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, 50 (1), 26-41

Protein-altering Variants Associated With Body Mass Index Implicate Pathways That Control Energy Intake and Expenditure in Obesity

Valérie Turcot  1 Yingchang Lu  2   3   4 Heather M Highland  5   6 Claudia Schurmann  3   4 Anne E Justice  5 Rebecca S Fine  7   8   9 Jonathan P Bradfield  10   11 Tõnu Esko  7   9   12 Ayush Giri  13 Mariaelisa Graff  5 Xiuqing Guo  14 Audrey E Hendricks  15   16 Tugce Karaderi  17   18 Adelheid Lempradl  19 Adam E Locke  20   21 Anubha Mahajan  17 Eirini Marouli  22 Suthesh Sivapalaratnam  23   24   25 Kristin L Young  5 Tamuno Alfred  3 Mary F Feitosa  26 Nicholas G D Masca  27   28 Alisa K Manning  7   24   29   30 Carolina Medina-Gomez  31   32 Poorva Mudgal  33 Maggie C Y Ng  33   34 Alex P Reiner  35   36 Sailaja Vedantam  7   8   9 Sara M Willems  37 Thomas W Winkler  38 Gonçalo Abecasis  20 Katja K Aben  39   40 Dewan S Alam  41 Sameer E Alharthi  22   42 Matthew Allison  43 Philippe Amouyel  44   45   46 Folkert W Asselbergs  47   48   49 Paul L Auer  50 Beverley Balkau  51 Lia E Bang  52 Inês Barroso  15   53   54 Lisa Bastarache  55 Marianne Benn  56   57 Sven Bergmann  58   59 Lawrence F Bielak  60 Matthias Blüher  61   62 Michael Boehnke  20 Heiner Boeing  63 Eric Boerwinkle  64   65 Carsten A Böger  66 Jette Bork-Jensen  67 Michiel L Bots  68 Erwin P Bottinger  3 Donald W Bowden  33   34   69 Ivan Brandslund  70   71 Gerome Breen  72   73 Murray H Brilliant  74 Linda Broer  32 Marco Brumat  75 Amber A Burt  76 Adam S Butterworth  77   78 Peter T Campbell  79 Stefania Cappellani  80 David J Carey  81 Eulalia Catamo  80 Mark J Caulfield  22   82 John C Chambers  83   84   85 Daniel I Chasman  7   86   87   88 Yii-Der I Chen  14 Rajiv Chowdhury  77 Cramer Christensen  89 Audrey Y Chu  90   91 Massimiliano Cocca  92 Francis S Collins  93 James P Cook  94 Janie Corley  95   96 Jordi Corominas Galbany  97   98 Amanda J Cox  33   34   99 David S Crosslin  100 Gabriel Cuellar-Partida  101   102 Angela D'Eustacchio  80 John Danesh  15   77   78   103 Gail Davies  94   95 Paul I W Bakker  68   104 Mark C H Groot  105   106 Renée Mutsert  107 Ian J Deary  94   95 George Dedoussis  108 Ellen W Demerath  109 Martin Heijer  110 Anneke I Hollander  98 Hester M Ruijter  111 Joe G Dennis  112 Josh C Denny  55 Emanuele Di Angelantonio  77   78 Fotios Drenos  113   114 Mengmeng Du  36   115 Marie-Pierre Dubé  1   116 Alison M Dunning  117 Douglas F Easton  112   117 Todd L Edwards  13 David Ellinghaus  118 Patrick T Ellinor  7   24   30 Paul Elliott  119 Evangelos Evangelou  84   120 Aliki-Eleni Farmaki  108   121 I Sadaf Farooqi  53   54 Jessica D Faul  122 Sascha Fauser  123 Shuang Feng  20 Ele Ferrannini  124   125 Jean Ferrieres  126 Jose C Florez  7   24   29   30 Ian Ford  127 Myriam Fornage  128 Oscar H Franco  31 Andre Franke  118 Paul W Franks  129   130   131 Nele Friedrich  132 Ruth Frikke-Schmidt  57   133 Tessel E Galesloot  40 Wei Gan  17 Ilaria Gandin  134 Paolo Gasparini  75   80 Jane Gibson  135 Vilmantas Giedraitis  136 Anette P Gjesing  67 Penny Gordon-Larsen  137   138 Mathias Gorski  38   66 Hans-Jörgen Grabe  139   140 Struan F A Grant  10   141   142 Niels Grarup  67 Helen L Griffiths  143 Megan L Grove  64 Vilmundur Gudnason  144   145 Stefan Gustafsson  146 Jeff Haessler  36 Hakon Hakonarson  10   141 Anke R Hammerschlag  147 Torben Hansen  67 Kathleen Mullan Harris  137   148 Tamara B Harris  149 Andrew T Hattersley  150 Christian T Have  67 Caroline Hayward  151 Liang He  152   153 Nancy L Heard-Costa  90   154 Andrew C Heath  155 Iris M Heid  38   156 Øyvind Helgeland  157   158 Jussi Hernesniemi  159   160   161 Alex W Hewitt  162   163   164 Oddgeir L Holmen  165 G Kees Hovingh  23 Joanna M M Howson  77 Yao Hu  166 Paul L Huang  24 Jennifer E Huffman  151 M Arfan Ikram  31   167   168 Erik Ingelsson  146   169 Anne U Jackson  20 Jan-Håkan Jansson  170   171 Gail P Jarvik  76   172 Gorm B Jensen  173 Yucheng Jia  14 Stefan Johansson  158   174 Marit E Jørgensen  175   176 Torben Jørgensen  57   177   178 J Wouter Jukema  179   180 Bratati Kahali  181   182   183   184 René S Kahn  185 Mika Kähönen  186   187 Pia R Kamstrup  56 Stavroula Kanoni  22 Jaakko Kaprio  153   188   189 Maria Karaleftheri  190 Sharon L R Kardia  60 Fredrik Karpe  191   192 Sekar Kathiresan  7   24   88 Frank Kee  193 Lambertus A Kiemeney  40 Eric Kim  14 Hidetoshi Kitajima  17 Pirjo Komulainen  194   195   196 Jaspal S Kooner  83   85   197   198 Charles Kooperberg  36 Tellervo Korhonen  153   189   199 Peter Kovacs  61 Helena Kuivaniemi  81   200   201 Zoltán Kutalik  59   202 Kari Kuulasmaa  189 Johanna Kuusisto  203 Markku Laakso  203 Timo A Lakka  194   195   196 David Lamparter  58   59 Ethan M Lange  204 Leslie A Lange  204 Claudia Langenberg  37 Eric B Larson  76   205   206 Nanette R Lee  207   208 Terho Lehtimäki  160   161 Cora E Lewis  209 Huaixing Li  166 Jin Li  169 Ruifang Li-Gao  107 Honghuang Lin  210 Keng-Hung Lin  211 Li-An Lin  128 Xu Lin  166 Lars Lind  212 Jaana Lindström  189 Allan Linneberg  178   213   214 Ching-Ti Liu  215 Dajiang J Liu  216 Yongmei Liu  217 Ken S Lo  1 Artitaya Lophatananon  218 Andrew J Lotery  143 Anu Loukola  153   188 Jian'an Luan  37 Steven A Lubitz  7   24   30 Leo-Pekka Lyytikäinen  160   161 Satu Männistö  189 Gaëlle Marenne  15 Angela L Mazul  5 Mark I McCarthy  17   191   192 Roberta McKean-Cowdin  219 Sarah E Medland  102 Karina Meidtner  220   221 Lili Milani  12 Vanisha Mistry  53   54 Paul Mitchell  222 Karen L Mohlke  204 Leena Moilanen  223 Marie Moitry  224   225 Grant W Montgomery  102   226 Dennis O Mook-Kanamori  107   227 Carmel Moore  78   228 Trevor A Mori  229 Andrew D Morris  230 Andrew P Morris  17   94 Martina Müller-Nurasyid  156   231   232 Patricia B Munroe  22   82 Mike A Nalls  233   234 Narisu Narisu  93 Christopher P Nelson  27   28 Matt Neville  191   192 Sune F Nielsen  56   57 Kjell Nikus  159 Pål R Njølstad  157   158 Børge G Nordestgaard  56   57 Dale R Nyholt  102   235 Jeffrey R O'Connel  236 Michelle L O'Donoghue  237 Loes M Olde Loohuis  238 Roel A Ophoff  185   238 Katharine R Owen  191   192 Chris J Packard  127 Sandosh Padmanabhan  127 Colin N A Palmer  239 Nicholette D Palmer  69 Gerard Pasterkamp  111   240 Aniruddh P Patel  7   24   88 Alison Pattie  96 Oluf Pedersen  67 Peggy L Peissig  74 Gina M Peloso  215 Craig E Pennell  241 Markus Perola  12   188   189   242 James A Perry  236 John R B Perry  37 Tune H Pers  67   243 Thomas N Person  74 Annette Peters  221   232   244 Eva R B Petersen  245 Patricia A Peyser  60 Ailith Pirie  117 Ozren Polasek  230   246 Tinca J Polderman  147 Hannu Puolijoki  247 Olli T Raitakari  248   249 Asif Rasheed  250 Rainer Rauramaa  194   195 Dermot F Reilly  91 Frida Renström  129   251 Myriam Rheinberger  66 Paul M Ridker  87   88   237 John D Rioux  1   116 Manuel A Rivas  7   252 David J Roberts  78   253   254 Neil R Robertson  17   191 Antonietta Robino  80 Olov Rolandsson  170   255 Igor Rudan  230 Katherine S Ruth  256 Danish Saleheen  250   257 Veikko Salomaa  189 Nilesh J Samani  27   28 Yadav Sapkota  102 Naveed Sattar  127 Robert E Schoen  258 Pamela J Schreiner  109 Matthias B Schulze  220   221 Robert A Scott  37 Marcelo P Segura-Lepe  84 Svati H Shah  259 Wayne H-H Sheu  260   261   262 Xueling Sim  20   263 Andrew J Slater  264   265 Kerrin S Small  266 Albert V Smith  144   145 Lorraine Southam  15   17 Timothy D Spector  266 Elizabeth K Speliotes  181   182   183 John M Starr  95   267 Kari Stefansson  144   268 Valgerdur Steinthorsdottir  268 Kathleen E Stirrups  22   25 Konstantin Strauch  156   269 Heather M Stringham  20 Michael Stumvoll  61   62 Liang Sun  152   153 Praveen Surendran  77 Amy J Swift  93 Hayato Tada  237   270 Katherine E Tansey  114   271 Jean-Claude Tardif  1 Kent D Taylor  14 Alexander Teumer  272 Deborah J Thompson  112 Gudmar Thorleifsson  268 Unnur Thorsteinsdottir  144   268 Betina H Thuesen  178 Anke Tönjes  273 Gerard Tromp  81   201 Stella Trompet  179   274 Emmanouil Tsafantakis  275 Jaakko Tuomilehto  189   276   277   278 Anne Tybjaerg-Hansen  57   133 Jonathan P Tyrer  117 Rudolf Uher  279 André G Uitterlinden  31   32 Matti Uusitupa  280 Sander W Laan  111 Cornelia M Duijn  31 Nienke Leeuwen  281   282 Jessica van Setten  47 Mauno Vanhala  283   284 Anette Varbo  56   57 Tibor V Varga  129 Rohit Varma  285 Digna R Velez Edwards  286 Sita H Vermeulen  40 Giovanni Veronesi  287 Henrik Vestergaard  67   176 Veronique Vitart  151 Thomas F Vogt  288 Uwe Völker  289   290 Dragana Vuckovic  75   80 Lynne E Wagenknecht  217 Mark Walker  291 Lars Wallentin  292 Feijie Wang  166 Carol A Wang  241 Shuai Wang  215 Yiqin Wang  166 Erin B Ware  60   122 Nicholas J Wareham  37 Helen R Warren  22   82 Dawn M Waterworth  293 Jennifer Wessel  294 Harvey D White  295 Cristen J Willer  181   182   296 James G Wilson  297 Daniel R Witte  298   299 Andrew R Wood  256 Ying Wu  204 Hanieh Yaghootkar  256 Jie Yao  14 Pang Yao  166 Laura M Yerges-Armstrong  236   300 Robin Young  77   127 Eleftheria Zeggini  15 Xiaowei Zhan  301 Weihua Zhang  83   84 Jing Hua Zhao  37 Wei Zhao  257 Wei Zhao  60 Wei Zhou  181   182 Krina T Zondervan  17   302 CHD Exome+ ConsortiumEPIC-CVD ConsortiumExomeBP ConsortiumGlobal Lipids Genetic ConsortiumGoT2D Genes ConsortiumEPIC InterAct ConsortiumINTERVAL StudyReproGen ConsortiumT2D-Genes ConsortiumMAGIC InvestigatorsUnderstanding Society Scientific GroupJerome I Rotter  14 John A Pospisilik  19 Fernando Rivadeneira  31   32 Ingrid B Borecki  26 Panos Deloukas  22   42 Timothy M Frayling  256 Guillaume Lettre  1   116 Kari E North  303 Cecilia M Lindgren  17   304 Joel N Hirschhorn  305   306   307   308 Ruth J F Loos  309   310   311
Affiliations

Protein-altering Variants Associated With Body Mass Index Implicate Pathways That Control Energy Intake and Expenditure in Obesity

Valérie Turcot et al. Nat Genet.

Erratum in

  • Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.
    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 YI, 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 J, 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 WH, 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; 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; Understanding Society Scientific Group. Turcot V, et al. Nat Genet. 2018 May;50(5):765-766. doi: 10.1038/s41588-018-0050-y. Nat Genet. 2018. PMID: 29549329
  • Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.
    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 YI, 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, Di 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 J, 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 WH, 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, 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; 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; Understanding Society Scientific Group. Turcot V, et al. Nat Genet. 2018 May;50(5):766-767. doi: 10.1038/s41588-018-0082-3. Nat Genet. 2018. PMID: 29549330
  • Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.
    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 YI, Chowdhury R, Christensen C, Chu AY, Cocca M, Collins FS, Cook JP, Corley J, Galbany JC, 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, Di 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 J, 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, Loohuis LMO, 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 WH, 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, Edwards DRV, 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, Zhao W, Zhou W, Zondervan KT; 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; Understanding Society Scientific Group, Rotter JI, Pospisilik JA, Rivadeneira F, Borecki IB, Deloukas P, Frayling TM, Lettre G, North KE, Lindgren CM, Hirschhorn JN, Loos RJF. Turcot V, et al. Nat Genet. 2019 Jul;51(7):1191-1192. doi: 10.1038/s41588-019-0447-2. Nat Genet. 2019. PMID: 31160809

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.

Figures

Figure 1
Figure 1. Effect sizes (y-axis) of the 14 BMI-associated R/LF coding variants by their minor allele frequency
Effect sizes are expressed in body weight (kg) per allele, assuming a SD of 4.5 kg and an average-sized person of 1.7m tall. Solid markers indicate that the minor allele is associated with higher BMI, and clear markers indicate that the minor allele is associated with lower BMI. Variants were identified in all-ancestry analyses (light blue diamonds), the European ancestry analyses (dark blue square) and women-only analyses (pink diamond). Effect sizes for previously identified GWAS loci are shown in navy blue diamonds. The dotted line represents 80% power, assuming α = 2×10−7 and N= 525,000 (discovery sample size).
Figure 2
Figure 2. Heatmap showing DEPICT gene set enrichment results for suggestive and significant rare and low-frequency coding SNVs
For any given square, the color indicates how strongly the corresponding gene (x-axis) is predicted to belong to the reconstituted gene set (y-axis), based on the gene’s Z-score for gene set inclusion in DEPICT’s reconstituted gene sets (red indicates a higher, blue a lower Z-score). To visually reduce redundancy and increase clarity, we chose one representative "meta-gene set" for each group of highly correlated gene sets based on affinity propagation clustering (Online Methods, Supplementary Note). Heatmap intensity and DEPICT P-values (Supplementary Table 17) correspond to the most significantly enriched gene set within the meta-gene set. Annotations for genes indicate (1) whether it has an OMIM annotation as underlying a monogenic obesity disorder (black/grey), (2) the MAF of the significant ExomeChip (EC) variant (blue), (3) whether the variant’s P-value reached array-wide significance (<2×10−7) or suggestive significance (<5×10−4) (purple), (4) whether the variant was novel, overlapping “relaxed” GWAS signals from Locke et al. (GWAS P<5×10−4), or overlapping “stringent” GWAS hits (GWAS P<5×10−8) (pink), and (5) whether the gene was included in the gene set enrichment analysis or excluded by filters (orange/brown) (Online Methods, Supplementary Note). Annotations for gene sets indicate if the meta-gene set was significant (green; FDR <0.01, <0.05, or not significant) in the DEPICT analysis of GWAS results. Here, two regions of particularly strong gene set membership are shown (see full heat map in Supplementary Figure 10a).

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