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 Alfred & 379 others 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, 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 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 journalArticle

32 Citations (Scopus)

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

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Energy Intake
Energy Metabolism
Body Mass Index
Obesity
Genes
Genome-Wide Association Study
Proteins
Gene Frequency
Terminator Codon
Adipocytes
Pain
Mutation
Therapeutics

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Turcot, V., Lu, Y., Highland, H. M., Schurmann, C., Justice, A. E., Fine, R. S., ... Loos, R. J. F. (2018). Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. Nature Genetics, 50(1), 26-35. https://doi.org/10.1038/s41588-017-0011-x
Turcot, Valérie ; Lu, Yingchang ; Highland, Heather M. ; Schurmann, Claudia ; Justice, Anne E. ; Fine, Rebecca S. ; Bradfield, Jonathan P. ; Esko, Tõnu ; Giri, Ayush ; Graff, Mariaelisa ; Guo, Xiuqing ; Hendricks, Audrey E. ; Karaderi, Tugce ; Lempradl, Adelheid ; 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 ; Mudgal, Poorva ; Ng, Maggie C.Y. ; Reiner, Alex P. ; Vedantam, Sailaja ; Willems, Sara M. ; Winkler, Thomas W. ; Abecasis, Gonçalo ; Aben, Katja K. ; Alam, Dewan S. ; Alharthi, Sameer E. ; Allison, Matthew ; Amouyel, Philippe ; Asselbergs, Folkert W. ; Auer, Paul L. ; Balkau, Beverley ; Bang, Lia E. ; Barroso, Inês ; Bastarache, Lisa ; Benn, Marianne ; Bergmann, Sven ; Bielak, Lawrence F. ; Blüher, Matthias ; Boehnke, Michael ; Boeing, Heiner ; Boerwinkle, Eric ; Böger, Carsten A. ; Bork-Jensen, Jette ; Bots, Michiel L. ; 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. ; Cappellani, Stefania ; Carey, David J. ; Catamo, Eulalia ; Caulfield, Mark J. ; Chambers, John C. ; Chasman, Daniel I. ; Chen, Yii Der I. ; Chowdhury, Rajiv ; Christensen, Cramer ; Chu, Audrey Y. ; Cocca, Massimiliano ; Cook, James P. ; Corley, Janie ; Corominas Galbany, Jordi ; Cox, Amanda J. ; 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 ; Demerath, Ellen W. ; Heijer, Martin ; Hollander, Anneke I. ; Ruijter, Hester M. ; Dennis, Joe G. ; Denny, Josh C. ; Angelantonio, Emanuele ; Drenos, Fotios ; Du, Mengmeng ; Dubé, Marie Pierre ; Dunning, Alison M. ; Easton, Douglas F. ; Edwards, Todd L. ; Ellinghaus, David ; Ellinor, Patrick T. ; Elliott, Paul ; Evangelou, Evangelos ; Farmaki, Aliki Eleni ; Farooqi, I. Sadaf ; Faul, Jessica D. ; Fauser, Sascha ; Feng, Shuang ; Ferrannini, Ele ; Ferrieres, Jean ; Florez, Jose C. ; Ford, Ian ; Fornage, Myriam ; Franco, Oscar H. ; Franke, Andre ; Franks, Paul W. ; Friedrich, Nele ; Frikke-Schmidt, Ruth ; Galesloot, Tessel E. ; Gan, Wei ; Gandin, Ilaria ; Gasparini, Paolo ; Gibson, Jane ; Giedraitis, Vilmantas ; Gjesing, Anette P. ; Gordon-Larsen, Penny ; Gorski, Mathias ; Grabe, Hans Jörgen ; 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 ; Harris, Kathleen Mullan ; Harris, Tamara B. ; Hattersley, Andrew T. ; 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. ; Hovingh, G. Kees ; Howson, Joanna M.M. ; 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 ; Johansson, Stefan ; Jørgensen, Marit E. ; Jørgensen, Torben ; 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 ; Kathiresan, Sekar ; Kee, Frank ; Kiemeney, Lambertus A. ; Kim, Eric ; Kitajima, Hidetoshi ; Komulainen, Pirjo ; Kooner, Jaspal S. ; Kooperberg, Charles ; Korhonen, Tellervo ; Kovacs, Peter ; Kuivaniemi, Helena ; Kutalik, Zoltán ; Kuulasmaa, Kari ; Kuusisto, Johanna ; Laakso, Markku ; Lakka, Timo 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 ; Li-Gao, Ruifang ; Lin, Honghuang ; Lin, Keng Hung ; Lin, Li An ; Lin, Xu ; Lind, Lars ; Lindström, Jaana ; Linneberg, Allan ; Liu, Ching Ti ; Liu, Dajiang ; Liu, Yongmei ; Lo, Ken S. ; Lophatananon, Artitaya ; Lotery, Andrew J. ; Loukola, Anu ; Luan, Jian'An ; 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 ; Mistry, Vanisha ; Mitchell, Paul ; Mohlke, Karen L. ; 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. ; Nalls, Mike A. ; Narisu, Narisu ; Nelson, Christopher P. ; 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. ; Owen, Katharine R. ; Packard, Chris J. ; 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. ; Perola, Markus ; Perry, James A. ; Perry, John R.B. ; 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. ; Rasheed, Asif ; Rauramaa, Rainer ; Reilly, Dermot F. ; 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 ; Ruth, Katherine S. ; Saleheen, Danish ; Salomaa, Veikko ; 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. ; Sim, Xueling ; Slater, Andrew J. ; Small, Kerrin S. ; 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. ; Stumvoll, Michael ; Sun, Liang ; Surendran, Praveen ; 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. ; Tönjes, Anke ; Tromp, Gerard ; Trompet, Stella ; 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 ; Van Setten, Jessica ; Vanhala, Mauno ; Varbo, Anette ; 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 ; Wagenknecht, Lynne E. ; Walker, Mark ; 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 ; White, Harvey D. ; Willer, Cristen J. ; Wilson, James G. ; Witte, Daniel R. ; Wood, Andrew R. ; Wu, Ying ; Yaghootkar, Hanieh ; Yao, Jie ; Yao, Pang ; Yerges-Armstrong, Laura M. ; Young, Robin ; Zeggini, Eleftheria ; Zhan, Xiaowei ; Zhang, Weihua ; Zhao, Jing Hua ; Zhao, Wei ; 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. ; Lindgren, Cecilia M. ; Hirschhorn, Joel N. ; Loos, Ruth J.F. / Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. In: Nature Genetics. 2018 ; Vol. 50, No. 1. pp. 26-35.
@article{77ce647a4e264178892d3edbd3ff972c,
title = "Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity",
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.",
author = "Val{\'e}rie Turcot and Yingchang Lu and Highland, {Heather M.} and Claudia Schurmann and Justice, {Anne E.} and Fine, {Rebecca S.} and Bradfield, {Jonathan P.} and T{\~o}nu Esko and Ayush Giri and Mariaelisa Graff and Xiuqing Guo and Hendricks, {Audrey E.} and Tugce Karaderi and Adelheid Lempradl and Locke, {Adam E.} and Anubha Mahajan and Eirini Marouli and Suthesh Sivapalaratnam and Young, {Kristin L.} and Tamuno Alfred and Feitosa, {Mary F.} and Masca, {Nicholas G.D.} and Manning, {Alisa K.} and Carolina Medina-Gomez and Poorva Mudgal and Ng, {Maggie C.Y.} and Reiner, {Alex P.} and Sailaja Vedantam and Willems, {Sara M.} and Winkler, {Thomas W.} and Gon{\cc}alo Abecasis and Aben, {Katja K.} and Alam, {Dewan S.} and Alharthi, {Sameer E.} and Matthew Allison and Philippe Amouyel and Asselbergs, {Folkert W.} and Auer, {Paul L.} and Beverley Balkau and Bang, {Lia E.} and In{\^e}s Barroso and Lisa Bastarache and Marianne Benn and Sven Bergmann and Bielak, {Lawrence F.} and Matthias Bl{\"u}her and Michael Boehnke and Heiner Boeing and Eric Boerwinkle and B{\"o}ger, {Carsten A.} and Jette Bork-Jensen and Bots, {Michiel L.} and Bottinger, {Erwin P.} and Bowden, {Donald W.} and Ivan Brandslund and Gerome Breen and Brilliant, {Murray H.} and Linda Broer and Marco Brumat and Burt, {Amber A.} and Butterworth, {Adam S.} and Campbell, {Peter T.} and Stefania Cappellani and Carey, {David J.} and Eulalia Catamo and Caulfield, {Mark J.} and Chambers, {John C.} and Chasman, {Daniel I.} and Chen, {Yii Der I.} and Rajiv Chowdhury and Cramer Christensen and Chu, {Audrey Y.} and Massimiliano Cocca and Cook, {James P.} and Janie Corley and {Corominas Galbany}, Jordi and Cox, {Amanda J.} and Crosslin, {David S.} and Gabriel Cuellar-Partida and Angela D'Eustacchio and John Danesh and Gail Davies and Bakker, {Paul I.W.} and Groot, {Mark C.H.} and Ren{\'e}e Mutsert and Deary, {Ian J.} and George Dedoussis and Demerath, {Ellen W.} and Martin Heijer and Hollander, {Anneke I.} and Ruijter, {Hester M.} and Dennis, {Joe G.} and Denny, {Josh C.} and Emanuele Angelantonio and Fotios Drenos and Mengmeng Du and Dub{\'e}, {Marie Pierre} and Dunning, {Alison M.} and Easton, {Douglas F.} and Edwards, {Todd L.} and David Ellinghaus and Ellinor, {Patrick T.} and Paul Elliott and Evangelos Evangelou and Farmaki, {Aliki Eleni} and Farooqi, {I. Sadaf} and Faul, {Jessica D.} and Sascha Fauser and Shuang Feng and Ele Ferrannini and Jean Ferrieres and Florez, {Jose C.} and Ian Ford and Myriam Fornage and Franco, {Oscar H.} and Andre Franke and Franks, {Paul W.} and Nele Friedrich and Ruth Frikke-Schmidt and Galesloot, {Tessel E.} and Wei Gan and Ilaria Gandin and Paolo Gasparini and Jane Gibson and Vilmantas Giedraitis and Gjesing, {Anette P.} and Penny Gordon-Larsen and Mathias Gorski and Grabe, {Hans J{\"o}rgen} and Grant, {Struan F.A.} and Niels Grarup and Griffiths, {Helen L.} and Grove, {Megan L.} and Vilmundur Gudnason and Stefan Gustafsson and Jeff Haessler and Hakon Hakonarson and Hammerschlag, {Anke R.} and Torben Hansen and Harris, {Kathleen Mullan} and Harris, {Tamara B.} and Hattersley, {Andrew T.} and Have, {Christian T.} and Caroline Hayward and Liang He and Heard-Costa, {Nancy L.} and Heath, {Andrew C.} and Heid, {Iris M.} and {\O}yvind Helgeland and Jussi Hernesniemi and Hewitt, {Alex W.} and Holmen, {Oddgeir L.} and Hovingh, {G. Kees} and Howson, {Joanna M.M.} and Yao Hu and Huang, {Paul L.} and Huffman, {Jennifer E.} and Ikram, {M. Arfan} and Erik Ingelsson and Jackson, {Anne U.} and Jansson, {Jan H{\aa}kan} and Jarvik, {Gail P.} and Jensen, {Gorm B.} and Yucheng Jia and Stefan Johansson and J{\o}rgensen, {Marit E.} and Torben J{\o}rgensen and Jukema, {J. Wouter} and Bratati Kahali and Kahn, {Ren{\'e} S.} and Mika K{\"a}h{\"o}nen and Kamstrup, {Pia R.} and Stavroula Kanoni and Jaakko Kaprio and Maria Karaleftheri and Kardia, {Sharon L.R.} and Fredrik Karpe and Sekar Kathiresan and Frank Kee and Kiemeney, {Lambertus A.} and Eric Kim and Hidetoshi Kitajima and Pirjo Komulainen and Kooner, {Jaspal S.} and Charles Kooperberg and Tellervo Korhonen and Peter Kovacs and Helena Kuivaniemi and Zolt{\'a}n Kutalik and Kari Kuulasmaa and Johanna Kuusisto and Markku Laakso and Lakka, {Timo A.} and David Lamparter and Lange, {Ethan M.} and Lange, {Leslie A.} and Claudia Langenberg and Larson, {Eric B.} and Lee, {Nanette R.} and Terho Lehtim{\"a}ki and Lewis, {Cora E.} and Huaixing Li and Jin Li and Ruifang Li-Gao and Honghuang Lin and Lin, {Keng Hung} and Lin, {Li An} and Xu Lin and Lars Lind and Jaana Lindstr{\"o}m and Allan Linneberg and Liu, {Ching Ti} and Dajiang Liu and Yongmei Liu and Lo, {Ken S.} and Artitaya Lophatananon and Lotery, {Andrew J.} and Anu Loukola and Jian'An Luan and Lubitz, {Steven A.} and Lyytik{\"a}inen, {Leo Pekka} and Satu M{\"a}nnist{\"o} and Ga{\"e}lle Marenne and Mazul, {Angela L.} and McCarthy, {Mark I.} and Roberta McKean-Cowdin and Medland, {Sarah E.} and Karina Meidtner and Lili Milani and Vanisha Mistry and Paul Mitchell and Mohlke, {Karen L.} and Leena Moilanen and Marie Moitry and Montgomery, {Grant W.} and Mook-Kanamori, {Dennis O.} and Carmel Moore and Mori, {Trevor A.} and Morris, {Andrew D.} and Morris, {Andrew P.} and Martina M{\"u}ller-Nurasyid and Munroe, {Patricia B.} and Nalls, {Mike A.} and Narisu Narisu and Nelson, {Christopher P.} and Matt Neville and Nielsen, {Sune F.} and Kjell Nikus and Nj{\o}lstad, {P{\aa}l R.} and Nordestgaard, {B{\o}rge G.} and Nyholt, {Dale R.} and O'Connel, {Jeffrey R.} and O'Donoghue, {Michelle L.} and {Olde Loohuis}, {Loes M.} and Ophoff, {Roel A.} and Owen, {Katharine R.} and Packard, {Chris J.} and Sandosh Padmanabhan and Palmer, {Colin N.A.} and Palmer, {Nicholette D.} and Gerard Pasterkamp and Patel, {Aniruddh P.} and Alison Pattie and Oluf Pedersen and Peissig, {Peggy L.} and Peloso, {Gina M.} and Pennell, {Craig E.} and Markus Perola and Perry, {James A.} and Perry, {John R.B.} and Pers, {Tune H.} and Person, {Thomas N.} and Annette Peters and Petersen, {Eva R.B.} and Peyser, {Patricia A.} and Ailith Pirie and Ozren Polasek and Polderman, {Tinca J.} and Hannu Puolijoki and Raitakari, {Olli T.} and Asif Rasheed and Rainer Rauramaa and Reilly, {Dermot F.} and Frida Renstr{\"o}m and Myriam Rheinberger and Ridker, {Paul M.} and Rioux, {John D.} and Rivas, {Manuel A.} and Roberts, {David J.} and Robertson, {Neil R.} and Antonietta Robino and Olov Rolandsson and Igor Rudan and Ruth, {Katherine S.} and Danish Saleheen and Veikko Salomaa and Samani, {Nilesh J.} and Yadav Sapkota and Naveed Sattar and Schoen, {Robert E.} and Schreiner, {Pamela J.} and Schulze, {Matthias B.} and Scott, {Robert A.} and Segura-Lepe, {Marcelo P.} and Shah, {Svati H.} and Sheu, {Wayne H.H.} and Xueling Sim and Slater, {Andrew J.} and Small, {Kerrin S.} and Smith, {Albert V.} and Lorraine Southam and Spector, {Timothy D.} and Speliotes, {Elizabeth K.} and Starr, {John M.} and Kari Stefansson and Valgerdur Steinthorsdottir and Stirrups, {Kathleen E.} and Konstantin Strauch and Stringham, {Heather M.} and Michael Stumvoll and Liang Sun and Praveen Surendran and Swift, {Amy J.} and Hayato Tada and Tansey, {Katherine E.} and Tardif, {Jean Claude} and Taylor, {Kent D.} and Alexander Teumer and Thompson, {Deborah J.} and Gudmar Thorleifsson and Unnur Thorsteinsdottir and Thuesen, {Betina H.} and Anke T{\"o}njes and Gerard Tromp and Stella Trompet and Emmanouil Tsafantakis and Jaakko Tuomilehto and Anne Tybjaerg-Hansen and Tyrer, {Jonathan P.} and Rudolf Uher and Uitterlinden, {Andr{\'e} G.} and Matti Uusitupa and Laan, {Sander W.} and Duijn, {Cornelia M.} and Nienke Leeuwen and {Van Setten}, Jessica and Mauno Vanhala and Anette Varbo and Varga, {Tibor V.} and Rohit Varma and {Velez Edwards}, {Digna R.} and Vermeulen, {Sita H.} and Giovanni Veronesi and Henrik Vestergaard and Veronique Vitart and Vogt, {Thomas F.} and Uwe V{\"o}lker and Dragana Vuckovic and Wagenknecht, {Lynne E.} and Mark Walker and Lars Wallentin and Feijie Wang and Wang, {Carol A.} and Shuai Wang and Yiqin Wang and Ware, {Erin B.} and Wareham, {Nicholas J.} and Warren, {Helen R.} and Waterworth, {Dawn M.} and Jennifer Wessel and White, {Harvey D.} and Willer, {Cristen J.} and Wilson, {James G.} and Witte, {Daniel R.} and Wood, {Andrew R.} and Ying Wu and Hanieh Yaghootkar and Jie Yao and Pang Yao and Yerges-Armstrong, {Laura M.} and Robin Young and Eleftheria Zeggini and Xiaowei Zhan and Weihua Zhang and Zhao, {Jing Hua} and Wei Zhao and Wei Zhou and Zondervan, {Krina T.} and Rotter, {Jerome I.} and Pospisilik, {John A.} and Fernando Rivadeneira and Borecki, {Ingrid B.} and Panos Deloukas and Frayling, {Timothy M.} and Guillaume Lettre and North, {Kari E.} and Lindgren, {Cecilia M.} and Hirschhorn, {Joel N.} and Loos, {Ruth J.F.}",
year = "2018",
month = "1",
day = "1",
doi = "10.1038/s41588-017-0011-x",
language = "English (US)",
volume = "50",
pages = "26--35",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "1",

}

Turcot, V, Lu, Y, Highland, HM, Schurmann, C, Justice, AE, Fine, RS, Bradfield, JP, Esko, T, Giri, A, Graff, M, Guo, X, Hendricks, AE, Karaderi, T, Lempradl, A, Locke, AE, Mahajan, A, Marouli, E, Sivapalaratnam, S, Young, KL, Alfred, T, Feitosa, MF, Masca, NGD, Manning, AK, Medina-Gomez, C, Mudgal, P, Ng, MCY, Reiner, AP, Vedantam, S, Willems, SM, Winkler, TW, Abecasis, G, Aben, KK, Alam, DS, Alharthi, SE, Allison, M, Amouyel, P, Asselbergs, FW, Auer, PL, Balkau, B, Bang, LE, Barroso, I, Bastarache, L, Benn, M, Bergmann, S, Bielak, LF, Blüher, M, Boehnke, M, Boeing, H, Boerwinkle, E, Böger, CA, Bork-Jensen, J, Bots, ML, Bottinger, EP, Bowden, DW, Brandslund, I, Breen, G, Brilliant, MH, Broer, L, Brumat, M, Burt, AA, Butterworth, AS, Campbell, PT, Cappellani, S, Carey, DJ, Catamo, E, Caulfield, MJ, Chambers, JC, Chasman, DI, Chen, YDI, Chowdhury, R, Christensen, C, Chu, AY, Cocca, M, Cook, JP, Corley, J, Corominas Galbany, J, Cox, AJ, Crosslin, DS, Cuellar-Partida, G, D'Eustacchio, A, Danesh, J, Davies, G, Bakker, PIW, Groot, MCH, Mutsert, R, Deary, IJ, Dedoussis, G, Demerath, EW, Heijer, M, Hollander, AI, Ruijter, HM, Dennis, JG, Denny, JC, Angelantonio, E, Drenos, F, Du, M, Dubé, MP, Dunning, AM, Easton, DF, Edwards, TL, Ellinghaus, D, Ellinor, PT, Elliott, P, Evangelou, E, Farmaki, AE, Farooqi, IS, Faul, JD, Fauser, S, Feng, S, Ferrannini, E, Ferrieres, J, Florez, JC, Ford, I, Fornage, M, Franco, OH, Franke, A, Franks, PW, Friedrich, N, Frikke-Schmidt, R, Galesloot, TE, Gan, W, Gandin, I, Gasparini, P, Gibson, J, Giedraitis, V, Gjesing, AP, Gordon-Larsen, P, Gorski, M, Grabe, HJ, Grant, SFA, Grarup, N, Griffiths, HL, Grove, ML, Gudnason, V, Gustafsson, S, Haessler, J, Hakonarson, H, Hammerschlag, AR, Hansen, T, Harris, KM, Harris, TB, Hattersley, AT, Have, CT, Hayward, C, He, L, Heard-Costa, NL, Heath, AC, Heid, IM, Helgeland, Ø, Hernesniemi, J, Hewitt, AW, Holmen, OL, Hovingh, GK, Howson, JMM, Hu, Y, Huang, PL, Huffman, JE, Ikram, MA, Ingelsson, E, Jackson, AU, Jansson, JH, Jarvik, GP, Jensen, GB, Jia, Y, Johansson, S, Jørgensen, ME, Jørgensen, T, Jukema, JW, Kahali, B, Kahn, RS, Kähönen, M, Kamstrup, PR, Kanoni, S, Kaprio, J, Karaleftheri, M, Kardia, SLR, Karpe, F, Kathiresan, S, Kee, F, Kiemeney, LA, Kim, E, Kitajima, H, Komulainen, P, Kooner, JS, Kooperberg, C, Korhonen, T, Kovacs, P, Kuivaniemi, H, Kutalik, Z, Kuulasmaa, K, Kuusisto, J, Laakso, M, Lakka, TA, Lamparter, D, Lange, EM, Lange, LA, Langenberg, C, Larson, EB, Lee, NR, Lehtimäki, T, Lewis, CE, Li, H, Li, J, Li-Gao, R, Lin, H, Lin, KH, Lin, LA, Lin, X, Lind, L, Lindström, J, Linneberg, A, Liu, CT, Liu, D, Liu, Y, Lo, KS, Lophatananon, A, Lotery, AJ, Loukola, A, Luan, JA, Lubitz, SA, Lyytikäinen, LP, Männistö, S, Marenne, G, Mazul, AL, McCarthy, MI, McKean-Cowdin, R, Medland, SE, Meidtner, K, Milani, L, Mistry, V, Mitchell, P, Mohlke, KL, Moilanen, L, Moitry, M, Montgomery, GW, Mook-Kanamori, DO, Moore, C, Mori, TA, Morris, AD, Morris, AP, Müller-Nurasyid, M, Munroe, PB, Nalls, MA, Narisu, N, Nelson, CP, Neville, M, Nielsen, SF, Nikus, K, Njølstad, PR, Nordestgaard, BG, Nyholt, DR, O'Connel, JR, O'Donoghue, ML, Olde Loohuis, LM, Ophoff, RA, Owen, KR, Packard, CJ, Padmanabhan, S, Palmer, CNA, Palmer, ND, Pasterkamp, G, Patel, AP, Pattie, A, Pedersen, O, Peissig, PL, Peloso, GM, Pennell, CE, Perola, M, Perry, JA, Perry, JRB, Pers, TH, Person, TN, Peters, A, Petersen, ERB, Peyser, PA, Pirie, A, Polasek, O, Polderman, TJ, Puolijoki, H, Raitakari, OT, Rasheed, A, Rauramaa, R, Reilly, DF, Renström, F, Rheinberger, M, Ridker, PM, Rioux, JD, Rivas, MA, Roberts, DJ, Robertson, NR, Robino, A, Rolandsson, O, Rudan, I, Ruth, KS, Saleheen, D, Salomaa, V, Samani, NJ, Sapkota, Y, Sattar, N, Schoen, RE, Schreiner, PJ, Schulze, MB, Scott, RA, Segura-Lepe, MP, Shah, SH, Sheu, WHH, Sim, X, Slater, AJ, Small, KS, Smith, AV, Southam, L, Spector, TD, Speliotes, EK, Starr, JM, Stefansson, K, Steinthorsdottir, V, Stirrups, KE, Strauch, K, Stringham, HM, Stumvoll, M, Sun, L, Surendran, P, Swift, AJ, Tada, H, Tansey, KE, Tardif, JC, Taylor, KD, Teumer, A, Thompson, DJ, Thorleifsson, G, Thorsteinsdottir, U, Thuesen, BH, Tönjes, A, Tromp, G, Trompet, S, Tsafantakis, E, Tuomilehto, J, Tybjaerg-Hansen, A, Tyrer, JP, Uher, R, Uitterlinden, AG, Uusitupa, M, Laan, SW, Duijn, CM, Leeuwen, N, Van Setten, J, Vanhala, M, Varbo, A, Varga, TV, Varma, R, Velez Edwards, DR, Vermeulen, SH, Veronesi, G, Vestergaard, H, Vitart, V, Vogt, TF, Völker, U, Vuckovic, D, Wagenknecht, LE, Walker, M, Wallentin, L, Wang, F, Wang, CA, Wang, S, Wang, Y, Ware, EB, Wareham, NJ, Warren, HR, Waterworth, DM, Wessel, J, White, HD, Willer, CJ, Wilson, JG, Witte, DR, Wood, AR, Wu, Y, Yaghootkar, H, Yao, J, Yao, P, Yerges-Armstrong, LM, Young, R, Zeggini, E, Zhan, X, Zhang, W, Zhao, JH, Zhao, W, Zhou, W, Zondervan, KT, Rotter, JI, Pospisilik, JA, Rivadeneira, F, Borecki, IB, Deloukas, P, Frayling, TM, Lettre, G, North, KE, Lindgren, CM, Hirschhorn, JN & Loos, RJF 2018, 'Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity' Nature Genetics, vol. 50, no. 1, pp. 26-35. https://doi.org/10.1038/s41588-017-0011-x

Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. / Turcot, Valérie; Lu, Yingchang; Highland, Heather M.; Schurmann, Claudia; Justice, Anne E.; Fine, Rebecca S.; Bradfield, Jonathan P.; Esko, Tõnu; Giri, Ayush; Graff, Mariaelisa; Guo, Xiuqing; Hendricks, Audrey E.; Karaderi, Tugce; Lempradl, Adelheid; 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; Mudgal, Poorva; Ng, Maggie C.Y.; Reiner, Alex P.; Vedantam, Sailaja; Willems, Sara M.; Winkler, Thomas W.; Abecasis, Gonçalo; Aben, Katja K.; Alam, Dewan S.; Alharthi, Sameer E.; Allison, Matthew; Amouyel, Philippe; Asselbergs, Folkert W.; Auer, Paul L.; Balkau, Beverley; Bang, Lia E.; Barroso, Inês; Bastarache, Lisa; Benn, Marianne; Bergmann, Sven; Bielak, Lawrence F.; Blüher, Matthias; Boehnke, Michael; Boeing, Heiner; Boerwinkle, Eric; Böger, Carsten A.; Bork-Jensen, Jette; Bots, Michiel L.; 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.; Cappellani, Stefania; Carey, David J.; Catamo, Eulalia; Caulfield, Mark J.; Chambers, John C.; Chasman, Daniel I.; Chen, Yii Der I.; Chowdhury, Rajiv; Christensen, Cramer; Chu, Audrey Y.; Cocca, Massimiliano; Cook, James P.; Corley, Janie; Corominas Galbany, Jordi; Cox, Amanda J.; 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; Demerath, Ellen W.; Heijer, Martin; Hollander, Anneke I.; Ruijter, Hester M.; Dennis, Joe G.; Denny, Josh C.; Angelantonio, Emanuele; Drenos, Fotios; Du, Mengmeng; Dubé, Marie Pierre; Dunning, Alison M.; Easton, Douglas F.; Edwards, Todd L.; Ellinghaus, David; Ellinor, Patrick T.; Elliott, Paul; Evangelou, Evangelos; Farmaki, Aliki Eleni; Farooqi, I. Sadaf; Faul, Jessica D.; Fauser, Sascha; Feng, Shuang; Ferrannini, Ele; Ferrieres, Jean; Florez, Jose C.; Ford, Ian; Fornage, Myriam; Franco, Oscar H.; Franke, Andre; Franks, Paul W.; Friedrich, Nele; Frikke-Schmidt, Ruth; Galesloot, Tessel E.; Gan, Wei; Gandin, Ilaria; Gasparini, Paolo; Gibson, Jane; Giedraitis, Vilmantas; Gjesing, Anette P.; Gordon-Larsen, Penny; Gorski, Mathias; Grabe, Hans Jörgen; 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; Harris, Kathleen Mullan; Harris, Tamara B.; Hattersley, Andrew T.; 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.; Hovingh, G. Kees; Howson, Joanna M.M.; 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; Johansson, Stefan; Jørgensen, Marit E.; Jørgensen, Torben; 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; Kathiresan, Sekar; Kee, Frank; Kiemeney, Lambertus A.; Kim, Eric; Kitajima, Hidetoshi; Komulainen, Pirjo; Kooner, Jaspal S.; Kooperberg, Charles; Korhonen, Tellervo; Kovacs, Peter; Kuivaniemi, Helena; Kutalik, Zoltán; Kuulasmaa, Kari; Kuusisto, Johanna; Laakso, Markku; Lakka, Timo 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; Li-Gao, Ruifang; Lin, Honghuang; Lin, Keng Hung; Lin, Li An; Lin, Xu; Lind, Lars; Lindström, Jaana; Linneberg, Allan; Liu, Ching Ti; Liu, Dajiang; Liu, Yongmei; Lo, Ken S.; Lophatananon, Artitaya; Lotery, Andrew J.; Loukola, Anu; Luan, Jian'An; 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; Mistry, Vanisha; Mitchell, Paul; Mohlke, Karen L.; 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.; Nalls, Mike A.; Narisu, Narisu; Nelson, Christopher P.; 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.; Owen, Katharine R.; Packard, Chris J.; 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.; Perola, Markus; Perry, James A.; Perry, John R.B.; 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.; Rasheed, Asif; Rauramaa, Rainer; Reilly, Dermot F.; 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; Ruth, Katherine S.; Saleheen, Danish; Salomaa, Veikko; 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.; Sim, Xueling; Slater, Andrew J.; Small, Kerrin S.; 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.; Stumvoll, Michael; Sun, Liang; Surendran, Praveen; 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.; Tönjes, Anke; Tromp, Gerard; Trompet, Stella; 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; Van Setten, Jessica; Vanhala, Mauno; Varbo, Anette; 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; Wagenknecht, Lynne E.; Walker, Mark; 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; White, Harvey D.; Willer, Cristen J.; Wilson, James G.; Witte, Daniel R.; Wood, Andrew R.; Wu, Ying; Yaghootkar, Hanieh; Yao, Jie; Yao, Pang; Yerges-Armstrong, Laura M.; Young, Robin; Zeggini, Eleftheria; Zhan, Xiaowei; Zhang, Weihua; Zhao, Jing Hua; Zhao, Wei; 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.; Lindgren, Cecilia M.; Hirschhorn, Joel N.; Loos, Ruth J.F.

In: Nature Genetics, Vol. 50, No. 1, 01.01.2018, p. 26-35.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

AU - Turcot, Valérie

AU - Lu, Yingchang

AU - Highland, Heather M.

AU - Schurmann, Claudia

AU - Justice, Anne E.

AU - Fine, Rebecca S.

AU - Bradfield, Jonathan P.

AU - Esko, Tõnu

AU - Giri, Ayush

AU - Graff, Mariaelisa

AU - Guo, Xiuqing

AU - Hendricks, Audrey E.

AU - Karaderi, Tugce

AU - Lempradl, Adelheid

AU - Locke, Adam E.

AU - Mahajan, Anubha

AU - Marouli, Eirini

AU - Sivapalaratnam, Suthesh

AU - Young, Kristin L.

AU - Alfred, Tamuno

AU - Feitosa, Mary F.

AU - Masca, Nicholas G.D.

AU - Manning, Alisa K.

AU - Medina-Gomez, Carolina

AU - Mudgal, Poorva

AU - Ng, Maggie C.Y.

AU - Reiner, Alex P.

AU - Vedantam, Sailaja

AU - Willems, Sara M.

AU - Winkler, Thomas W.

AU - Abecasis, Gonçalo

AU - Aben, Katja K.

AU - Alam, Dewan S.

AU - Alharthi, Sameer E.

AU - Allison, Matthew

AU - Amouyel, Philippe

AU - Asselbergs, Folkert W.

AU - Auer, Paul L.

AU - Balkau, Beverley

AU - Bang, Lia E.

AU - Barroso, Inês

AU - Bastarache, Lisa

AU - Benn, Marianne

AU - Bergmann, Sven

AU - Bielak, Lawrence F.

AU - Blüher, Matthias

AU - Boehnke, Michael

AU - Boeing, Heiner

AU - Boerwinkle, Eric

AU - Böger, Carsten A.

AU - Bork-Jensen, Jette

AU - Bots, Michiel L.

AU - Bottinger, Erwin P.

AU - Bowden, Donald W.

AU - Brandslund, Ivan

AU - Breen, Gerome

AU - Brilliant, Murray H.

AU - Broer, Linda

AU - Brumat, Marco

AU - Burt, Amber A.

AU - Butterworth, Adam S.

AU - Campbell, Peter T.

AU - Cappellani, Stefania

AU - Carey, David J.

AU - Catamo, Eulalia

AU - Caulfield, Mark J.

AU - Chambers, John C.

AU - Chasman, Daniel I.

AU - Chen, Yii Der I.

AU - Chowdhury, Rajiv

AU - Christensen, Cramer

AU - Chu, Audrey Y.

AU - Cocca, Massimiliano

AU - Cook, James P.

AU - Corley, Janie

AU - Corominas Galbany, Jordi

AU - Cox, Amanda J.

AU - Crosslin, David S.

AU - Cuellar-Partida, Gabriel

AU - D'Eustacchio, Angela

AU - Danesh, John

AU - Davies, Gail

AU - Bakker, Paul I.W.

AU - Groot, Mark C.H.

AU - Mutsert, Renée

AU - Deary, Ian J.

AU - Dedoussis, George

AU - Demerath, Ellen W.

AU - Heijer, Martin

AU - Hollander, Anneke I.

AU - Ruijter, Hester M.

AU - Dennis, Joe G.

AU - Denny, Josh C.

AU - Angelantonio, Emanuele

AU - Drenos, Fotios

AU - Du, Mengmeng

AU - Dubé, Marie Pierre

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PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85039153797&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85039153797&partnerID=8YFLogxK

U2 - 10.1038/s41588-017-0011-x

DO - 10.1038/s41588-017-0011-x

M3 - Article

VL - 50

SP - 26

EP - 35

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 1

ER -