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

Valérie Turcot, Yingchang Lu, Heather M. Highland, Claudia Schurmann, Anne E. Justice, Rebecca S. Fine, Jonathan P. Bradfield, Tõnu Esko, Ayush Giri, Mariaelisa Graff, Xiuqing Guo, Audrey E. Hendricks, Tugce Karaderi, Adelheid Lempradl, Adam E. Locke, Anubha Mahajan, Eirini Marouli, Suthesh Sivapalaratnam, Kristin L. Young, Tamuno AlfredMary F. Feitosa, Nicholas G.D. Masca, Alisa K. Manning, Carolina Medina-Gomez, Poorva Mudgal, Maggie C.Y. Ng, Alex P. Reiner, Sailaja Vedantam, Sara M. Willems, Thomas W. Winkler, Gonçalo Abecasis, Katja K. Aben, Dewan S. Alam, Sameer E. Alharthi, Matthew Allison, Philippe Amouyel, Folkert W. Asselbergs, Paul L. Auer, Beverley Balkau, Lia E. Bang, Inês Barroso, Lisa Bastarache, Marianne Benn, Sven Bergmann, Lawrence F. Bielak, Matthias Blüher, Michael Boehnke, Heiner Boeing, Eric Boerwinkle, Carsten A. Böger, Jette Bork-Jensen, Michiel L. Bots, Erwin P. Bottinger, Donald W. Bowden, Ivan Brandslund, Gerome Breen, Murray H. Brilliant, Linda Broer, Marco Brumat, Amber A. Burt, Adam S. Butterworth, Peter T. Campbell, Stefania Cappellani, David J. Carey, Eulalia Catamo, Mark J. Caulfield, John C. Chambers, Daniel I. Chasman, Yii Der I. Chen, Rajiv Chowdhury, Cramer Christensen, Audrey Y. Chu, Massimiliano Cocca, Francis S. Collins, James P. Cook, Janie Corley, Jordi Corominas Galbany, Amanda J. Cox, David S. Crosslin, Gabriel Cuellar-Partida, Angela D'Eustacchio, John Danesh, Gail Davies, Paul I.W. Bakker, Mark C.H. Groot, Renée Mutsert, Ian J. Deary, George Dedoussis, Ellen W. Demerath, Martin Heijer, Anneke I. Hollander, Hester M. Ruijter, Joe G. Dennis, Josh C. Denny, Emanuele Angelantonio, Fotios Drenos, Mengmeng Du, Marie Pierre Dubé, Alison M. Dunning, Douglas F. Easton, Todd L. Edwards, David Ellinghaus, Patrick T. Ellinor, Paul Elliott, Evangelos Evangelou, Aliki Eleni Farmaki, I. Sadaf Farooqi, Jessica D. Faul, Sascha Fauser, Shuang Feng, Ele Ferrannini, Jean Ferrieres, Jose C. Florez, Ian Ford, Myriam Fornage, Oscar H. Franco, Andre Franke, Paul W. Franks, Nele Friedrich, Ruth Frikke-Schmidt, Tessel E. Galesloot, Wei Gan, Ilaria Gandin, Paolo Gasparini, Jane Gibson, Vilmantas Giedraitis, Anette P. Gjesing, Penny Gordon-Larsen, Mathias Gorski, Hans Jörgen Grabe, Struan F.A. Grant, Niels Grarup, Helen L. Griffiths, Megan L. Grove, Vilmundur Gudnason, Stefan Gustafsson, Jeff Haessler, Hakon Hakonarson, Anke R. Hammerschlag, Torben Hansen, Kathleen Mullan Harris, Tamara B. Harris, Andrew T. Hattersley, Christian T. Have, Caroline Hayward, Liang He, Nancy L. Heard-Costa, Andrew C. Heath, Iris M. Heid, Øyvind Helgeland, Jussi Hernesniemi, Alex W. Hewitt, Oddgeir L. Holmen, G. Kees Hovingh, Joanna M.M. Howson, Yao Hu, Paul L. Huang, Jennifer E. Huffman, M. Arfan Ikram, Erik Ingelsson, Anne U. Jackson, Jan Håkan Jansson, Gail P. Jarvik, Gorm B. Jensen, Yucheng Jia, Stefan Johansson, Marit E. Jørgensen, Torben Jørgensen, J. Wouter Jukema, Bratati Kahali, René S. Kahn, Mika Kähönen, Pia R. Kamstrup, Stavroula Kanoni, Jaakko Kaprio, Maria Karaleftheri, Sharon L.R. Kardia, Fredrik Karpe, Sekar Kathiresan, Frank Kee, Lambertus A. Kiemeney, Eric Kim, Hidetoshi Kitajima, Pirjo Komulainen, Jaspal S. Kooner, Charles Kooperberg, Tellervo Korhonen, Peter Kovacs, Helena Kuivaniemi, Zoltán Kutalik, Kari Kuulasmaa, Johanna Kuusisto, Markku Laakso, Timo A. Lakka, David Lamparter, Ethan M. Lange, Leslie A. Lange, Claudia Langenberg, Eric B. Larson, Nanette R. Lee, Terho Lehtimäki, Cora E. Lewis, Huaixing Li, Jin Li, Ruifang Li-Gao, Honghuang Lin, Keng Hung Lin, Li An Lin, Xu Lin, Lars Lind, Jaana Lindström, Allan Linneberg, Ching Ti Liu, Dajiang J. Liu, Yongmei Liu, Ken S. Lo, Artitaya Lophatananon, Andrew J. Lotery, Anu Loukola, Jian'An Luan, Steven A. Lubitz, Leo Pekka Lyytikäinen, Satu Männistö, Gaëlle Marenne, Angela L. Mazul, Mark I. McCarthy, Roberta McKean-Cowdin, Sarah E. Medland, Karina Meidtner, Lili Milani, Vanisha Mistry, Paul Mitchell, Karen L. Mohlke, Leena Moilanen, Marie Moitry, Grant W. Montgomery, Dennis O. Mook-Kanamori, Carmel Moore, Trevor A. Mori, Andrew D. Morris, Andrew P. Morris, Martina Müller-Nurasyid, Patricia B. Munroe, Mike A. Nalls, Narisu Narisu, Christopher P. Nelson, Matt Neville, Sune F. Nielsen, Kjell Nikus, Pål R. Njølstad, Børge G. Nordestgaard, Dale R. Nyholt, Jeffrey R. O'Connel, Michelle L. O'Donoghue, Loes M. Olde Loohuis, Roel A. Ophoff, Katharine R. Owen, Chris J. Packard, Sandosh Padmanabhan, Colin N.A. Palmer, Nicholette D. Palmer, Gerard Pasterkamp, Aniruddh P. Patel, Alison Pattie, Oluf Pedersen, Peggy L. Peissig, Gina M. Peloso, Craig E. Pennell, Markus Perola, James A. Perry, John R.B. Perry, Tune H. Pers, Thomas N. Person, Annette Peters, Eva R.B. Petersen, Patricia A. Peyser, Ailith Pirie, Ozren Polasek, Tinca J. Polderman, Hannu Puolijoki, Olli T. Raitakari, Asif Rasheed, Rainer Rauramaa, Dermot F. Reilly, Frida Renström, Myriam Rheinberger, Paul M. Ridker, John D. Rioux, Manuel A. Rivas, David J. Roberts, Neil R. Robertson, Antonietta Robino, Olov Rolandsson, Igor Rudan, Katherine S. Ruth, Danish Saleheen, Veikko Salomaa, Nilesh J. Samani, Yadav Sapkota, Naveed Sattar, Robert E. Schoen, Pamela J. Schreiner, Matthias B. Schulze, Robert A. Scott, Marcelo P. Segura-Lepe, Svati H. Shah, Wayne H.H. Sheu, Xueling Sim, Andrew J. Slater, Kerrin S. Small, Albert V. Smith, Lorraine Southam, Timothy D. Spector, Elizabeth K. Speliotes, John M. Starr, Kari Stefansson, Valgerdur Steinthorsdottir, Kathleen E. Stirrups, Konstantin Strauch, Heather M. Stringham, Michael Stumvoll, Liang Sun, Praveen Surendran, Amy J. Swift, Hayato Tada, Katherine E. Tansey, Jean Claude Tardif, Kent D. Taylor, Alexander Teumer, Deborah J. Thompson, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Betina H. Thuesen, Anke Tönjes, Gerard Tromp, Stella Trompet, Emmanouil Tsafantakis, Jaakko Tuomilehto, Anne Tybjaerg-Hansen, Jonathan P. Tyrer, Rudolf Uher, André G. Uitterlinden, Matti Uusitupa, Sander W. Laan, Cornelia M. Duijn, Nienke Leeuwen, Jessica Van Setten, Mauno Vanhala, Anette Varbo, Tibor V. Varga, Rohit Varma, Digna R. Velez Edwards, Sita H. Vermeulen, Giovanni Veronesi, Henrik Vestergaard, Veronique Vitart, Thomas F. Vogt, Uwe Völker, Dragana Vuckovic, Lynne E. Wagenknecht, Mark Walker, Lars Wallentin, Feijie Wang, Carol A. Wang, Shuai Wang, Yiqin Wang, Erin B. Ware, Nicholas J. Wareham, Helen R. Warren, Dawn M. Waterworth, Jennifer Wessel, Harvey D. White, Cristen J. Willer, James G. Wilson, Daniel R. Witte, Andrew R. Wood, Ying Wu, Hanieh Yaghootkar, Jie Yao, Pang Yao, Laura M. Yerges-Armstrong, Robin Young, Eleftheria Zeggini, Xiaowei Zhan, Weihua Zhang, Jing Hua Zhao, Wei Zhao, Wei Zhou, Krina T. Zondervan, Jerome I. Rotter, John A. Pospisilik, Fernando Rivadeneira, Ingrid B. Borecki, Panos Deloukas, Timothy M. Frayling, Guillaume Lettre, Kari E. North, Cecilia M. Lindgren, Joel N. Hirschhorn, Ruth J.F. Loos

Research output: Contribution to journalArticlepeer-review

113 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)26-35
Number of pages10
JournalNature Genetics
Volume50
Issue number1
DOIs
StatePublished - Jan 1 2018

Bibliographical note

Funding Information:
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 Nuffield Department of Clinical Medicine Award, Clarendon Scholarship. M.I.M. is a Wellcome Trust Senior Investigator (WT098381) and an NIH Research Senior Investigator. M.D. is supported by the NCI (R25CA94880, P30CA008748). P.R.N. is supported by the European Research Council (AdG; 293574), the Research Council of Norway, the University of Bergen, the KG Jebsen Foundation and the Helse Vest, Norwegian Diabetes Association. P.T.E. is supported by the NIH (1R01HL092577, R01HL128914, K24HL105780), by an Established Investigator Award from the American Heart Association (13EIA14220013) and by the Foundation Leducq (14CVD01). P.L.A. was supported by NHLBI R21HL121422 and R01DK089256. P.L.H. is supported by the NIH (NS33335, HL57818). R.S.F. is supported by the NIH (T32GM096911). R.J.F.L. is supported by the NIH (R01DK110113, U01HG007417, R01DK101855, R01DK107786). S.A.L. is supported by the NIH (K23HL114724) and a Doris Duke Charitable Foundation Clinical Scientist Development Award. T.D.S. holds an ERC Advanced Principal Investigator award. T.A.M. is supported by an NHMRC Fellowship (APP1042255). T.H.P. received Lundbeck Foundation and Benzon Foundation support. V.T. is supported by a postdoctoral fellowship from the Canadian Institutes of Health Research (CIHR). Z.K. is supported by the Leenaards Foundation, the Swiss National Science Foundation (31003A-143914) and SystemsX. ch (51RTP0_151019). Part of this work was conducted using the UK Biobank resource (project numbers 1251 and 9072). A full list of acknowledgments appears in the Supplementary Note.

Funding Information:
G. Thorleifsson, V. Steinthorsdottir, U.T. and K. Stefansson are employed by deCODE Genetics/Amgen, Inc.I. Barroso and spouse own stock in GlaxoSmithKline and Incyte, Ltd.S. Kathiresan has received grant support from Bayer Healthcare and Amarin; holds equity in San Therapeutics and Catabasis; and has received personal fees for participation in scientific advisory boards for Bayer Healthcare, Catabasis, Regeneron Genetics Center, Merck, Celera, Genomics PLC, Novartis, Sanofi, AstraZeneca, Alnylam, Eli Lilly Company, Leerink Partners, Noble Insights and Ionis Pharmaceuticals. A.Y.C., D.F.R. and T.F.V. are employees of Merck Sharp Dohme Corp., New Jersey, USA. D.I.C. receives genotyping and collaborative scientific support from Amgen and receives support for genetic analysis from AstraZeneca. P.M.R. receives genotyping and collaborative scientific support from Amgen and receives support for genetic analysis from AstraZeneca. M.J.C. is Chief Scientist for Genomics England, a UK government company.

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