Skip to content

Journal Article

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

Authors

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

Publication date

Jan 2018

Summary

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.

Published in

Nature Genetics

Volume and page numbers

50 , 26 -41

DOI

https://dx.doi.org/10.1038/s41588-017-0011-x

ISSN

16

Subjects

Medicine, Science And Technology, Health, Biology, and Genetics

Notes

Not held in Hilary Doughty Research Library - bibliographic reference only

#524889


Research home

Research home

News

Latest findings, new research

Publications search

Search all research by subject and author

Podcasts

Researchers discuss their findings and what they mean for society

Projects

Background and context, methods and data, aims and outputs

Events

Conferences, seminars and workshops

Survey methodology

Specialist research, practice and study

Taking the long view

ISER's annual report

Themes

Key research themes and areas of interest