove, V Gudnason, S Gustafsson, J Haessler, H Hakonarson, AR Hammerschlag, T Hansen, AE Locke, KM Harris, TB Harris, AT Hattersley, CT Have, C Hayward, L He, NL Heard-Costa, AC Heath, IM Heid, Ø Helgeland, A Mahajan, J Hernesniemi, AW Hewitt, OL Holmen, GK Hovingh, JMM Howson, Y Hu, PL Huang, JE Huffman, MA Ikram, E Ingelsson, E Marouli, AU Jackson, J-H Jansson, GP Jarvik, GB Jensen, Y Jia, S Johansson, ME Jørgensen, T Jørgensen, JW Jukema, B Kahali, S Sivapalaratnam, RS Kahn, M Kähönen, PR Kamstrup, S Kanoni, J Kaprio, M Karaleftheri, SLR Kardia, F Karpe, S Kathiresan, F Kee, KL Young, LA Kiemeney

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.

Funding

A.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 Department, Division of Gastroenterology, the University of Michigan Biological Sciences Scholars Program and the Central Society for Clinical Research. C.J.W. is supported by the NIH (HL094535, HL109946). D.J.L. is supported by R01HG008983 and R21DA040177. D.R.W. is supported by the Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation. V. Salomaa has been supported by the Finnish Foundation for Cardiovascular Research. F.W.A. is supported by Dekker scholarship–Junior Staff Member 2014T001 Netherlands Heart Foundation and the UCL Hospitals NIHR Biomedical Research Centre. F.D. is supported by the UK MRC (MC_UU_12013/1-9). G.C.-P. received scholarship support from the University of Queensland and QIMR Berghofer. G.L. is funded by the Montreal Heart Institute Foundation and the Canada Research Chair program. H.Y. and T.M.F. are supported by the European Research Council (323195; SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC). I.M.H. is supported by BMBF (01ER1206) and BMBF (01ER1507m), the NIH and the Max Planck Society. J. Haessler was supported by NHLBI R21HL121422. J.N.H. is supported by NIH R01DK075787. K.E.N. was supported by the NIH (R01DK089256, R01HD057194, U01HG007416, R01DK101855) and the American Heart Association (13GRNT16490017). M.A.R. is supported by the N

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Citation

Nature Genetics, 2018, 50 (1), pp. 26-41

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/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Cardiovascular Sciences

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Nature Genetics

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Nature Publishing Group

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1061-4036

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1546-1718

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2017-11-15

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2017

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2018-08-07

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https://doi.org/10.1038/s41588-017-0011-x

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https://www.nature.com/articles/s41588-017-0011-x

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Supplementary information is available for this paper at https://doi.org/10.1038/s41588-017-0011-x

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en

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https://leicester.figshare.com/account/articles/10198037

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

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