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

Publication type

Journal Article

Published in

Nature Genetics

Authors

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 Alfred, Mary 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 and Ruth J. F. Loos

Publication date

Summary

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.

Volume and page numbers

50, 26-41

DOI

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

ISSN

16

Subjects

Medicine, Science And Technology, Health, Biology and Genetics

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