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 & 230 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, 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, Sune F. Nielsen, Craig E. Pennell, David J. Roberts, Carol A. Wang, James G. Wilson, Wei Zhou

Research output: Contribution to journalArticle

71 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
Pages (from-to)26-35
Number of pages10
JournalNature Genetics
Volume50
Issue number1
DOIs
Publication statusPublished - 1 Jan 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

Cite this

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 ; Collins, Francis S. ; 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 J. ; 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. ; Nielsen, Sune F. ; Pennell, Craig E. ; Roberts, David J. ; Wang, Carol A. ; Wilson, James G. ; Zhou, Wei. / 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.
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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 Collins, {Francis S.} 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 Liu, {Dajiang J.} 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 Nielsen, {Sune F.} and Pennell, {Craig E.} and Roberts, {David J.} and Wang, {Carol A.} and Wilson, {James G.} and Wei Zhou",
year = "2018",
month = "1",
day = "1",
doi = "10.1038/s41588-017-0011-x",
language = "English",
volume = "50",
pages = "26--35",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group - Macmillan Publishers",
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}

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, Collins, FS, 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, DJ, 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, Nielsen, SF, Pennell, CE, Roberts, DJ, Wang, CA, Wilson, JG & Zhou, W 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; Collins, Francis S.; 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 J.; 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.; Nielsen, Sune F.; Pennell, Craig E.; Roberts, David J.; Wang, Carol A.; Wilson, James G.; Zhou, Wei.

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 - Collins, Francis S.

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

AU - Dunning, Alison M.

AU - Easton, Douglas F.

AU - Edwards, Todd L.

AU - Ellinghaus, David

AU - Ellinor, Patrick T.

AU - Elliott, Paul

AU - Evangelou, Evangelos

AU - Farmaki, Aliki Eleni

AU - Farooqi, I. Sadaf

AU - Faul, Jessica D.

AU - Fauser, Sascha

AU - Feng, Shuang

AU - Ferrannini, Ele

AU - Ferrieres, Jean

AU - Florez, Jose C.

AU - Ford, Ian

AU - Fornage, Myriam

AU - Franco, Oscar H.

AU - Franke, Andre

AU - Franks, Paul W.

AU - Friedrich, Nele

AU - Frikke-Schmidt, Ruth

AU - Galesloot, Tessel E.

AU - Gan, Wei

AU - Gandin, Ilaria

AU - Gasparini, Paolo

AU - Gibson, Jane

AU - Giedraitis, Vilmantas

AU - Gjesing, Anette P.

AU - Gordon-Larsen, Penny

AU - Gorski, Mathias

AU - Grabe, Hans Jörgen

AU - Grant, Struan F.A.

AU - Grarup, Niels

AU - Griffiths, Helen L.

AU - Grove, Megan L.

AU - Gudnason, Vilmundur

AU - Gustafsson, Stefan

AU - Haessler, Jeff

AU - Hakonarson, Hakon

AU - Hammerschlag, Anke R.

AU - Hansen, Torben

AU - Harris, Kathleen Mullan

AU - Harris, Tamara B.

AU - Hattersley, Andrew T.

AU - Have, Christian T.

AU - Hayward, Caroline

AU - He, Liang

AU - Heard-Costa, Nancy L.

AU - Heath, Andrew C.

AU - Heid, Iris M.

AU - Helgeland, Øyvind

AU - Hernesniemi, Jussi

AU - Hewitt, Alex W.

AU - Holmen, Oddgeir L.

AU - Hovingh, G. Kees

AU - Howson, Joanna M.M.

AU - Hu, Yao

AU - Huang, Paul L.

AU - Huffman, Jennifer E.

AU - Ikram, M. Arfan

AU - Ingelsson, Erik

AU - Jackson, Anne U.

AU - Jansson, Jan Håkan

AU - Jarvik, Gail P.

AU - Jensen, Gorm B.

AU - Jia, Yucheng

AU - Johansson, Stefan

AU - Jørgensen, Marit E.

AU - Jørgensen, Torben

AU - Jukema, J. Wouter

AU - Kahali, Bratati

AU - Kahn, René S.

AU - Kähönen, Mika

AU - Kamstrup, Pia R.

AU - Kanoni, Stavroula

AU - Kaprio, Jaakko

AU - Karaleftheri, Maria

AU - Kardia, Sharon L.R.

AU - Karpe, Fredrik

AU - Kathiresan, Sekar

AU - Kee, Frank

AU - Kiemeney, Lambertus A.

AU - Kim, Eric

AU - Kitajima, Hidetoshi

AU - Komulainen, Pirjo

AU - Kooner, Jaspal S.

AU - Kooperberg, Charles

AU - Korhonen, Tellervo

AU - Kovacs, Peter

AU - Kuivaniemi, Helena

AU - Kutalik, Zoltán

AU - Kuulasmaa, Kari

AU - Kuusisto, Johanna

AU - Laakso, Markku

AU - Lakka, Timo A.

AU - Lamparter, David

AU - Lange, Ethan M.

AU - Lange, Leslie A.

AU - Langenberg, Claudia

AU - Larson, Eric B.

AU - Lee, Nanette R.

AU - Lehtimäki, Terho

AU - Lewis, Cora E.

AU - Li, Huaixing

AU - Li, Jin

AU - Li-Gao, Ruifang

AU - Lin, Honghuang

AU - Lin, Keng Hung

AU - Lin, Li An

AU - Lin, Xu

AU - Lind, Lars

AU - Lindström, Jaana

AU - Linneberg, Allan

AU - Liu, Ching Ti

AU - Liu, Dajiang J.

AU - Liu, Yongmei

AU - Lo, Ken S.

AU - Lophatananon, Artitaya

AU - Lotery, Andrew J.

AU - Loukola, Anu

AU - Luan, Jian'An

AU - Lubitz, Steven A.

AU - Lyytikäinen, Leo Pekka

AU - Männistö, Satu

AU - Marenne, Gaëlle

AU - Mazul, Angela L.

AU - McCarthy, Mark I.

AU - McKean-Cowdin, Roberta

AU - Medland, Sarah E.

AU - Meidtner, Karina

AU - Milani, Lili

AU - Mistry, Vanisha

AU - Mitchell, Paul

AU - Mohlke, Karen L.

AU - Moilanen, Leena

AU - Moitry, Marie

AU - Montgomery, Grant W.

AU - Mook-Kanamori, Dennis O.

AU - Moore, Carmel

AU - Mori, Trevor A.

AU - Morris, Andrew D.

AU - Morris, Andrew P.

AU - Müller-Nurasyid, Martina

AU - Munroe, Patricia B.

AU - Nalls, Mike A.

AU - Nielsen, Sune F.

AU - Pennell, Craig E.

AU - Roberts, David J.

AU - Wang, Carol A.

AU - Wilson, James G.

AU - Zhou, Wei

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

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 -