04590nas a2200889 4500008004100000022001400041245009700055210006900152260001500221300001100236490000700247520195700254653003502211653002102246653003202267653002202299653001102321653003602332100002502368700001702393700002202410700001702432700002202449700002202471700002102493700002902514700002402543700002102567700001702588700002002605700002002625700002502645700001702670700002002687700002302707700002402730700001902754700002302773700002202796700002102818700002202839700002202861700002002883700001902903700002302922700002302945700002402968700002202992700002003014700001603034700001903050700002303069700002503092700002703117700002503144700001603169700002303185700002203208700002803230700002003258700001803278700001803296700002503314700002103339700002103360700001603381700002003397700002003417700002103437700002403458710002603482710002103508710003803529710005203567710004503619856003603664 2015 ENG d a1526-632X00aCommon variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease.0 aCommon variation in COL4A1COL4A2 is associated with sporadic cer c2015 Mar 3 a918-260 v843 a
OBJECTIVES: We hypothesized that common variants in the collagen genes COL4A1/COL4A2 are associated with sporadic forms of cerebral small vessel disease.
METHODS: We conducted meta-analyses of existing genotype data among individuals of European ancestry to determine associations of 1,070 common single nucleotide polymorphisms (SNPs) in the COL4A1/COL4A2 genomic region with the following: intracerebral hemorrhage and its subtypes (deep, lobar) (1,545 cases, 1,485 controls); ischemic stroke and its subtypes (cardioembolic, large vessel disease, lacunar) (12,389 cases, 62,004 controls); and white matter hyperintensities (2,733 individuals with ischemic stroke and 9,361 from population-based cohorts with brain MRI data). We calculated a statistical significance threshold that accounted for multiple testing and linkage disequilibrium between SNPs (p < 0.000084).
RESULTS: Three intronic SNPs in COL4A2 were significantly associated with deep intracerebral hemorrhage (lead SNP odds ratio [OR] 1.29, 95% confidence interval [CI] 1.14-1.46, p = 0.00003; r(2) > 0.9 between SNPs). Although SNPs associated with deep intracerebral hemorrhage did not reach our significance threshold for association with lacunar ischemic stroke (lead SNP OR 1.10, 95% CI 1.03-1.18, p = 0.0073), and with white matter hyperintensity volume in symptomatic ischemic stroke patients (lead SNP OR 1.07, 95% CI 1.01-1.13, p = 0.016), the direction of association was the same. There was no convincing evidence of association with white matter hyperintensities in population-based studies or with non-small vessel disease cerebrovascular phenotypes.
CONCLUSIONS: Our results indicate an association between common variation in the COL4A2 gene and symptomatic small vessel disease, particularly deep intracerebral hemorrhage. These findings merit replication studies, including in ethnic groups of non-European ancestry.
10aCerebral Small Vessel Diseases10aCollagen Type IV10aGenetic Association Studies10aGenetic Variation10aHumans10aPolymorphism, Single Nucleotide1 aRannikmae, Kristiina1 aDavies, Gail1 aThomson, Pippa, A1 aBevan, Steve1 aDevan, William, J1 aFalcone, Guido, J1 aTraylor, Matthew1 aAnderson, Christopher, D1 aBattey, Thomas, W K1 aRadmanesh, Farid1 aDeka, Ranjan1 aWoo, Jessica, G1 aMartin, Lisa, J1 aJimenez-Conde, Jordi1 aSelim, Magdy1 aBrown, Devin, L1 aSilliman, Scott, L1 aKidwell, Chelsea, S1 aMontaner, Joan1 aLangefeld, Carl, D1 aSlowik, Agnieszka1 aHansen, Bjorn, M1 aLindgren, Arne, G1 aMeschia, James, F1 aFornage, Myriam1 aBis, Joshua, C1 aDebette, Stephanie1 aIkram, Mohammad, A1 aLongstreth, Will, T1 aSchmidt, Reinhold1 aZhang, Cathy, R1 aYang, Qiong1 aSharma, Pankaj1 aKittner, Steven, J1 aMitchell, Braxton, D1 aHolliday, Elizabeth, G1 aLevi, Christopher, R1 aAttia, John1 aRothwell, Peter, M1 aPoole, Deborah, L1 aBoncoraglio, Giorgio, B1 aPsaty, Bruce, M1 aMalik, Rainer1 aRost, Natalia1 aWorrall, Bradford, B1 aDichgans, Martin1 aVan Agtmael, Tom1 aWoo, Daniel1 aMarkus, Hugh, S1 aSeshadri, Sudha1 aRosand, Jonathan1 aSudlow, Cathie, L M1 aMETASTROKE Consortium1 aCHARGE WMH Group1 aISGC ICH GWAS Study Collaboration1 aWMH in Ischemic Stroke GWAS Study Collaboration1 aInternational Stroke Genetics Consortium uhttps://chs-nhlbi.org/node/686404070nas a2200865 4500008004100000022001400041245010200055210006900157260001600226300001200242490000700254520151500261653001901776653003401795653001101829653002301840653002601863653001101889100001801900700002301918700002401941700002101965700002601986700002102012700002102033700002702054700002402081700002002105700001902125700002302144700002302167700002502190700001902215700001902234700002302253700002002276700002202296700002202318700001902340700001902359700002302378700002502401700001802426700001902444700002002463700002302483700001802506700002002524700002002544700002002564700002302584700002302607700001902630700002002649700001702669700001802686700002102704700002102725700002102746700002802767700002502795700002302820700002102843700002502864700002002889700002002909700003602929700002002965700001902985700001903004700002103023710004703044710007703091856003603168 2015 eng d a1526-632X00aShared genetic basis for migraine and ischemic stroke: A genome-wide analysis of common variants.0 aShared genetic basis for migraine and ischemic stroke A genomewi c2015 May 26 a2132-450 v843 aOBJECTIVE: To quantify genetic overlap between migraine and ischemic stroke (IS) with respect to common genetic variation.
METHODS: We applied 4 different approaches to large-scale meta-analyses of genome-wide data on migraine (23,285 cases and 95,425 controls) and IS (12,389 cases and 62,004 controls). First, we queried known genome-wide significant loci for both disorders, looking for potential overlap of signals. We then analyzed the overall shared genetic load using polygenic scores and estimated the genetic correlation between disease subtypes using data derived from these models. We further interrogated genomic regions of shared risk using analysis of covariance patterns between the 2 phenotypes using cross-phenotype spatial mapping.
RESULTS: We found substantial genetic overlap between migraine and IS using all 4 approaches. Migraine without aura (MO) showed much stronger overlap with IS and its subtypes than migraine with aura (MA). The strongest overlap existed between MO and large artery stroke (LAS; p = 6.4 × 10(-28) for the LAS polygenic score in MO) and between MO and cardioembolic stroke (CE; p = 2.7 × 10(-20) for the CE score in MO).
CONCLUSIONS: Our findings indicate shared genetic susceptibility to migraine and IS, with a particularly strong overlap between MO and both LAS and CE pointing towards shared mechanisms. Our observations on MA are consistent with a limited role of common genetic variants in this subtype.
10aBrain Ischemia10aGenome-Wide Association Study10aHumans10aMigraine with Aura10aMigraine without Aura10aStroke1 aMalik, Rainer1 aFreilinger, Tobias1 aWinsvold, Bendik, S1 aAnttila, Verneri1 aHeiden, Jason, Vander1 aTraylor, Matthew1 ade Vries, Boukje1 aHolliday, Elizabeth, G1 aTerwindt, Gisela, M1 aSturm, Jonathan1 aBis, Joshua, C1 aHopewell, Jemma, C1 aFerrari, Michel, D1 aRannikmae, Kristiina1 aWessman, Maija1 aKallela, Mikko1 aKubisch, Christian1 aFornage, Myriam1 aMeschia, James, F1 aLehtimäki, Terho1 aSudlow, Cathie1 aClarke, Robert1 aChasman, Daniel, I1 aMitchell, Braxton, D1 aMaguire, Jane1 aKaprio, Jaakko1 aFarrall, Martin1 aRaitakari, Olli, T1 aKurth, Tobias1 aIkram, Arfan, M1 aReiner, Alex, P1 aLongstreth, W T1 aRothwell, Peter, M1 aStrachan, David, P1 aSharma, Pankaj1 aSeshadri, Sudha1 aQuaye, Lydia1 aCherkas, Lynn1 aSchürks, Markus1 aRosand, Jonathan1 aLigthart, Lannie1 aBoncoraglio, Giorgio, B1 aSmith, George, Davey1 aDuijn, Cornelia, M1 aStefansson, Kari1 aWorrall, Bradford, B1 aNyholt, Dale, R1 aMarkus, Hugh, S1 avan den Maagdenberg, Arn, M J M1 aCotsapas, Chris1 aZwart, John, A1 aPalotie, Aarno1 aDichgans, Martin1 aInternational Headache Genetics Consortium1 aMETASTROKE Collaboration of the International Stroke Genetics Consortium uhttps://chs-nhlbi.org/node/681316401nas a2205425 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2018 eng d a1546-171800aMultiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.0 aMultiancestry genomewide association study of 520000 subjects id c2018 Apr a524-5370 v503 aStroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.
1 aMalik, Rainer1 aChauhan, Ganesh1 aTraylor, Matthew1 aSargurupremraj, Muralidharan1 aOkada, Yukinori1 aMishra, Aniket1 aRutten-Jacobs, Loes1 aGiese, Anne-Katrin1 avan der Laan, Sander, W1 aGretarsdottir, Solveig1 aAnderson, Christopher, D1 aChong, Michael1 aAdams, Hieab, H H1 aAgo, Tetsuro1 aAlmgren, Peter1 aAmouyel, Philippe1 aAy, Hakan1 aBartz, Traci, M1 aBenavente, Oscar, R1 aBevan, Steve1 aBoncoraglio, Giorgio, B1 aBrown, Robert, D1 aButterworth, Adam, S1 aCarrera, Caty1 aCarty, Cara, L1 aChasman, Daniel, I1 aChen, Wei-Min1 aCole, John, W1 aCorrea, Adolfo1 aCotlarciuc, Ioana1 aCruchaga, Carlos1 aDanesh, John1 ade Bakker, Paul, I W1 aDeStefano, Anita, L1 aHoed, Marcel, den1 aDuan, Qing1 aEngelter, Stefan, T1 aFalcone, Guido, J1 aGottesman, Rebecca, F1 aGrewal, Raji, P1 aGudnason, Vilmundur1 aGustafsson, Stefan1 aHaessler, Jeffrey1 aHarris, Tamara, B1 aHassan, Ahamad1 aHavulinna, Aki, S1 aHeckbert, Susan, R1 aHolliday, Elizabeth, G1 aHoward, George1 aHsu, Fang-Chi1 aHyacinth, Hyacinth, I1 aIkram, Arfan, M1 aIngelsson, Erik1 aIrvin, Marguerite, R1 aJian, Xueqiu1 aJimenez-Conde, Jordi1 aJohnson, Julie, A1 aJukema, Wouter1 aKanai, Masahiro1 aKeene, Keith, L1 aKissela, Brett, M1 aKleindorfer, Dawn, O1 aKooperberg, Charles1 aKubo, Michiaki1 aLange, Leslie, A1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLee, Jin-Moo1 aLemmens, Robin1 aLeys, Didier1 aLewis, Cathryn, M1 aLin, Wei-Yu1 aLindgren, Arne, G1 aLorentzen, Erik1 aMagnusson, Patrik, K1 aMaguire, Jane1 aManichaikul, Ani1 aMcArdle, Patrick, F1 aMeschia, James, F1 aMitchell, Braxton, D1 aMosley, Thomas, H1 aNalls, Michael, A1 aNinomiya, Toshiharu1 aO'Donnell, Martin, J1 aPsaty, Bruce, M1 aPulit, Sara, L1 aRannikmae, Kristiina1 aReiner, Alexander, P1 aRexrode, Kathryn, M1 aRice, Kenneth1 aRich, Stephen, S1 aRidker, Paul, M1 aRost, Natalia, S1 aRothwell, Peter, M1 aRotter, Jerome, I1 aRundek, Tatjana1 aSacco, Ralph, L1 aSakaue, Saori1 aSale, Michèle, M1 aSalomaa, Veikko1 aSapkota, Bishwa, R1 aSchmidt, Reinhold1 aSchmidt, Carsten, O1 aSchminke, Ulf1 aSharma, Pankaj1 aSlowik, Agnieszka1 aSudlow, Cathie, L M1 aTanislav, Christian1 aTatlisumak, Turgut1 aTaylor, Kent, D1 aThijs, Vincent, N S1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aTiedt, Steffen1 aTrompet, Stella1 aTzourio, Christophe1 aDuijn, Cornelia, M1 aWalters, Matthew1 aWareham, Nicholas, J1 aWassertheil-Smoller, Sylvia1 aWilson, James, G1 aWiggins, Kerri, L1 aYang, Qiong1 aYusuf, Salim1 aBis, Joshua, C1 aPastinen, Tomi1 aRuusalepp, Arno1 aSchadt, Eric, E1 aKoplev, Simon1 aBjörkegren, Johan, L M1 aCodoni, Veronica1 aCivelek, Mete1 aSmith, Nicholas, L1 aTrégouët, David, A1 aChristophersen, Ingrid, E1 aRoselli, Carolina1 aLubitz, Steven, A1 aEllinor, Patrick, T1 aTai, Shyong, E1 aKooner, Jaspal, S1 aKato, Norihiro1 aHe, Jiang1 aHarst, Pim1 aElliott, Paul1 aChambers, John, C1 aTakeuchi, Fumihiko1 aJohnson, Andrew, D1 aSanghera, Dharambir, K1 aMelander, Olle1 aJern, Christina1 aStrbian, Daniel1 aFernandez-Cadenas, Israel1 aLongstreth, W T1 aRolfs, Arndt1 aHata, Jun1 aWoo, Daniel1 aRosand, Jonathan1 aParé, Guillaume1 aHopewell, Jemma, C1 aSaleheen, Danish1 aStefansson, Kari1 aWorrall, Bradford, B1 aKittner, Steven, J1 aSeshadri, Sudha1 aFornage, Myriam1 aMarkus, Hugh, S1 aHowson, Joanna, M M1 aKamatani, Yoichiro1 aDebette, Stephanie1 aDichgans, Martin1 aMalik, Rainer1 aChauhan, Ganesh1 aTraylor, Matthew1 aSargurupremraj, Muralidharan1 aOkada, Yukinori1 aMishra, Aniket1 aRutten-Jacobs, Loes1 aGiese, Anne-Katrin1 avan der Laan, Sander, W1 aGretarsdottir, Solveig1 aAnderson, Christopher, D1 aChong, Michael1 aAdams, Hieab, H H1 aAgo, Tetsuro1 aAlmgren, Peter1 aAmouyel, Philippe1 aAy, Hakan1 aBartz, Traci, M1 aBenavente, Oscar, R1 aBevan, Steve1 aBoncoraglio, Giorgio, B1 aBrown, Robert, D1 aButterworth, Adam, S1 aCarrera, Caty1 aCarty, Cara, L1 aChasman, Daniel, I1 aChen, Wei-Min1 aCole, John, W1 aCorrea, Adolfo1 aCotlarciuc, Ioana1 aCruchaga, Carlos1 aDanesh, John1 ade Bakker, Paul, I W1 aDeStefano, Anita, L1 aHoed, Marcel, den1 aDuan, Qing1 aEngelter, Stefan, T1 aFalcone, Guido, J1 aGottesman, Rebecca, F1 aGrewal, Raji, P1 aGudnason, Vilmundur1 aGustafsson, Stefan1 aHaessler, Jeffrey1 aHarris, Tamara, B1 aHassan, Ahamad1 aHavulinna, Aki, S1 aHeckbert, Susan, R1 aHolliday, Elizabeth, G1 aHoward, George1 aHsu, Fang-Chi1 aHyacinth, Hyacinth, I1 aIkram, Arfan, M1 aIngelsson, Erik1 aIrvin, Marguerite, R1 aJian, Xueqiu1 aJimenez-Conde, Jordi1 aJohnson, Julie, A1 aJukema, Wouter1 aKanai, Masahiro1 aKeene, Keith, L1 aKissela, Brett, M1 aKleindorfer, Dawn, O1 aKooperberg, Charles1 aKubo, Michiaki1 aLange, Leslie, A1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLee, Jin-Moo1 aLemmens, Robin1 aLeys, Didier1 aLewis, Cathryn, M1 aLin, Wei-Yu1 aLindgren, Arne, G1 aLorentzen, Erik1 aMagnusson, Patrik, K1 aMaguire, Jane1 aManichaikul, Ani1 aMcArdle, Patrick, F1 aMeschia, James, F1 aMitchell, Braxton, D1 aMosley, Thomas, H1 aNalls, Michael, A1 aNinomiya, Toshiharu1 aO'Donnell, Martin, J1 aPsaty, Bruce, M1 aPulit, Sara, L1 aRannikmae, Kristiina1 aReiner, Alexander, P1 aRexrode, Kathryn, M1 aRice, Kenneth1 aRich, Stephen, S1 aRidker, Paul, M1 aRost, Natalia, S1 aRothwell, Peter, M1 aRotter, Jerome, I1 aRundek, Tatjana1 aSacco, Ralph, L1 aSakaue, Saori1 aSale, Michèle, M1 aSalomaa, Veikko1 aSapkota, Bishwa, R1 aSchmidt, Reinhold1 aSchmidt, Carsten, O1 aSchminke, Ulf1 aSharma, Pankaj1 aSlowik, Agnieszka1 aSudlow, Cathie, L M1 aTanislav, Christian1 aTatlisumak, Turgut1 aTaylor, Kent, D1 aThijs, Vincent, N S1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aTiedt, Steffen1 aTrompet, Stella1 aTzourio, Christophe1 aDuijn, Cornelia, M1 aWalters, Matthew1 aWareham, Nicholas, J1 aWassertheil-Smoller, Sylvia1 aWilson, James, G1 aWiggins, Kerri, L1 aYang, Qiong1 aYusuf, Salim1 aAmin, Najaf1 aAparicio, Hugo, S1 aArnett, Donna, K1 aAttia, John1 aBeiser, Alexa, S1 aBerr, Claudine1 aBuring, Julie, E1 aBustamante, Mariana1 aCaso, Valeria1 aCheng, Yu-Ching1 aChoi, Seung, Hoan1 aChowhan, Ayesha1 aCullell, Natalia1 aDartigues, Jean-François1 aDelavaran, Hossein1 aDelgado, Pilar1 aDörr, Marcus1 aEngström, Gunnar1 aFord, Ian1 aGurpreet, Wander, S1 aHamsten, Anders1 aHeitsch, Laura1 aHozawa, Atsushi1 aIbanez, Laura1 aIlinca, Andreea1 aIngelsson, Martin1 aIwasaki, Motoki1 aJackson, Rebecca, D1 aJood, Katarina1 aJousilahti, Pekka1 aKaffashian, Sara1 aKalra, Lalit1 aKamouchi, Masahiro1 aKitazono, Takanari1 aKjartansson, Olafur1 aKloss, Manja1 aKoudstaal, Peter, J1 aKrupinski, Jerzy1 aLabovitz, Daniel, L1 aLaurie, Cathy, C1 aLevi, Christopher, R1 aLi, Linxin1 aLind, Lars1 aLindgren, Cecilia, M1 aLioutas, Vasileios1 aLiu, Yong, Mei1 aLopez, Oscar, L1 aMakoto, Hirata1 aMartinez-Majander, Nicolas1 aMatsuda, Koichi1 aMinegishi, Naoko1 aMontaner, Joan1 aMorris, Andrew, P1 aMuiño, Elena1 aMüller-Nurasyid, Martina1 aNorrving, Bo1 aOgishima, Soichi1 aParati, Eugenio, A1 aPeddareddygari, Leema, Reddy1 aPedersen, Nancy, L1 aPera, Joanna1 aPerola, Markus1 aPezzini, Alessandro1 aPileggi, Silvana1 aRabionet, Raquel1 aRiba-Llena, Iolanda1 aRibasés, Marta1 aRomero, Jose, R1 aRoquer, Jaume1 aRudd, Anthony, G1 aSarin, Antti-Pekka1 aSarju, Ralhan1 aSarnowski, Chloe1 aSasaki, Makoto1 aSatizabal, Claudia, L1 aSatoh, Mamoru1 aSattar, Naveed1 aSawada, Norie1 aSibolt, Gerli1 aSigurdsson, Ásgeir1 aSmith, Albert1 aSobue, Kenji1 aSoriano-Tárraga, Carolina1 aStanne, Tara1 aStine, Colin1 aStott, David, J1 aStrauch, Konstantin1 aTakai, Takako1 aTanaka, Hideo1 aTanno, Kozo1 aTeumer, Alexander1 aTomppo, Liisa1 aTorres-Aguila, Nuria, P1 aTouze, Emmanuel1 aTsugane, Shoichiro1 aUitterlinden, André, G1 aValdimarsson, Einar, M1 avan der Lee, Sven, J1 aVölzke, Henry1 aWakai, Kenji1 aWeir, David1 aWilliams, Stephen, R1 aWolfe, Charles, D A1 aWong, Quenna1 aXu, Huichun1 aYamaji, Taiki1 aSanghera, Dharambir, K1 aMelander, Olle1 aJern, Christina1 aStrbian, Daniel1 aFernandez-Cadenas, Israel1 aLongstreth, W T1 aRolfs, Arndt1 aHata, Jun1 aWoo, Daniel1 aRosand, Jonathan1 aParé, Guillaume1 aHopewell, Jemma, C1 aSaleheen, Danish1 aStefansson, Kari1 aWorrall, Bradford, B1 aKittner, Steven, J1 aSeshadri, Sudha1 aFornage, Myriam1 aMarkus, Hugh, S1 aHowson, Joanna, M M1 aKamatani, Yoichiro1 aDebette, Stephanie1 aDichgans, Martin1 aAFGen Consortium1 aCohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium1 aInternational Genomics of Blood Pressure (iGEN-BP) Consortium1 aINVENT Consortium1 aSTARNET1 aBioBank Japan Cooperative Hospital Group1 aCOMPASS Consortium1 aEPIC-CVD Consortium1 aEPIC-InterAct Consortium1 aInternational Stroke Genetics Consortium (ISGC)1 aMETASTROKE Consortium1 aNeurology Working Group of the CHARGE Consortium1 aNINDS Stroke Genetics Network (SiGN)1 aUK Young Lacunar DNA Study1 aMEGASTROKE Consortium1 aMEGASTROKE Consortium: uhttps://chs-nhlbi.org/node/7683