Exome-wide association study of plasma lipids in >300,000 individuals.
Dajiang J LiuGina M PelosoHaojie YuAdam S ButterworthXiao WangAnubha MahajanDanish SaleheenConnor EmdinDewan AlamAlexessander Couto AlvesPhilippe AmouyelEmanuele Di AngelantonioDominique ArveilerThemistocles L AssimesPaul L AuerUsman BaberChristie M BallantyneLia E BangMarianne BennJoshua C BisMichael BoehnkeEric BoerwinkleJette Bork-JensenErwin P BottingerIvan BrandslundMorris BrownFabio BusoneroMark J CaulfieldJohn C ChambersDaniel I ChasmanY Eugene ChenYii-Der Ida ChenRajiv ChowdhuryCramer ChristensenAudrey Y ChuJohn M ConnellFrancesco CuccaL Adrienne CupplesScott M DamrauerGail DaviesIan J DearyGeorge DedoussisJoshua C DennyAnna DominiczakMarie-Pierre DubéTapani EbelingGudny EiriksdottirTõnu EskoAliki-Eleni FarmakiMary F FeitosaMarco FerrarioJean FerrieresIan FordMyriam FornagePaul W FranksTimothy M FraylingRuth Frikke-SchmidtLars G FritschePhilippe FrossardValentin FusterSanthi K GaneshWei GaoMelissa E GarciaChristian GiegerFranco GiulianiniMark O GoodarziHarald GrallertNiels GrarupLeif GroopMegan L GroveVilmundur GudnasonTorben HansenTamara B HarrisCaroline HaywardJoel N HirschhornOddgeir L HolmenJennifer HuffmanYong HuoKristian HveemSehrish JabeenAnne U JacksonJohanna JakobsdottirMarjo-Riitta JarvelinGorm B JensenMarit E JørgensenJ Wouter JukemaJohanne M JustesenPia R KamstrupStavroula KanoniFredrik KarpeFrank KeeAmit V KheraDerek KlarinHeikki A KoistinenJaspal S KoonerCharles KooperbergKari KuulasmaaJohanna KuusistoMarkku LaaksoTimo LakkaClaudia LangenbergAnne LangstedLenore J LaunerTorsten LauritzenDavid C M LiewaldLi An LinAllan LinnebergRuth J F LoosYingchang LuXiangfeng LuReedik MägiAnders MalarstigAni ManichaikulAlisa K ManningPekka MäntyselkäEirini MarouliNicholas G D MascaAndrea MaschioJames B MeigsOlle MelanderAndres MetspaluAndrew P MorrisAlanna C MorrisonAntonella MulasMartina Müller-NurasyidPatricia B MunroeMatt J NevilleJonas Bille NielsenSune F NielsenBørge G NordestgaardJose M OrdovasRoxana MehranChristoper J O'DonnellMarju Orho-MelanderCliona M MolonyPieter MuntendamSandosh PadmanabhanColin N A PalmerDorota PaskoAniruddh P PatelOluf PedersenMarkus PerolaAnnette PetersCharlotta PisingerGiorgio PistisOzren PolasekNeil PoulterBruce M PsatyDaniel J RaderAsif RasheedRainer RauramaaDermot F ReillyAlex P ReinerFrida RenströmStephen S RichPaul M RidkerJohn D RiouxNeil R RobertsonDan M RodenJerome I RotterIgor RudanVeikko SalomaaNilesh J SamaniSerena SannaNaveed SattarEllen M SchmidtRobert A ScottPeter SeverRaquel S SevillaChristian M ShafferXueling SimSuthesh SivapalaratnamKerrin S SmallAlbert V SmithBlair H SmithSangeetha SomayajulaLorraine SouthamTimothy D SpectorElizabeth K SpeliotesJohn M StarrKathleen E StirrupsNathan StitzielKonstantin StrauchHeather M StringhamPraveen SurendranHayato TadaAlan R TallHua TangJean-Claude TardifKent D TaylorStella TrompetPhilip S TsaoJaakko TuomilehtoAnne Tybjaerg-HansenNatalie R van ZuydamAnette VarboTibor V VargaJarmo VirtamoMelanie WaldenbergerNan WangNick J WarehamHelen R WarrenPeter E WeekeJoshua WeinstockJennifer WesselJames G WilsonPeter W F WilsonMing XuHanieh YaghootkarRobin YoungEleftheria ZegginiHe ZhangNeil S ZhengWeihua ZhangYan ZhangWei ZhouYanhua ZhouMagdalena Zoledziewskanull nullnull nullnull nullnull nullnull nullJoanna M M HowsonJohn DaneshMark I McCarthyChad A CowanGoncalo AbecasisPanos DeloukasKiran MusunuruCristen J WillerSekar KathiresanPublished in: Nature genetics (2017)
We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.
Keyphrases
- coronary artery disease
- type diabetes
- genome wide
- copy number
- adipose tissue
- cardiovascular disease
- age related macular degeneration
- cystic fibrosis
- endothelial cells
- heart failure
- percutaneous coronary intervention
- gene expression
- metabolic syndrome
- low density lipoprotein
- coronary artery bypass grafting
- big data
- climate change
- atrial fibrillation
- genome wide association study
- deep learning
- left ventricular
- sickle cell disease
- high fat diet induced