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 Cocca, M Collins, FS Cook, JP Corley, J Corominas Galbany, J Pennell, CE Cox, AJ Crosslin, DS Gjesing, AP Thompson, DJ Zhan, X Feitosa, MF Cuellar-Partida, G D'Eustacchio, A Danesh, J Davies, G Bakker, PIW Groot, MCH Perola, M Mutsert, R Deary, IJ Zhang, W Kutalik, Z Dedoussis, G Demerath, EW Lehtimäki, T Gordon-Larsen, P Heijer, M Hollander, AI Ruijter, HM Dennis, JG Perry, JA Zhao, JH Denny, JC Ophoff, RA Angelantonio, E Drenos, F Du, M Dubé, M-P Lewis, CE Dunning, AM Gorski, M Easton, DF Zhao, W Grabe, H-J Vedantam, S Alharthi, SE Lempradl, A Grant, SFA Grarup, N Griffiths, HL Grove, ML Gudnason, V Li, H Zhou, W Gustafsson, S Haessler, J Hakonarson, H Thorleifsson, G Perry, JRB Hammerschlag, AR Hansen, T Locke, AE Harris, KM Harris, TB Lamparter, D Hattersley, AT Have, CT Li, J Hayward, C Thorsteinsdottir, U He, L Pers, TH Heard-Costa, NL Heath, AC Heid, IM Zondervan, KT Helgeland, Ø Mahajan, A Hernesniemi, J Hewitt, AW Holmen, OL Thuesen, BH Li-Gao, R Hovingh, GK Kitajima, H Howson, JMM CHD Exome+ Consortium Hu, Y Huang, PL Huffman, JE Ikram, MA Ingelsson, E Marouli, E Tönjes, A Jackson, AU Jansson, J-H Lin, H Bang, LE Feng, S Jarvik, GP Jensen, GB Jia, Y Johansson, S Jørgensen, ME Jørgensen, T Tromp, G Jukema, JW Kahali, B Patel, AP Sivapalaratnam, S Kahn, RS Person, TN Lin, K-H Kähönen, M Kamstrup, PR Kanoni, S Kaprio, J Trompet, S Karaleftheri, M Surendran, P Kardia, SLR Karpe, F Kathiresan, S Kee, F Peters, A Young, KL Lin, L-A Kiemeney, LA Lin, X Franco, OH Galesloot, TE Ellinor, PT Lind, L Masca, NGD Lindström, J Linneberg, A Liu, C-T Petersen, ERB Liu, DJ Liu, Y Lo, KS EPIC-CVD Consortium Tsafantakis, E Lophatananon, A Lotery, AJ Elliott, P Loukola, A Luan, J Manning, AK Lubitz, SA Peyser, PA Lyytikäinen, L-P ExomeBP Consortium Männistö, S Tuomilehto, J Marenne, G Mazul, AL McCarthy, MI McKean-Cowdin, R Evangelou, E Medland, SE Meidtner, K Milani, L Global Lipids Genetic Consortium Pirie, A Medina-Gomez, C Owen, KR Mistry, V Mitchell, P Mohlke, KL Moilanen, L Moitry, M Montgomery, GW Farmaki, A-E GoT2D Genes Consortium Mook-Kanamori, DO Moore, C Polasek, O Alfred, T Mori, TA Morris, AD Mudgal, P Morris, AP Müller-Nurasyid, M Munroe, PB EPIC InterAct Consortium Nalls, MA Narisu, N Farooqi, IS Nelson, CP Tybjaerg-Hansen, A Polderman, TJ Neville, M Nielsen, SF Nikus, K Njølstad, PR INTERVAL Study Ng, MCY Nordestgaard, BG Nyholt, DR O'Connel, JR O'Donoghue, ML Tyrer, JP Faul, JD Puolijoki, H Olde Loohuis, LM Willems, SM Lange, EM Komulainen, P Raitakari, OT Hendricks, AE Rasheed, A Rauramaa, R Reilly, DF Allison, M Renström, F Rheinberger, M Ridker, PM ReproGen Consortium Rioux, JD Rivas, MA Kooner, JS Roberts, DJ Winkler, TW Ferrannini, E Robertson, NR Uher, R Robino, A Rolandsson, O T2D-Genes Consortium Rudan, I Ruth, KS Saleheen, D Salomaa, V Kooperberg, C Samani, NJ Sapkota, Y Sattar, N Uitterlinden, AG Ferrieres, J Swift, AJ Abecasis, G Schoen, RE Schreiner, PJ Schulze, MB Scott, RA Segura-Lepe, MP Korhonen, T Shah, SH Sheu, WH-H Uusitupa, M Fauser, S Sim, X Slater, AJ Florez, JC Small, KS Aben, KK Smith, AV Southam, L Spector, TD Kovacs, P Speliotes, EK MAGIC Investigators Laan, SW Starr, JM Stefansson, K Steinthorsdottir, V Stirrups, KE Ford, I Strauch, K Stringham, HM Alam, DS Stumvoll, M Understanding Society Scientific Group Kuivaniemi, H Duijn, CM Sun, L Franke, A Packard, CJ Leeuwen, N Edwards, TL van Setten, J Vanhala, M Varbo, A Gan, W Varga, TV Amouyel, P Varma, R Velez Edwards, DR Vermeulen, SH Padmanabhan, S Veronesi, G Franks, PW Kuulasmaa, K Vestergaard, H Barroso, I Vitart, V Vogt, TF Völker, U Vuckovic, D Wagenknecht, LE Asselbergs, FW Palmer, CNA Walker, M Wallentin, L Wang, F Rotter, JI Kuusisto, J Friedrich, N Wang, CA Wang, S Wang, Y Ware, EB Wareham, NJ Reiner, AP Warren, HR Waterworth, DM Pospisilik, JA Auer, PL Wessel, J Laakso, M White, HD Frikke-Schmidt, R Willer, CJ Wilson, JG Witte, DR Palmer, ND Wood, AR Rivadeneira, F Wu, Y Yaghootkar, H Yao, J Yao, P Lakka, TA Balkau, B Yerges-Armstrong, LM Karaderi, T Young, R Pasterkamp, G Borecki, IB Zeggini, E Lange, LA Tada, H Deloukas, P Kim, E Frayling, TM Lettre, G North, KE Lindgren, CM Gandin, I Hirschhorn, JN Bastarache, L Loos, RJF Tansey, KE Benn, M Langenberg, C Pattie, A Bergmann, S Bielak, LF Blüher, M Boehnke, M Boeing, H Boerwinkle, E Gasparini, P Tardif, J-C Böger, CA Bork-Jensen, J Bots, ML Pedersen, O Larson, EB Bottinger, EP Bowden, DW Brandslund, I Breen, G Brilliant, MH Fornage, M Broer, L Brumat, M Gibson, J Burt, AA Peissig, PL Butterworth, AS Lee, NR Campbell, PT Cappellani, S Carey, DJ Taylor, KD Catamo, E Caulfield, MJ Chambers, JC Chasman, DI Chen, Y-DI Peloso, GM Giedraitis, V Chowdhury, R Ellinghaus, D Christensen, C Teumer, A Chu, AY |
Keywords: | 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 |
Issue Date: | 2017 |
Publisher: | NATURE PUBLISHING GROUP |
Citation: | Nature genetics, 2018, 50 (1), pp. 26 - 41 |
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. |
URI: | http://bura.brunel.ac.uk/handle/2438/15676 |
DOI: | http://dx.doi.org/10.1038/s41588-017-0011-x |
ISSN: | 1061-4036 1546-1718 |
Appears in Collections: | Dept of Life Sciences Research Papers
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