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Stroke genetics informs drug discovery and risk prediction across ancestries

dc.rights.licenseopenen_US
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorMISHRA, Aniket
dc.contributor.authorMALIK, Rainer
dc.contributor.authorHACHIYA, Tsuyoshi
dc.contributor.authorJURGENSON, Tuuli
dc.contributor.authorNAMBA, Shinichi
dc.contributor.authorPOSNER, Daniel C.
dc.contributor.authorKAMANU, Frederick K.
dc.contributor.authorKOIDO, Masaru
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorLE GRAND, Quentin
dc.contributor.authorSHI, Mingyang
dc.contributor.authorHE, Yunye
dc.contributor.authorGEORGAKIS, Marios K.
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorCARO, Ilana
dc.contributor.authorKREBS, Kristi
dc.contributor.authorLIAW, Yi-Ching
dc.contributor.authorVAURA, Felix C.
dc.contributor.authorLIN, Kuang
dc.contributor.authorWINSVOLD, Bendik Slagsvold
dc.contributor.authorSRINIVASASAINAGENDRA, Vinodh
dc.contributor.authorPARODI, Livia
dc.contributor.authorBAE, Hee-Joon
dc.contributor.authorCHAUHAN, Ganesh
dc.contributor.authorCHONG, Michael R
dc.contributor.authorTOMPPO, Liisa
dc.contributor.authorROSHCHUPKIN, Gennady V.
dc.contributor.authorHABIB, Naomi
dc.contributor.authorJEE, Yon Ho
dc.contributor.authorTHOMASSEN, Jesper Qvist
dc.contributor.authorABEDI, Vida
dc.contributor.authorCARCEL-MARQUEZ, Jara
dc.contributor.authorNYGAARD, Marianne
dc.contributor.authorLEONARD, Hampton L.
dc.contributor.authorYANG, Chaojie
dc.contributor.authorYONOVA-DOING, Ekaterina
dc.contributor.authorKNOL, Maria J.
dc.contributor.authorLEWIS, Adam J..
dc.contributor.authorJUDY, Renae L
dc.contributor.authorAGO, Tetsuro
dc.contributor.authorAMOUYEL, Philippe
dc.contributor.authorARMSTRONG, Nicole D.
dc.contributor.authorBAKKER, Mark R.
dc.contributor.authorBARTZ, Traci M.
dc.contributor.authorBENNETT, David A.
dc.contributor.authorBIS, Joshua C.
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorBORDES, Constance
dc.contributor.authorBORTE, Sigrid
dc.contributor.authorCAIN, Anael
dc.contributor.authorRIDKER, Paul M.
dc.contributor.authorCHO, Kelly
dc.contributor.authorCHEN, Zhengming
dc.contributor.authorCRUCHAGA, Carlos
dc.contributor.authorCOLE, John W.
dc.contributor.authorDE JAGER, Phil L.
dc.contributor.authorDE CID, Rafael
dc.contributor.authorENDRES, Matthias
dc.contributor.authorFERREIRA, Leslie E.
dc.contributor.authorGEERLINGS, Mirjam I.
dc.contributor.authorGASCA, Natalie C.
dc.contributor.authorGUDNASON, Vilmundur
dc.contributor.authorHATA, Jun
dc.contributor.authorHE, Jing
dc.contributor.authorHEATH, Alicia K.
dc.contributor.authorHO, Yuk-Lam
dc.contributor.authorHAVULINNA, Aki S.
dc.contributor.authorHOPEWELL, Jemma .C
dc.contributor.authorHYACINTH, Hyacinth I.
dc.contributor.authorINOUYE, Michael
dc.contributor.authorJACOB, Mina A.
dc.contributor.authorJEON, Christina E.
dc.contributor.authorJERN, Christina
dc.contributor.authorKAMOUCHI, Masahiro
dc.contributor.authorKEENE, Keith L.
dc.contributor.authorKITAZONO, Takanari
dc.contributor.authorKITTNER, Steven J.
dc.contributor.authorKONUMA, Takahiro
dc.contributor.authorKUMAR, Amit
dc.contributor.authorLACAZE, Paul
dc.contributor.authorLAUNER, Lenore J.
dc.contributor.authorLEE, Keon-Joo
dc.contributor.authorLEPIK, Kaido
dc.contributor.authorLI, Jiang
dc.contributor.authorLI, Liming
dc.contributor.authorMANICHAIKUL, Ani
dc.contributor.authorMARKUS, Hugh S.
dc.contributor.authorMARSTON, Nicholas A.
dc.contributor.authorMEITINGER, Thomas
dc.contributor.authorMITCHELL, Braxton D.
dc.contributor.authorMONTELLANO, Felipe A.
dc.contributor.authorMORISAKI, Takayuki
dc.contributor.authorMOSLEY, Thomas H.
dc.contributor.authorNALLS, Mike A.
dc.contributor.authorNORDESTGAARD, Borge G.
dc.contributor.authorO'DONNELL, Martin J.
dc.contributor.authorOKADA, Yukinori
dc.contributor.authorONLAND-MORET, N. Charlotte
dc.contributor.authorOVBIAGELE, Bruce
dc.contributor.authorPETERS, Annette
dc.contributor.authorPSATY, Bruce M
dc.contributor.authorRICH, Stephen S..
dc.contributor.authorROSAND, Jonathan
dc.contributor.authorSABATINE, Marc S.
dc.contributor.authorSACCO, Ralph L.
dc.contributor.authorSALEHEEN, Danish
dc.contributor.authorSANDSET, Else Charlotte
dc.contributor.authorSALOMAA, Veikko
dc.contributor.authorSARGURUPREMRAJ, Muralidharan
dc.contributor.authorSASAKI, Makoto
dc.contributor.authorSATIZABAL, Claudia L.
dc.contributor.authorSCHMIDT, Carsten O.
dc.contributor.authorSHIMIZU, Atsushi
dc.contributor.authorSMITH, Nicholas L.
dc.contributor.authorSLOANE, Kelly L.
dc.contributor.authorSUTOH, Yoichi
dc.contributor.authorSUN, Yan V.
dc.contributor.authorTANNO, Kozo
dc.contributor.authorTIEDT, Steffen
dc.contributor.authorTATLISUMAK, Turgut
dc.contributor.authorTORRES-AGUILA, Nuria P.
dc.contributor.authorTIWARI, Hemant K.
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorTREGOUET, David-Alexandre
dc.contributor.authorTROMPET, Stella
dc.contributor.authorTULADHAR, Anil Man
dc.contributor.authorTYBJAERG-HANSEN, Anne
dc.contributor.authorVAN VUGT, Marion
dc.contributor.authorVIBO, Riina
dc.contributor.authorVERMA, Shefali S.
dc.contributor.authorWIGGINS, Kerri L.
dc.contributor.authorWENNBERG, Patrik
dc.contributor.authorWOO, Daniel
dc.contributor.authorWILSON, Peter W. F.
dc.contributor.authorXU, Huichun
dc.contributor.authorYANG, Qiong
dc.contributor.authorYOON, Kyungheon
dc.contributor.authorMILLWOOD, Iona Y.
dc.contributor.authorGIEGER, Christian
dc.contributor.authorNINOMIYA, Toshiharu
dc.contributor.authorGRABE, Hans J.
dc.contributor.authorJUKEMA, J. Wouter
dc.contributor.authorRISSANEN, Ina L.
dc.contributor.authorSTRBIAN, Daniel
dc.contributor.authorKIM, Young Jin
dc.contributor.authorCHEN, Pei-Hsin
dc.contributor.authorMAYERHOFER, Ernst
dc.contributor.authorHOWSON, Joanna M. M.
dc.contributor.authorIRVIN, Marguerite R.
dc.contributor.authorADAMS, Hieab
dc.contributor.authorWASSERTHEIL-SMOLLER, Sylvia
dc.contributor.authorCHRISTENSEN, Kaare
dc.contributor.authorIKRAM, Mohammad A.
dc.contributor.authorRUNDEK, Tatjana
dc.contributor.authorWORRALL, Bradford B.
dc.contributor.authorLATHROP, G. Mark
dc.contributor.authorRIAZ, Moeen
dc.contributor.authorSIMONSICK, Eleanor M.
dc.contributor.authorKORV, Janika
dc.contributor.authorFRANCA, Paulo H. C.
dc.contributor.authorZAND, Ramin
dc.contributor.authorPRASAD, Kameshwar
dc.contributor.authorFRIKKE-SCHMIDT, Ruth
dc.contributor.authorDE LEEUW, Frank-Erik
dc.contributor.authorLIMAN, Thomas
dc.contributor.authorHAEUSLER, Karl Georg
dc.contributor.authorRUIGROK, Ynte M..
dc.contributor.authorHEUSCHMANN, Peter Ulrich
dc.contributor.authorLONGSTRETH, W T.
dc.contributor.authorJUNG, Keum Ji
dc.contributor.authorBASTARACHE, Lisa
dc.contributor.authorPARE, Guillaume
dc.contributor.authorDAMRAUER, Scott M.
dc.contributor.authorCHASMAN, Daniel I.
dc.contributor.authorROTTER, Jerome I.
dc.contributor.authorANDERSON, Christopher D.
dc.contributor.authorZWART, John-Anker
dc.contributor.authorNIIRANEN, Teemu J.
dc.contributor.authorFORNAGE, Myriam
dc.contributor.authorLIAW, Yung-Po
dc.contributor.authorSESHADRI, Sudha
dc.contributor.authorFERNANDEZ-CADENAS, Israel
dc.contributor.authorWALTERS, Robin G.
dc.contributor.authorRUFF, Christian T.
dc.contributor.authorOWOLABI, Mayowa O.
dc.contributor.authorHUFFMAN, Jennifer E.
dc.contributor.authorMILANI, Lili
dc.contributor.authorKAMATANI, Yoichiro
dc.contributor.authorDICHGANS, Martin
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorDEBETTE, Stephanie
dc.date.accessioned2022-11-02T09:59:35Z
dc.date.available2022-11-02T09:59:35Z
dc.date.issued2022-09-30
dc.identifier.issn1476-4687 (Electronic) 0028-0836 (Linking)en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/170187
dc.description.abstractEnPrevious genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
dc.language.isoENen_US
dc.rightsAttribution 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/us/*
dc.title.enStroke genetics informs drug discovery and risk prediction across ancestries
dc.typeArticle de revueen_US
dc.identifier.doi10.1038/s41586-022-05165-3en_US
dc.subject.halSciences du Vivant [q-bio]/Santé publique et épidémiologieen_US
dc.identifier.pubmed36180795en_US
bordeaux.journalNatureen_US
bordeaux.page1-15en_US
bordeaux.hal.laboratoriesBordeaux Population Health Research Center (BPH) - UMR 1219en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionINSERMen_US
bordeaux.teamELEANOR_BPHen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
hal.identifierhal-03837613
hal.version1
hal.date.transferred2022-11-02T23:44:22Z
hal.exporttrue
dc.rights.ccPas de Licence CCen_US
bordeaux.COinSctx_ver=Z39.88-2004&amp;rft_val_fmt=info:ofi/fmt:kev:mtx:journal&amp;rft.jtitle=Nature&amp;rft.date=2022-09-30&amp;rft.spage=1-15&amp;rft.epage=1-15&amp;rft.eissn=1476-4687%20(Electronic)%200028-0836%20(Linking)&amp;rft.issn=1476-4687%20(Electronic)%200028-0836%20(Linking)&amp;rft.au=MISHRA,%20Aniket&amp;MALIK,%20Rainer&amp;HACHIYA,%20Tsuyoshi&amp;JURGENSON,%20Tuuli&amp;NAMBA,%20Shinichi&amp;rft.genre=article


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