Li, XihaoXihaoLiChen, HanHanChenSelvaraj, Margaret SunithaMargaret SunithaSelvarajVan Buren, EricEricVan BurenZhou, HufengHufengZhouWang, YuxuanYuxuanWangSun, RyanRyanSunMcCaw, Zachary RZachary RMcCawYu, ZhiZhiYuJiang, Min-ZhiMin-ZhiJiangDiCorpo, DanielDanielDiCorpoGaynor, Sheila MSheila MGaynorDey, RounakRounakDeyArnett, Donna KDonna KArnettBenjamin, Emelia JEmelia JBenjaminBis, Joshua CJoshua CBisBlangero, JohnJohnBlangeroBoerwinkle, EricEricBoerwinkleBowden, Donald WDonald WBowdenBrody, Jennifer AJennifer ABrodyCade, Brian EBrian ECadeCarson, April PApril PCarsonCarlson, Jenna CJenna CCarlsonChami, NathalieNathalieChamiChen, Yii-Der IdaYii-Der IdaChenCurran, Joanne EJoanne ECurrande Vries, Paul SPaul Sde VriesFornage, MyriamMyriamFornageFranceschini, NoraNoraFranceschiniFreedman, Barry IBarry IFreedmanGu, CharlesCharlesGuHeard-Costa, Nancy LNancy LHeard-CostaHe, JiangJiangHeHou, LifangLifangHouHung, Yi-JenYi-JenHungIrvin, Marguerite RMarguerite RIrvinKaplan, Robert CRobert CKaplanKardia, Sharon L RSharon L RKardiaKelly, Tanika NTanika NKellyKonigsberg, IainIainKonigsbergKooperberg, CharlesCharlesKooperbergKral, Brian GBrian GKralLi, ChangweiChangweiLiLi, YunYunLiLin, HonghuangHonghuangLinLiu, Ching-TiChing-TiLiuLoos, Ruth J FRuth J FLoosMahaney, Michael CMichael CMahaneyMartin, Lisa WLisa WMartinMathias, Rasika ARasika AMathiasMitchell, Braxton DBraxton DMitchellMontasser, May EMay EMontasserMorrison, Alanna CAlanna CMorrisonNaseri, TakeTakeNaseriNorth, Kari EKari ENorthPalmer, Nicholette DNicholette DPalmerPeyser, Patricia APatricia APeyserPsaty, Bruce MBruce MPsatyRedline, SusanSusanRedlineReiner, Alexander PAlexander PReinerRich, Stephen SStephen SRichSitlani, Colleen MColleen MSitlaniSmith, Jennifer AJennifer ASmithTaylor, Kent DKent DTaylorTiwari, Hemant KHemant KTiwariVasan, Ramachandran SRamachandran SVasanViali, Satupa'iteaSatupa'iteaVialiWang, ZheZheWangWessel, JenniferJenniferWesselYanek, Lisa RLisa RYanekYu, BingBingYuDupuis, JoséeJoséeDupuisMeigs, James BJames BMeigsAuer, Paul LPaul LAuerRaffield, Laura MLaura MRaffieldManning, Alisa KAlisa KManningRice, Kenneth MKenneth MRiceRotter, Jerome IJerome IRotterPeloso, Gina MGina MPelosoNatarajan, PradeepPradeepNatarajanLi, ZilinZilinLiLiu, ZhonghuaZhonghuaLiuLin, XihongXihongLinLEE-MING CHUANGYI-CHENG CHANGet al.2025-12-122025-12-122025-02https://scholars.lib.ntu.edu.tw/handle/123456789/734536Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally scalable analytical pipeline for functionally informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple traits, and further empowers rare variant association analysis by incorporating multiple functional annotations. We applied MultiSTAAR to jointly analyze three lipid traits in 61,838 multi-ethnic samples from the Trans-Omics for Precision Medicine (TOPMed) Program. We discovered and replicated new associations with lipid traits missed by single-trait analysis.en[SDGs]SDG2[SDGs]SDG3journal article10.1038/s43588-024-00764-839920506