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Browsing by Author "Traylor, M."

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  • COL4A2 is associated with lacunar ischemic stroke and deep ICH: meta-analyses among 21,500 cases and 40,600 controls
    Publication . Rannikmäe, K.; Sivakumaran, V.; Millar, H.; Malik, R.; Anderson, C.D.; Chong, M.; Dave, T.; Falcone, G.J.; Fernandez-Cadenas, I.; Jimenez-Conde, J.; Lindgren, A.; Montaner, J.; O'Donnell, M.; Paré, G.; Radmanesh, F.; Rost, N.S.; Slowik, A.; Söderholm, M.; Traylor, M.; Pulit, S.L.; Seshadri, S.; Worrall, B.B.; Woo, D.; Markus, H.S.; Mitchell, B.D.; Dichgans, M.; Rosand, J.; Sudlow, CLM; Stroke Genetics Network (SiGN); METASTROKE Collaboration; International Stroke Genetics Consortium (ISGC)
    Objective: To determine whether common variants in familial cerebral small vessel disease (SVD) genes confer risk of sporadic cerebral SVD. Methods: We meta-analyzed genotype data from individuals of European ancestry to determine associations of common single nucleotide polymorphisms (SNPs) in 6 familial cerebral SVD genes (COL4A1, COL4A2, NOTCH3, HTRA1, TREX1, and CECR1) with intracerebral hemorrhage (ICH) (deep, lobar, all; 1,878 cases, 2,830 controls) and ischemic stroke (IS) (lacunar, cardioembolic, large vessel disease, all; 19,569 cases, 37,853 controls). We applied data quality filters and set statistical significance thresholds accounting for linkage disequilibrium and multiple testing. Results: A locus in COL4A2 was associated (significance threshold p < 3.5 × 10−4) with both lacunar IS (lead SNP rs9515201: odds ratio [OR] 1.17, 95% confidence interval [CI] 1.11–1.24, p = 6.62 × 10−8) and deep ICH (lead SNP rs4771674: OR 1.28, 95% CI 1.13–1.44, p = 5.76 × 10−5). A SNP in HTRA1 was associated (significance threshold p < 5.5 × 10−4) with lacunar IS (rs79043147: OR 1.23, 95% CI 1.10–1.37, p = 1.90 × 10−4) and less robustly with deep ICH. There was no clear evidence for association of common variants in either COL4A2 or HTRA1 with non-SVD strokes or in any of the other genes with any stroke phenotype. Conclusions: These results provide evidence of shared genetic determinants and suggest common pathophysiologic mechanisms of distinct ischemic and hemorrhagic cerebral SVD stroke phenotypes, offering new insights into the causal mechanisms of cerebral SVD.
    2017-10Journal article Restricted access Show more
  • Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies
    Publication . Traylor, M.; Farrall, M.; Holliday, E.G.; Sudlow, C.; Hopewell, J.C.; Cheng, Y.C.; Fornage, M.; Ikram, M.A.; Malik, R.; Bevan, S.; Thorsteinsdottir, U.; Nalls, M.A.; Longstreth, W.; Wiggins, K.L.; Yadav, S.; Parati, E.A.; Destefano, A.L.; Worrall, B.B.; Kittner, S.J.; Khan, M.S.; Reiner, A.P.; Helgadottir, A.; Achterberg, S.; Fernandez-Cadenas, I.; Abboud, S.; Schmidt, R.; Walters, M.; Chen, W.M.; Ringelstein, E.B.; O'Donnell, M.; Ho, W.K.; Pera, J.; Lemmens, R.; Norrving, B.; Higgins, P.; Benn, M.; Sale, M.; Kuhlenbäumer, G.; Doney, A.S.; Vicente, A.M.; Delavaran, H.; Algra, A.; Davies, G.; Oliveira, S.A.; Palmer, C.N.; Deary, I.; Schmidt, H.; Pandolfo, M.; Montaner, J.; Carty, C.; de Bakker, P.I.; Kostulas, K.; Ferro, J.M.; van Zuydam, N.R,; Valdimarsson, E.; Nordestgaard, B.G.; Lindgren, A.; Thijs, V.; Slowik, A.; Saleheen, D.; Paré, G.; Berger, K.; Thorleifsson, G.; Australian Stroke Genetics Collaborative, Wellcome Trust Case Control Consortium 2 (WTCCC2); Hofman, A.; Mosley, T.H.; Mitchell, B.D.; Furie, K.; Clarke, R.; Levi, C.; Seshadri, S.; Gschwendtner, A.; Boncoraglio, G.B.; Sharma, P.; Bis, J.C.; Gretarsdottir, S.; Psaty, B.M.; Rothwell, P.M.; Rosand, J.; Meschia, J.F.; Stefansson, K.; Dichgans, M.; Markus, H.S.; International Stroke Genetics Consortium.
    Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes.
    2012-10-05Journal article Open access Show more
  • Low-frequency and common genetic variation in ischemic stroke: The METASTROKE collaboration
    Publication . Malik, R.; Traylor, M.; Pulit, S.L.; Bevan, S.; Hopewell, J.C.; Holliday, E.G.; Zhao, W.; Abrantes, P.; Amouyel, P.; Attia, J.R.; Battey, T.W.; Berger, K.; Boncoraglio, G.B.; Chauhan, G.; Cheng, Y.C.; Chen, W.M.; Clarke, R.; Cotlarciuc, I.; Debette, S.; Falcone, G.J.; Ferro, J.M.; Gamble, D.M.; Ilinca, A.; Kittner, S.J.; Kourkoulis, C.E.; Lemmens, R.; Levi, C.R.; Lichtner, P.; Lindgren, A.; Liu, J.; Meschia, J.F.; Mitchell, B.D.; Oliveira, S.A.; Pera, J.; Reiner, A.P.; Rothwell, P.M.; Sharma, P.; Slowik, A.; Sudlow, C.L.; Tatlisumak, T.; Thijs, V.; Vicente, A.M.; Woo, D.; Seshadri, S.; Saleheen, D.; Rosand, J.; Markus, H.S.; Worrall, B.B.; Dichgans, M.; ISGC Analysis Group; METASTROKE collaboration; Wellcome Trust Case Control Consortium 2 (WTCCC2); NINDS Stroke Genetics Network (SiGN)
    Objective: To investigate the influence of common and low-frequency genetic variants on the risk of ischemic stroke (all IS) and etiologic stroke subtypes. Methods: We meta-analyzed 12 individual genome-wide association studies comprising 10,307 cases and 19,326 controls imputed to the 1000 Genomes (1 KG) phase I reference panel. We selected variants showing the highest degree of association (p , 1E-5) in the discovery phase for replication in Caucasian (13,435 cases and 29,269 controls) and South Asian (2,385 cases and 5,193 controls) samples followed by a transethnic meta-analysis. We further investigated the p value distribution for different bins of allele frequencies for all IS and stroke subtypes. Results: We showed genome-wide significance for 4 loci: ABO for all IS, HDAC9 for large vessel disease (LVD), and both PITX2 and ZFHX3 for cardioembolic stroke (CE). We further refined the association peaks for ABO and PITX2. Analyzing different allele frequency bins, we showed significant enrichment in low-frequency variants (allele frequency ,5%) for both LVD and small vessel disease, and an enrichment of higher frequency variants (allele frequency 10% and 30%) for CE (all p , 1E-5). Conclusions: Our findings suggest that the missing heritability in IS subtypes can in part be attributed to low-frequency and rare variants. Larger sample sizes are needed to identify the variants associated with all IS and stroke subtypes.
    2016-03Journal article Restricted access Show more