biostudies-literatureLiu HNICHD NIH HHSNCATS NIH HHSNIDDK NIH HHSNHLBI NIH HHSNHGRI NIH HHSNIAMS NIH HHSCSRD VAeadp4753https://www.ebi.ac.uk/biostudies/studies/S-EPMC12013656biostudies-literatureUnknown387(6734)Kidney dysfunction is a major cause of mortality, but its genetic architecture remains elusive. In this study, we conducted a multiancestry genome-wide association study in 2.2 million individuals and identified 1026 (97 previously unknown) independent loci. Ancestry-specific analysis indicated an attenuation of newly identified signals on common variants in European ancestry populations and the power of population diversity for further discoveries. We defined genotype effects on allele-specific gene expression and regulatory circuitries in more than 700 human kidneys and 237,000 cells. We found 1363 coding variants disrupting 782 genes, with 601 genes also targeted by regulatory variants and convergence in 161 genes. Integrating 32 types of genetic information, we present the "Kidney DiseScience (New York, N.Y.)Kidney multiome-based genetic scorecard reveals convergent coding and regulatory variants.PMC12013656K25 DK128563K12 HD043483R01 DK087635K24 HL157960I01 CX001897K26 DK138425U01 HG011176U01 HG011175U01 HG008685R01 HG011345R01 HL163972R01 DK132630R01 DK132299U01 HG011172R01 DK117445R01 HL151152R01 DK076077P30 DK019525P50 DK114786U01 HG006379U01 HG008680UL1 TR001878U01 HG011167U01 HG011166K12 AR084232R01 DK105821U01 HG011169U01 HG011181U01 HG008657UM1 DK126194P30 DK050306Siminovitch KTarng DCSiceron SGaynor SThornton TVerweij NDornbos PMarchini JOtto JConnolly JJO'Keeffe SKwok PYRolston DKiryluk KHaas MWatanabe KLeBlanc MGFerrando ABaldassari AWollack CAyer AHe JGHS-RGC DiscovEHR CollaborationRetterer KEdwards TLHsieh FJRitchie MDGilly AGhoussaini MStahl EHu HPenn Medicine BioBankNerz KPYang SFLin NDittrich NLandheer KSantos SHung AMHindy GYu SLimdi NAEom GVy HMTReynoso RMighty JSirugo GPenn Medicine BioBank¶Ross JJarvik GPLotta LAGanel LNishtala NJones MBLopez ANadkarni GNMaxwell EKGhosh AManoochehri KForsythe CRevez JYe BRasheed HBrumpton BMBai XDrivas TGDamask ARico-Varela JMarcketta AEconomides APanea RPaulding CQiu CRana NMansfield AJMandla RAveritt AMayerhofer EBradford YLivingstone MVerma AHernandez JStephanowski JSharma DKalyuskin ENafde MKrasheninina OAbecasis GZawistowski MSolari GLattari MLi DChen LKenny EEFranceschini NMeyer MChen CHChen ECampos AKosmicki JLi SPadilla MSDe TDunn JThomas LFZiyatdinov ADu HMalhotra SEdelstein EChen SASul JSMercader JMLiu HZollner SMa ZSreeram SZheng JGokhale SZou YHankins JMbatchou JZavala VHa EPandey AAlvarez SRegeneron Genetics Center‡Delaneau OGuan JWiller CMartinez SRMorse Kripke CGorovits AHart SMitnaul LRodriguez-Flores JRevez Ferreira MAChalla PWiley LKHallan SIMahajan VLuo YAranyi TTzoneva GCremona LMGuvenek AFlorez JCSkead KZhang JWolf SEAustin EZhang LGuerreiro RLee MYBaras ADamrauer SMChen HCZhang CZhang BZhang AAkbari PHaas MERiaz MWendt FGeraghty BWeaver JCastineira EPMule PGelfman SSchiavo RNakka PGuevara KVoight BFWu KHKessler MKottyan LCarey DJBuchanan AWu JYDudek SMSarwar MTang MMartin CLNaseer NKarlson EWDeubler ASalerno WBurch KBras JDerOhannessian SZhou JWilson MPZarate SBoutkov BBalasubramanian SKapoor MMower JPunuru KPAbedini AFenney ARegeneron Genetics CenterHan ARisman MLocke AHobbs BTran TWalunas TLKo YABovijn JAsvold BOSilver JGHS-RGC DiscovEHR Collaboration§Kumar VRajagopal VWang CCoppola GJorgenson ESultan BSun LHveem KPandit AGoyal MVedantam SShang NJudy RWang RLanche RHaubein NPoindexter ABackman JSun KSheng XPerez-Beals AMajarian TDHabegger LPradhan MGignoux CRAqeel MParikshak NWeng CGraham SDumoulin BKhiabanian HPortnoy JGillies CPagan MRader DJRasool AMoscati ASusztak KOverton JDJoseph TMitra GRivera-Picart JHawes AHerman JShuldiner AChoi SVadivieso FHellwege JNBanerjee NReid JGSchwartz RGurski LAlkelai APalmer WVerma SSBeechert CKhan AVasireddy SLWei WQGu ZBao SJoshi ASidore CJallow MWBrown JCole JBTao RPalmer MFuller ESosina OfalseKidney multiome-based genetic scorecard reveals convergent coding and regulatory variants.Kidney dysfunction is a major cause of mortality, but its genetic architecture remains elusive. In this study, we conducted a multiancestry genome-wide association study in 2.2 million individuals and identified 1026 (97 previously unknown) independent loci. Ancestry-specific analysis indicated an attenuation of newly identified signals on common variants in European ancestry populations and the power of population diversity for further discoveries. We defined genotype effects on allele-specific gene expression and regulatory circuitries in more than 700 human kidneys and 237,000 cells. We found 1363 coding variants disrupting 782 genes, with 601 genes also targeted by regulatory variants and convergence in 161 genes. Integrating 32 types of genetic information, we present the "Kidney Dise2025-01-01T00:00:00Z2025 Feb2026-04-12T15:17:09.018Z2026-04-07T13:18:00.848ZS-EPMC120136563991358210.1126/science.adp4753