Publication

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

Journal Paper/Review - Dec 22, 2017

Units
PubMed
Doi

Citation
Packard C, Pers T, Person T, Peters A, Petersen E, Peyser P, Pirie A, Polasek O, Polderman T, Puolijoki H, Raitakari O, Perry J, Perry J, Perola M, Padmanabhan S, Palmer C, Palmer N, Pasterkamp G, Patel A, Pattie A, Pedersen O, Peissig P, Peloso G, Pennell C, Rasheed A, Rauramaa R, Reilly D, Samani N, Sapkota Y, Sattar N, Schoen R, Schreiner P, Schulze M, Scott R, Segura-Lepe M, Shah S, Sheu W, Salomaa V, Saleheen D, Ruth K, Renström F, Rheinberger M, Ridker P, Rioux J, Rivas M, Roberts D, Robertson N, Robino A, Rolandsson O, Rudan I, Sim X, Lin K, Lubitz S, Lyytikäinen L, Männistö S, Marenne G, Mazul A, McCarthy M, McKean-Cowdin R, Medland S, Meidtner K, Milani L, Luan J, Loukola A, Lotery A, Lin L, Lin X, Lind L, Lindström J, Linneberg A, Liu C, Liu D, Liu Y, Lo K, Lophatananon A, Mistry V, Mitchell P, Mohlke K, Neville M, Nielsen S, Nikus K, Njølstad P, Nordestgaard B, Nyholt D, O'Connel J, O'Donoghue M, Olde Loohuis L, Ophoff R, Nelson C, Narisu N, Nalls M, Moilanen L, Moitry M, Montgomery G, Mook-Kanamori D, Moore C, Mori T, Morris A, Morris A, Müller-Nurasyid M, Munroe P, Owen K, Slater A, Walker M, Witte D, Wood A, Wu Y, Yaghootkar H, Yao J, Yao P, Yerges-Armstrong L, Young R, Zeggini E, Zhan X, Wilson J, Willer C, White H, Wallentin L, Wang F, Wang C, Wang S, Wang Y, Ware E, Wareham N, Warren H, Waterworth D, Wessel J, Zhang W, Zhao J, Zhao W, CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, EPIC InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Loos R, Hirschhorn J, Lindgren C, Zhou W, Zondervan K, Rotter J, Pospisilik J, Rivadeneira F, Borecki I, Deloukas P, Frayling T, Lettre G, North K, Understanding Society Scientific Group, Small K, Swift A, Tada H, Tansey K, Tardif J, Taylor K, Teumer A, Thompson D, Thorleifsson G, Thorsteinsdottir U, Thuesen B, Surendran P, Sun L, Stumvoll M, Smith A, Southam L, Spector T, Speliotes E, Starr J, Stefansson K, Steinthorsdottir V, Stirrups K, Strauch K, Stringham H, Tönjes A, Tromp G, Trompet S, Varga T, Varma R, Velez Edwards D, Vermeulen S, Veronesi G, Vestergaard H, Vitart V, Vogt T, Völker U, Vuckovic D, Varbo A, Vanhala M, van Setten J, Tsafantakis E, Tuomilehto J, Tybjaerg-Hansen A, Tyrer J, Uher R, Uitterlinden A, Uusitupa M, Laan S, Duijn C, Leeuwen N, Wagenknecht L, Lin H, Bots M, Caulfield M, Chambers J, Chasman D, Chen Y, Chowdhury R, Christensen C, Chu A, Cocca M, Collins F, Cook J, Catamo E, Carey D, Cappellani S, Bottinger E, Bowden D, Brandslund I, Breen G, Brilliant M, Broer L, Brumat M, Burt A, Butterworth A, Campbell P, Corley J, Corominas Galbany J, Cox A, Ruijter H, Dennis J, Denny J, Di Angelantonio E, Drenos F, Du M, Dubé M, Dunning A, Easton D, Edwards T, Hollander A, Heijer M, Demerath E, Crosslin D, Cuellar-Partida G, D'Eustacchio A, Danesh J, Davies G, Bakker P, Groot M, Mutsert R, Deary I, Dedoussis G, Ellinghaus D, Turcot V, Locke A, Mahajan A, Marouli E, Sivapalaratnam S, Young K, Alfred T, Feitosa M, Masca N, Manning A, Medina-Gomez C, Lempradl A, Karaderi T, Hendricks A, Lu Y, Highland H, Schurmann C, Justice A, Fine R, Bradfield J, Esko T, Giri A, Graff M, Guo X, Mudgal P, Ng M, Reiner A, Barroso I, Bastarache L, Benn M, Bergmann S, Bielak L, Blüher M, Boehnke M, Boeing H, Boerwinkle E, Böger C, Bang L, Balkau B, Auer P, Vedantam S, Willems S, Winkler T, Abecasis G, Aben K, Alam D, Alharthi S, Allison M, Amouyel P, Asselbergs F, Bork-Jensen J, Ellinor P, Howson J, Jukema J, Kahali B, Kahn R, Kähönen M, Kamstrup P, Kanoni S, Kaprio J, Karaleftheri M, Kardia S, Karpe F, Jørgensen T, Jørgensen M, Johansson S, Hu Y, Huang P, Huffman J, Ikram M, Ingelsson E, Jackson A, Jansson J, Jarvik G, Jensen G, Jia Y, Kathiresan S, Kee F, Kiemeney L, Lamparter D, Lange E, Lange L, Langenberg C, Larson E, Lee N, Lehtimäki T, Lewis C, Li H, Li J, Lakka T, Laakso M, Kuusisto J, Kim E, Kitajima H, Komulainen P, Kooner J, Kooperberg C, Korhonen T, Kovacs P, Kuivaniemi H, Kutalik Z, Kuulasmaa K, Li-Gao R, Elliott P, Franks P, Friedrich N, Frikke-Schmidt R, Galesloot T, Gan W, Gandin I, Gasparini P, Gibson J, Giedraitis V, Gjesing A, Franke A, Franco O, Fornage M, Evangelou E, Farmaki A, Farooqi I, Faul J, Fauser S, Feng S, Ferrannini E, Ferrieres J, Florez J, Ford I, Gordon-Larsen P, Gorski M, Grabe H, Have C, Hayward C, He L, Heard-Costa N, Heath A, Heid I, Helgeland Ø, Hernesniemi J, Hewitt A, Holmen O, Hattersley A, Harris T, Harris K, Grant S, Grarup N, Griffiths H, Grove M, Gudnason V, Gustafsson S, Haessler J, Hakonarson H, Hammerschlag A, Hansen T, Hovingh G. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. Nat Genet 2017; 50:26-41.
Type
Journal Paper/Review (English)
Journal
Nat Genet 2017; 50
Publication Date
Dec 22, 2017
Issn Electronic
1546-1718
Pages
26-41
Brief description/objective

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.