Large-scale genome-wide association study of coronary artery disease in genetically diverse populations.
Catherine TcheandjieuXiang ZhuAustin T HilliardShoa L ClarkeValerio NapolioniShining MaKyung Min LeeHuaying FangFei ChenYingchang LuNoah L TsaoSridharan RaghavanSatoshi KoyamaBryan R GormanMarijana VujkovicDerek M KlarinMichael G LevinNicholas A Sinnott-ArmstrongGenevieve L WojcikMary E PlomondonThomas M MaddoxStephen W WaldoAlexander G BickSaiju PyarajanJie HuangRebecca SongYuk-Lam Anne HoSteven BuyskeCharles KooperbergJeffrey HaesslerRuth J F LoosRon DoMarie VerbanckKumardeep ChaudharyKari E NorthChristy L AveryMariaelisa GraffChristopher A HaimanLoïc Le MarchandLynne R WilkensJoshua C BisHampton LeonardBotong ShenLeslie A LangeAyush GiriOzan DikilitasIftikhar J KulloIan B StanawayGail P JarvikAdam S GordonScott HebbringBahram NamjouKenneth M KaufmanKaoru ItoKazuyoshi IshigakiYoichiro KamataniShefali S VermaMarylyn DeRiggi RitchieRachel L KemberAris BarasLuca A Lottanull nullnull nullnull nullnull nullSekar KathiresanElizabeth R HauserDonald R MillerJennifer S LeeDanish SaleheenPeter D ReavenKelly ChoJ Michael GazianoPradeep NatarajanJennifer E HuffmanBenjamin F VoightDaniel James RaderKyong-Mi ChangJulie A LynchScott M DamrauerPeter W F WilsonHua TangYan V SunPhilip S TsaoChristopher J O'DonnellThemistocles L AssimesPublished in: Nature medicine (2022)
We report a genome-wide association study (GWAS) of coronary artery disease (CAD) incorporating nearly a quarter of a million cases, in which existing studies are integrated with data from cohorts of white, Black and Hispanic individuals from the Million Veteran Program. We document near equivalent heritability of CAD across multiple ancestral groups, identify 95 novel loci, including nine on the X chromosome, detect eight loci of genome-wide significance in Black and Hispanic individuals, and demonstrate that two common haplotypes at the 9p21 locus are responsible for risk stratification in all populations except those of African origin, in which these haplotypes are virtually absent. Moreover, in the largest GWAS for angiographically derived coronary atherosclerosis performed to date, we find 15 loci of genome-wide significance that robustly overlap with established loci for clinical CAD. Phenome-wide association analyses of novel loci and polygenic risk scores (PRSs) augment signals related to insulin resistance, extend pleiotropic associations of these loci to include smoking and family history, and precisely document the markedly reduced transferability of existing PRSs to Black individuals. Downstream integrative analyses reinforce the critical roles of vascular endothelial, fibroblast, and smooth muscle cells in CAD susceptibility, but also point to a shared biology between atherosclerosis and oncogenesis. This study highlights the value of diverse populations in further characterizing the genetic architecture of CAD.
Keyphrases
- genome wide association study
- coronary artery disease
- genome wide
- percutaneous coronary intervention
- cardiovascular events
- coronary artery bypass grafting
- dna methylation
- insulin resistance
- cardiovascular disease
- gene expression
- metabolic syndrome
- high fat diet
- skeletal muscle
- heart failure
- aortic stenosis
- type diabetes
- coronary artery
- electronic health record
- atrial fibrillation
- polycystic ovary syndrome
- acute coronary syndrome
- machine learning
- left ventricular
- big data
- aortic valve
- glycemic control