04818nas a2201141 4500008004100000022001400041245011000055210006900165260001300234300001100247490000700258520157500265653001001840653003901850653001701889653000901906653003701915653001901952653003201971653002402003653002002027653004002047653001102087653003802098653003402136653001102170653000902181653001602190653001502206653003602221653002602257653001102283100002002294700002002314700002302334700001902357700002102376700002202397700002702419700001802446700001602464700002302480700001802503700002602521700001702547700001802564700001402582700002102596700002702617700002302644700001802667700001702685700001902702700002002721700002302741700002402764700002302788700001702811700001702828700002302845700001902868700002202887700001902909700002402928700001602952700001502968700002002983700002103003700002103024700002103045700001903066700002003085700002203105700002303127700002403150700003003174700002203204700002603226700002003252700002503272700002003297700002003317700002203337700002003359700001903379700002203398700002003420700002203440700002103462700002803483700002003511700002303531700001703554700002103571700002503592710002303617856003603640 2016 eng d a1524-462800aGenome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2.0 aGenomeWide Association Analysis of YoungOnset Stroke Identifies c2016 Feb a307-160 v473 a
BACKGROUND AND PURPOSE: Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset <60 years.
METHODS: The discovery stage of our genome-wide association studies included 4505 cases and 21 968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5×10(-6) and performed in silico association analyses in an independent sample of ≤1003 cases and 7745 controls.
RESULTS: One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10(-9)). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII-activating protease levels, a product of HABP2.
CONCLUSIONS: HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.
10aAdult10aAfrican Continental Ancestry Group10aAge of Onset10aAged10aAsian Continental Ancestry Group10aBrain Ischemia10aChromosomes, Human, Pair 1010aComputer Simulation10aDNA, Intergenic10aEuropean Continental Ancestry Group10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aOdds Ratio10aPolymorphism, Single Nucleotide10aSerine Endopeptidases10aStroke1 aCheng, Yu-Ching1 aStanne, Tara, M1 aGiese, Anne-Katrin1 aHo, Weang, Kee1 aTraylor, Matthew1 aAmouyel, Philippe1 aHolliday, Elizabeth, G1 aMalik, Rainer1 aXu, Huichun1 aKittner, Steven, J1 aCole, John, W1 aO'Connell, Jeffrey, R1 aDanesh, John1 aRasheed, Asif1 aZhao, Wei1 aEngelter, Stefan1 aGrond-Ginsbach, Caspar1 aKamatani, Yoichiro1 aLathrop, Mark1 aLeys, Didier1 aThijs, Vincent1 aMetso, Tiina, M1 aTatlisumak, Turgut1 aPezzini, Alessandro1 aParati, Eugenio, A1 aNorrving, Bo1 aBevan, Steve1 aRothwell, Peter, M1 aSudlow, Cathie1 aSlowik, Agnieszka1 aLindgren, Arne1 aWalters, Matthew, R1 aJannes, Jim1 aShen, Jess1 aCrosslin, David1 aDoheny, Kimberly1 aLaurie, Cathy, C1 aKanse, Sandip, M1 aBis, Joshua, C1 aFornage, Myriam1 aMosley, Thomas, H1 aHopewell, Jemma, C1 aStrauch, Konstantin1 aMüller-Nurasyid, Martina1 aGieger, Christian1 aWaldenberger, Melanie1 aPeters, Annette1 aMeisinger, Christine1 aIkram, Arfan, M1 aLongstreth, W T1 aMeschia, James, F1 aSeshadri, Sudha1 aSharma, Pankaj1 aWorrall, Bradford1 aJern, Christina1 aLevi, Christopher1 aDichgans, Martin1 aBoncoraglio, Giorgio, B1 aMarkus, Hugh, S1 aDebette, Stephanie1 aRolfs, Arndt1 aSaleheen, Danish1 aMitchell, Braxton, D1 aWTCCC-2 Consortium uhttps://chs-nhlbi.org/node/699106988nas a2201993 4500008004100000022001400041245011600055210006900171260001600240520137500256100001201631700001301643700001801656700002201674700002201696700002501718700001801743700002701761700002001788700002801808700001901836700002001855700002101875700001801896700001601914700002801930700001901958700002501977700002302002700002302025700002302048700002502071700001902096700002102115700002102136700002202157700002102179700002302200700001502223700001802238700001902256700002102275700001702296700001702313700001602330700002002346700002802366700001802394700001902412700002002431700001702451700001802468700001802486700002202504700002102526700002102547700002902568700002302597700002202620700001702642700002202659700003202681700002102713700002302734700002102757700003102778700001402809700002202823700001902845700001602864700002102880700002102901700002302922700002302945700002402968700001902992700002103011700002303032700002103055700002003076700002403096700001803120700001703138700002003155700001803175700002003193700002403213700002103237700002103258700002503279700002203304700001603326700002103342700001703363700002203380700002303402700002003425700001803445700002403463700002203487700002203509700001903531700001903550700001703569700002803586700002403614700002303638700002503661700002003686700002403706700002103730700002403751700002203775700002203797700002303819700002203842700001703864700002103881700002103902700001703923700002003940700001803960700002503978700001904003700002104022700001904043700002004062700002104082700002504103700001804128700001904146700002004165700001904185700001904204700002004223700002904243700002004272700001104292700002304303700002004326700001904346700002004365700002604385700002404411700001904435700002104454700002004475700002404495700002104519700002304540700002804563700001804591700002304609700001704632700001904649700002604668700001904694700001904713700001804732700002304750700002104773700002304794700002304817700001904840700001904859710003904878710004104917856003604958 2016 eng d a1533-345000aSOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function.0 aSOS2 and ACP1 Loci Identified through LargeScale Exome Chip Anal c2016 Dec 053 aGenome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7×10(-7)), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4×10(-8) by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.
1 aLi, Man1 aLi, Yong1 aWeeks, Olivia1 aMijatovic, Vladan1 aTeumer, Alexander1 aHuffman, Jennifer, E1 aTromp, Gerard1 aFuchsberger, Christian1 aGorski, Mathias1 aLyytikäinen, Leo-Pekka1 aNutile, Teresa1 aSedaghat, Sanaz1 aSorice, Rossella1 aTin, Adrienne1 aYang, Qiong1 aAhluwalia, Tarunveer, S1 aArking, Dan, E1 aBihlmeyer, Nathan, A1 aBöger, Carsten, A1 aCarroll, Robert, J1 aChasman, Daniel, I1 aCornelis, Marilyn, C1 aDehghan, Abbas1 aFaul, Jessica, D1 aFeitosa, Mary, F1 aGambaro, Giovanni1 aGasparini, Paolo1 aGiulianini, Franco1 aHeid, Iris1 aHuang, Jinyan1 aImboden, Medea1 aJackson, Anne, U1 aJeff, Janina1 aJhun, Min, A1 aKatz, Ronit1 aKifley, Annette1 aKilpeläinen, Tuomas, O1 aKumar, Ashish1 aLaakso, Markku1 aLi-Gao, Ruifang1 aLohman, Kurt1 aLu, Yingchang1 aMägi, Reedik1 aMalerba, Giovanni1 aMihailov, Evelin1 aMohlke, Karen, L1 aMook-Kanamori, Dennis, O1 aRobino, Antonietta1 aRuderfer, Douglas1 aSalvi, Erika1 aSchick, Ursula, M1 aSchulz, Christina-Alexandra1 aSmith, Albert, V1 aSmith, Jennifer, A1 aTraglia, Michela1 aYerges-Armstrong, Laura, M1 aZhao, Wei1 aGoodarzi, Mark, O1 aKraja, Aldi, T1 aLiu, Chunyu1 aWessel, Jennifer1 aBoerwinkle, Eric1 aBorecki, Ingrid, B1 aBork-Jensen, Jette1 aBottinger, Erwin, P1 aBraga, Daniele1 aBrandslund, Ivan1 aBrody, Jennifer, A1 aCampbell, Archie1 aCarey, David, J1 aChristensen, Cramer1 aCoresh, Josef1 aCrook, Errol1 aCurhan, Gary, C1 aCusi, Daniele1 ade Boer, Ian, H1 ade Vries, Aiko, P J1 aDenny, Joshua, C1 aDevuyst, Olivier1 aDreisbach, Albert, W1 aEndlich, Karlhans1 aEsko, Tõnu1 aFranco, Oscar, H1 aFulop, Tibor1 aGerhard, Glenn, S1 aGlümer, Charlotte1 aGottesman, Omri1 aGrarup, Niels1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aHayward, Caroline1 aHocking, Lynne1 aHofman, Albert1 aHu, Frank, B1 aHusemoen, Lise, Lotte N1 aJackson, Rebecca, D1 aJørgensen, Torben1 aJørgensen, Marit, E1 aKähönen, Mika1 aKardia, Sharon, L R1 aKönig, Wolfgang1 aKooperberg, Charles1 aKriebel, Jennifer1 aLauner, Lenore, J1 aLauritzen, Torsten1 aLehtimäki, Terho1 aLevy, Daniel1 aLinksted, Pamela1 aLinneberg, Allan1 aLiu, Yongmei1 aLoos, Ruth, J F1 aLupo, Antonio1 aMeisinger, Christine1 aMelander, Olle1 aMetspalu, Andres1 aMitchell, Paul1 aNauck, Matthias1 aNürnberg, Peter1 aOrho-Melander, Marju1 aParsa, Afshin1 aPedersen, Oluf1 aPeters, Annette1 aPeters, Ulrike1 aPolasek, Ozren1 aPorteous, David1 aProbst-Hensch, Nicole, M1 aPsaty, Bruce, M1 aQi, Lu1 aRaitakari, Olli, T1 aReiner, Alex, P1 aRettig, Rainer1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRossouw, Jacques, E1 aSchmidt, Frank1 aSiscovick, David1 aSoranzo, Nicole1 aStrauch, Konstantin1 aToniolo, Daniela1 aTurner, Stephen, T1 aUitterlinden, André, G1 aUlivi, Sheila1 aVelayutham, Dinesh1 aVölker, Uwe1 aVölzke, Henry1 aWaldenberger, Melanie1 aWang, Jie, Jin1 aWeir, David, R1 aWitte, Daniel1 aKuivaniemi, Helena1 aFox, Caroline, S1 aFranceschini, Nora1 aGoessling, Wolfram1 aKöttgen, Anna1 aChu, Audrey, Y1 aCHARGE Glycemic-T2D Working Group,1 aCHARGE Blood Pressure Working Group, uhttps://chs-nhlbi.org/node/725503140nas a2200649 4500008004100000022001400041245009100055210006900146260001600215520129400231100003201525700002001557700001701577700001801594700001601612700002201628700002501650700002301675700001901698700002001717700002101737700002001758700002101778700002101799700001701820700002001837700001901857700001801876700001801894700001901912700002201931700002001953700002001973700002001993700002202013700001902035700002002054700002102074700001602095700002102111700002502132700002302157700001902180700002102199700001902220700002302239700002002262700002002282700002302302700001902325700001802344700001702362700002602379700003002405700001902435856003602454 2021 eng d a1573-728400aMeta-analysis of epigenome-wide association studies of carotid intima-media thickness.0 aMetaanalysis of epigenomewide association studies of carotid int c2021 Jun 063 aCommon carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = -0.0264, p value = 3.5 × 10) in the discovery panel and was replicated in replication panel (beta = -0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.
1 aPortilla-Fernández, Eliana1 aHwang, Shih-Jen1 aWilson, Rory1 aMaddock, Jane1 aHill, David1 aTeumer, Alexander1 aMishra, Pashupati, P1 aBrody, Jennifer, A1 aJoehanes, Roby1 aLigthart, Symen1 aGhanbari, Mohsen1 aKavousi, Maryam1 aRoks, Anton, J M1 aDanser, A, H Jan1 aLevy, Daniel1 aPeters, Annette1 aGhasemi, Sahar1 aSchminke, Ulf1 aDörr, Marcus1 aGrabe, Hans, J1 aLehtimäki, Terho1 aKähönen, Mika1 aHurme, Mikko, A1 aBartz, Traci, M1 aSotoodehnia, Nona1 aBis, Joshua, C1 aThiery, Joachim1 aKoenig, Wolfgang1 aOng, Ken, K1 aBell, Jordana, T1 aMeisinger, Christine1 aWardlaw, Joanna, M1 aStarr, John, M1 aSeissler, Jochen1 aThen, Cornelia1 aRathmann, Wolfgang1 aIkram, Arfan, M1 aPsaty, Bruce, M1 aRaitakari, Olli, T1 aVölzke, Henry1 aDeary, Ian, J1 aWong, Andrew1 aWaldenberger, Melanie1 aO'Donnell, Christopher, J1 aDehghan, Abbas uhttps://chs-nhlbi.org/node/8789