Rocheleau, GhislainGhislainRocheleauClarke, Shoa LShoa LClarkeAuguste, GaëlleGaëlleAugusteHasbani, Natalie RNatalie RHasbaniMorrison, Alanna CAlanna CMorrisonHeath, Adam SAdam SHeathBielak, Lawrence FLawrence FBielakIyer, Kruthika RKruthika RIyerYoung, Erica PErica PYoungStitziel, Nathan ONathan OStitzielJun, GooGooJunLaurie, CeceliaCeceliaLaurieBroome, Jai GJai GBroomeKhan, Alyna TAlyna TKhanArnett, Donna KDonna KArnettBecker, Lewis CLewis CBeckerBis, Joshua CJoshua CBisBoerwinkle, EricEricBoerwinkleBowden, Donald WDonald WBowdenCarson, April PApril PCarsonEllinor, Patrick TPatrick TEllinorFornage, MyriamMyriamFornageFranceschini, NoraNoraFranceschiniFreedman, Barry IBarry IFreedmanHeard-Costa, Nancy LNancy LHeard-CostaHou, LifangLifangHouChen, Yii-Der IdaYii-Der IdaChenKenny, Eimear EEimear EKennyKooperberg, CharlesCharlesKooperbergKral, Brian GBrian GKralLoos, Ruth J FRuth J FLoosLutz, Sharon MSharon MLutzManson, JoAnn EJoAnn EMansonMartin, Lisa WLisa WMartinMitchell, Braxton DBraxton DMitchellNassir, RamiRamiNassirPalmer, Nicholette DNicholette DPalmerPost, Wendy SWendy SPostPreuss, Michael HMichael HPreussPsaty, Bruce MBruce MPsatyRaffield, Laura MLaura MRaffieldRegan, Elizabeth AElizabeth AReganRich, Stephen SStephen SRichSmith, Jennifer AJennifer ASmithTaylor, Kent DKent DTaylorYanek, Lisa RLisa RYanekYoung, Kendra AKendra AYoungHilliard, Austin TAustin THilliardTcheandjieu, CatherineCatherineTcheandjieuPeyser, Patricia APatricia APeyserVasan, Ramachandran SRamachandran SVasanRotter, Jerome IJerome IRotterMiller, Clint LClint LMillerAssimes, Themistocles LThemistocles LAssimesde Vries, Paul SPaul Sde VriesDo, RonRonDoYI-CHENG CHANGet. al2026-01-062026-01-062024-10-09https://scholars.lib.ntu.edu.tw/handle/123456789/735068Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.entrue[SDGs]SDG3journal article10.1038/s41467-024-52939-6393847612-s2.0-85194218687