Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.
Anne E JusticeTugce KaraderiHeather M HighlandKristin L YoungMariaelisa GraffYingchang LuValérie TurcotPaul L AuerRebecca S FineXiuqing GuoClaudia SchurmannAdelheid LempradlEirini MarouliAnubha MahajanThomas W WinklerAdam E LockeCarolina Medina-GomezTõnu EskoSailaja VedantamAyush GiriKen Sin LoTamuno AlfredPoorva MudgalMaggie C Y NgNancy Heard- CostaMary F FeitosaAlisa K ManningSara M WillemsSuthesh SivapalaratnamGoncalo AbecasisDewan S AlamMatthew AllisonPhillippe AmouyelZorayr ArzumanyanBeverley BalkauLisa BastaracheSven BergmannLawrence F BielakMatthias BlüherMichael BoehnkeHeiner BoeingEric BoerwinkleCarsten A BögerJette Bork-JensenErwin P BottingerDonald W BowdenIvan BrandslundLinda BroerAmber A BurtAdam S ButterworthMark J CaulfieldGiancarlo CesanaJohn C ChambersDaniel I ChasmanYii-Der Ida ChenRajiv ChowdhuryCramer ChristensenAudrey Y ChuFrancis S CollinsJames P CookAmanda J CoxDavid S CrosslinJohn DaneshPaul I W de BakkerSimon de DenusRenée de MutsertGeorge DedoussisEllen W DemerathJoe G DennisJosh C DennyEmanuele Di AngelantonioMarcus DörrFotios DrenosMarie-Pierre DubéAlison M DunningDouglas F EastonPaul ElliottEvangelos EvangelouAliki-Eleni FarmakiShuang FengEle FerranniniJean FerrieresJose C FlorezMyriam FornageCaroline S FoxPaul W FranksNele FriedrichWei GanIlaria GandinPaolo GaspariniVilmantas GiedraitisGiorgia GirottoMathias GorskiHarald GrallertNiels GrarupMegan L GroveStefan GustafssonJeff HaesslerTorben HansenAndrew T HattersleyCaroline HaywardIris M HeidOddgeir L HolmenG Kees HovinghJoanna M M HowsonYao HuYi-Jen HungKristian HveemMohammad Arfan IkramErik IngelssonAnne U JacksonGail P JarvikYucheng JiaTorben JørgensenPekka JousilahtiJohanne Marie JustesenBratati KahaliMaria KaraleftheriSharon L R KardiaFredrik KarpeFrank KeeHidetoshi KitajimaPirjo KomulainenJaspal S KoonerPeter KovacsBernhard K KrämerKari KuulasmaaJohanna KuusistoMarkku LaaksoTimo A LakkaDavid LamparterLeslie A LangeClaudia LangenbergEric B LarsonNanette R LeeWen-Jane LeeTerho LehtimäkiCora E LewisHuaixing LiJin LiRuifang Li-GaoLi-An LinXu LinLars LindJaana LindströmAllan LinnebergChing-Ti LiuDajiang J LiuJian'an LuanLeo-Pekka LyytikainenStuart MacgregorReedik MägiSatu MännistöGaëlle MarenneJonathan MartenNicholas G D MascaMark I McCarthyKarina MeidtnerEvelin MihailovLeena MoilanenMarie MoitryDennis O Mook-KanamoriAnna MorganAndrew P MorrisMartina Müller-NuraysidPatricia B MunroeNarisu NarisuChristopher P NelsonMatthew J NevilleIoanna NtallaJeffrey R O'ConnellKatharine R OwenOluf PedersenGina M PelosoCraig E PennellMarkus PerolaJames A PerryJohn R B PerryTune H PersAilith EwingOzren PolasekOlli T RaitakariAsif RasheedChelsea K RaulersonRainer RauramaaDermot F ReillyAlex P ReinerPaul M RidkerManuel A RivasNeil R RobertsonAntonietta RobinoIgor RudanKatherine S RuthDanish SaleheenVeikko V SalomaaNilesh J SamaniPamela J SchreinerMatthias B SchulzeRobert A ScottMarcelo Segura-LepeXueling S SimAndrew J SlaterKerrin S SmallBlair H SmithJennifer A SmithLorraine SouthamTimothy D SpectorElizabeth K SpeliotesKári StefánssonValgerdur SteinthorsdottirKathleen E StirrupsKonstantin StrauchHeather M StringhamMichael StumvollLiang SunPraveen SurendranKarin M A SwartJean-Claude TardifKent D TaylorAlexander TeumerDeborah J ThompsonGudmar ThorleifssonUnnur ThorsteinsdottirBetina H ThuesenAnke TönjesMina TorresEmmanouil TsafantakisJaakko TuomilehtoAndré G UitterlindenMatti UusitupaCornelia M van DuijnMauno VanhalaRohit VarmaSita H VermeulenHenrik VestergaardVeronique VitartThomas F VogtDragana VuckovicLynne E WagenknechtMark WalkerLars WallentinFeijie WangCarol A WangShuai WangNicholas J WarehamHelen R WarrenDawn M WaterworthJennifer WesselHarvey D WhiteCristen J WillerJames G WilsonAndrew R WoodYing WuHanieh YaghootkarJie YaoLaura M Yerges-ArmstrongRobin YoungEleftheria ZegginiXiaowei ZhanWeihua ZhangJing Hua ZhaoWei ZhaoHe ZhengWei ZhouM Carola ZillikensFernando RivadeneiraIngrid B BoreckiJohn Andrew PospisilikPanagiotis DeloukasTimothy M FraylingGuillaume LettreKaren L MohlkeJerome I RotterZoltán KutalikJoel N HirschhornL Adrienne CupplesRuth J F LoosKari E NorthCecilia M Lindgrennull nullnull nullnull nullnull nullnull nullnull nullnull nullnull nullnull nullnull nullPublished in: Nature genetics (2019)
Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
Keyphrases
- copy number
- genome wide
- adipose tissue
- body mass index
- dna methylation
- genome wide identification
- fatty acid
- insulin resistance
- metabolic syndrome
- small molecule
- emergency department
- physical activity
- amino acid
- weight gain
- skeletal muscle
- bone mineral density
- bioinformatics analysis
- postmenopausal women
- weight loss
- body weight