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

Publication

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

Journal Paper/Review - Dec 22, 2017

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

Citation

Packard C, Pers T, Person T, Peters A, Petersen E, Peyser P, Pirie A, Polasek O, Polderman T, Puolijoki H, Raitakari O, Perry J, Perry J, Perola M, Padmanabhan S, Palmer C, Palmer N, Pasterkamp G, Patel A, Pattie A, Pedersen O, Peissig P, Peloso G, Pennell C, Rasheed A, Rauramaa R, Reilly D, Samani N, Sapkota Y, Sattar N, Schoen R, Schreiner P, Schulze M, Scott R, Segura-Lepe M, Shah S, Sheu W, Salomaa V, Saleheen D, Ruth K, Renström F, Rheinberger M, Ridker P, Rioux J, Rivas M, Roberts D, Robertson N, Robino A, Rolandsson O, Rudan I, Sim X, Lin K, Lubitz S, Lyytikäinen L, Männistö S, Marenne G, Mazul A, McCarthy M, McKean-Cowdin R, Medland S, Meidtner K, Milani L, Luan J, Loukola A, Lotery A, Lin L, Lin X, Lind L, Lindström J, Linneberg A, Liu C, Liu D, Liu Y, Lo K, Lophatananon A, Mistry V, Mitchell P, Mohlke K, Neville M, Nielsen S, Nikus K, Njølstad P, Nordestgaard B, Nyholt D, O'Connel J, O'Donoghue M, Olde Loohuis L, Ophoff R, Nelson C, Narisu N, Nalls M, Moilanen L, Moitry M, Montgomery G, Mook-Kanamori D, Moore C, Mori T, Morris A, Morris A, Müller-Nurasyid M, Munroe P, Owen K, Slater A, Walker M, Witte D, Wood A, Wu Y, Yaghootkar H, Yao J, Yao P, Yerges-Armstrong L, Young R, Zeggini E, Zhan X, Wilson J, Willer C, White H, Wallentin L, Wang F, Wang C, Wang S, Wang Y, Ware E, Wareham N, Warren H, Waterworth D, Wessel J, Zhang W, Zhao J, Zhao W, 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, Loos R, Hirschhorn J, Lindgren C, Zhou W, Zondervan K, Rotter J, Pospisilik J, Rivadeneira F, Borecki I, Deloukas P, Frayling T, Lettre G, North K, Understanding Society Scientific Group, Small K, Swift A, Tada H, Tansey K, Tardif J, Taylor K, Teumer A, Thompson D, Thorleifsson G, Thorsteinsdottir U, Thuesen B, Surendran P, Sun L, Stumvoll M, Smith A, Southam L, Spector T, Speliotes E, Starr J, Stefansson K, Steinthorsdottir V, Stirrups K, Strauch K, Stringham H, Tönjes A, Tromp G, Trompet S, Varga T, Varma R, Velez Edwards D, Vermeulen S, Veronesi G, Vestergaard H, Vitart V, Vogt T, Völker U, Vuckovic D, Varbo A, Vanhala M, van Setten J, Tsafantakis E, Tuomilehto J, Tybjaerg-Hansen A, Tyrer J, Uher R, Uitterlinden A, Uusitupa M, Laan S, Duijn C, Leeuwen N, Wagenknecht L, Lin H, Bots M, Caulfield M, Chambers J, Chasman D, Chen Y, Chowdhury R, Christensen C, Chu A, Cocca M, Collins F, Cook J, Catamo E, Carey D, Cappellani S, Bottinger E, Bowden D, Brandslund I, Breen G, Brilliant M, Broer L, Brumat M, Burt A, Butterworth A, Campbell P, Corley J, Corominas Galbany J, Cox A, Ruijter H, Dennis J, Denny J, Di Angelantonio E, Drenos F, Du M, Dubé M, Dunning A, Easton D, Edwards T, Hollander A, Heijer M, Demerath E, Crosslin D, Cuellar-Partida G, D'Eustacchio A, Danesh J, Davies G, Bakker P, Groot M, Mutsert R, Deary I, Dedoussis G, Ellinghaus D, Turcot V, Locke A, Mahajan A, Marouli E, Sivapalaratnam S, Young K, Alfred T, Feitosa M, Masca N, Manning A, Medina-Gomez C, Lempradl A, Karaderi T, Hendricks A, Lu Y, Highland H, Schurmann C, Justice A, Fine R, Bradfield J, Esko T, Giri A, Graff M, Guo X, Mudgal P, Ng M, Reiner A, Barroso I, Bastarache L, Benn M, Bergmann S, Bielak L, Blüher M, Boehnke M, Boeing H, Boerwinkle E, Böger C, Bang L, Balkau B, Auer P, Vedantam S, Willems S, Winkler T, Abecasis G, Aben K, Alam D, Alharthi S, Allison M, Amouyel P, Asselbergs F, Bork-Jensen J, Ellinor P, Howson J, Jukema J, Kahali B, Kahn R, Kähönen M, Kamstrup P, Kanoni S, Kaprio J, Karaleftheri M, Kardia S, Karpe F, Jørgensen T, Jørgensen M, Johansson S, Hu Y, Huang P, Huffman J, Ikram M, Ingelsson E, Jackson A, Jansson J, Jarvik G, Jensen G, Jia Y, Kathiresan S, Kee F, Kiemeney L, Lamparter D, Lange E, Lange L, Langenberg C, Larson E, Lee N, Lehtimäki T, Lewis C, Li H, Li J, Lakka T, Laakso M, Kuusisto J, Kim E, Kitajima H, Komulainen P, Kooner J, Kooperberg C, Korhonen T, Kovacs P, Kuivaniemi H, Kutalik Z, Kuulasmaa K, Li-Gao R, Elliott P, Franks P, Friedrich N, Frikke-Schmidt R, Galesloot T, Gan W, Gandin I, Gasparini P, Gibson J, Giedraitis V, Gjesing A, Franke A, Franco O, Fornage M, Evangelou E, Farmaki A, Farooqi I, Faul J, Fauser S, Feng S, Ferrannini E, Ferrieres J, Florez J, Ford I, Gordon-Larsen P, Gorski M, Grabe H, Have C, Hayward C, He L, Heard-Costa N, Heath A, Heid I, Helgeland Ø, Hernesniemi J, Hewitt A, Holmen O, Hattersley A, Harris T, Harris K, Grant S, Grarup N, Griffiths H, Grove M, Gudnason V, Gustafsson S, Haessler J, Hakonarson H, Hammerschlag A, Hansen T, Hovingh G. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. Nat Genet 2017; 50:26-41.

Type

Journal Paper/Review (English)

Journal

Nat Genet 2017; 50

Publication Date

Dec 22, 2017

Issn Electronic

1546-1718

Pages

26-41

Brief description/objective

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.