Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.
Valérie TurcotYingchang LuHeather M HighlandClaudia SchurmannAnne E JusticeRebecca S FineJonathan P BradfieldTõnu EskoAyush GiriMariaelisa GraffXiuqing GuoAudrey E HendricksTugce KaraderiAdelheid LempradlAdam E LockeAnubha MahajanEirini MarouliSuthesh SivapalaratnamKristin L YoungTamuno AlfredMary F FeitosaNicholas G D MascaAlisa K ManningCarolina Medina-GomezPoorva MudgalMaggie C Y NgAlex P ReinerSailaja VedantamSara M WillemsThomas W WinklerGonçalo AbecasisKatja K AbenDewan S AlamSameer E AlharthiMatthew AllisonPhilippe AmouyelFolkert W AsselbergsPaul L AuerBeverley BalkauLia E BangInês BarrosoLisa BastaracheMarianne BennSven BergmannLawrence F BielakMatthias BlüherMichael BoehnkeHeiner BoeingEric BoerwinkleCarsten A BögerJette Bork-JensenMichiel L BotsErwin P BottingerDonald W BowdenIvan BrandslundGerome BreenMurray H BrilliantLinda BroerMarco BrumatAmber A BurtAdam S ButterworthPeter T CampbellStefania CappellaniDavid J CareyEulalia CatamoMark J CaulfieldJohn C ChambersDaniel I 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TsafantakisJaakko TuomilehtoAnne Tybjaerg-HansenJonathan P TyrerRudolf UherAndré G UitterlindenMatti UusitupaSander W LaanCornelia M DuijnNienke LeeuwenJessica van SettenMauno VanhalaAnette VarboTibor V VargaRohit VarmaDigna R Velez EdwardsSita H VermeulenGiovanni VeronesiHenrik VestergaardVeronique VitartThomas F VogtUwe VölkerDragana VuckovicLynne E WagenknechtMark WalkerLars WallentinFeijie WangCarol A WangShuai WangYiqin WangErin B WareNicholas J WarehamHelen R WarrenDawn M WaterworthJennifer WesselHarvey D WhiteCristen J WillerJames G WilsonDaniel R WitteAndrew R WoodYing WuHanieh YaghootkarJie YaoPang YaoLaura M Yerges-ArmstrongRobin YoungEleftheria ZegginiXiaowei ZhanWeihua ZhangJing Hua ZhaoWei ZhaoWei ZhaoWei ZhouKrina T Zondervannull nullnull nullnull nullnull nullnull nullnull nullnull nullnull nullnull nullnull nullnull nullJerome I RotterJohn Andrew PospisilikFernando RivadeneiraIngrid B BoreckiPanagiotis DeloukasTimothy M FraylingGuillaume LettreKari E NorthCecilia M LindgrenJoel N HirschhornRuth J F LoosPublished in: Nature genetics (2017)
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.