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

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 Di 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 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

Nat Genet 2018 01 22;50(1):26-41. Epub 2017 Dec 22.

Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

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.

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http://dx.doi.org/10.1038/s41588-017-0011-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5945951PMC
January 2018
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References

(Supplied by CrossRef)
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W Wen et al.
Hum. Mol. Genet 2014
Article in Nature
AE Locke et al.
Nature 2015
Article in PLoS Genet.
TW Winkler et al.
PLoS Genet. 2015
Article in Nat. Genet.
M Akiyama et al.
Nat. Genet. 2017
Article in Cell
AA Klaauw van der et al.
Cell 2015
Article in Am. J. Hum. Genet.
SL Edwards et al.
Am. J. Hum. Genet. 2013
Article in J. Clin. Invest.
G Stratigopoulos et al.
J. Clin. Invest. 2016
Article in J. Biol. Chem.
G Stratigopoulos et al.
J. Biol. Chem. 2011

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