TY - JOUR
T1 - COL4A2 is associated with lacunar ischemic stroke and deep ICH
T2 - Meta-analyses among 21,500 cases and 40,600 controls
AU - Rannikme, Kristiina
AU - Sivakumaran, Vhinoth
AU - Millar, Henry
AU - Malik, Rainer
AU - Anderson, Christopher D.
AU - Chong, Mike
AU - Dave, Tushar
AU - Falcone, Guido J.
AU - Fernandez-Cadenas, Israel
AU - Jimenez-Conde, Jordi
AU - Lindgren, Arne
AU - Montaner, Joan
AU - O'Donnell, Martin
AU - Paré, Guillaume
AU - Radmanesh, Farid
AU - Rost, Natalia S.
AU - Slowik, Agnieszka
AU - Söderholm, Martin
AU - Traylor, Matthew
AU - Pulit, Sara L.
AU - Seshadri, Sudha
AU - Worrall, Brad B.
AU - Woo, Daniel
AU - Markus, Hugh S.
AU - Mitchell, Braxton D.
AU - Dichgans, Martin
AU - Rosand, Jonathan
AU - Sudlow, Cathie L.M.
N1 - Funding Information:
This work was funded in part by NIH grants U01 NS069208 and P30 DK072488 (SiGN). M.D. and R.M. were supported by grants from the Deutsche Forschungsgemeinschaft (CRC 1123 [B3] and Munich Cluster for Systems Neurology [SyNergy]), the German Federal Ministry of Education and Research (BMBF, e:Med programme e:AtheroSysMed), the FP7/2007–2103 European Union project CVgenes@target (grant agreement Health-F2-2013-601456), the European Union Horizon2020 projects SVDs@target (grant agreement 66688) and CoSTREAM (grant agreement 667375), the Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain), the Vascular Dementia Research Foundation, and the Jackstaedt Foundation. G.P. and M.C. were supported by the Canadian Stroke Network, Canadian Institutes of Health Research, and Heart & Stroke Foundation. N.S.R. acknowledges the National Institute of Neurologic Disorders and Stroke K23NS064052, R01NS086905, and R01NS082285. J.R. acknowledges the National Institute of Neurologic Disorders and Stroke R01NS059727 and Keane Stroke Genetics Fund. H.S.M. is supported by a National Institute for Health Research Senior Investigator award and support from the Cambridge University Hospitals Comprehensive Biomedical Research Centre. C.D.A. acknowledges funding from NIH K23 NS086873. A.L. is supported by Region Skåne, Lund University, the Swedish Heart and Lung Foundation, the Freemasons Lodge of Instructions EOS Lund, and the Swedish Stroke Association.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/10/24
Y1 - 2017/10/24
N2 - 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 3 1024) with both lacunar IS (lead SNP rs9515201: odds ratio [OR] 1.17, 95%confidence interval [CI] 1.11-1.24, p 56.62 31028) and deep ICH (lead SNP rs4771674: OR 1.28, 95%CI 1.13-1.44, p 55.76 3 1025). A SNP in HTRA1 was associated (significance threshold p , 5.5 3 1024) with lacunar IS (rs79043147: OR 1.23, 95%CI 1.10-1.37, p 5 1.90 3 1024) 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.
AB - 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 3 1024) with both lacunar IS (lead SNP rs9515201: odds ratio [OR] 1.17, 95%confidence interval [CI] 1.11-1.24, p 56.62 31028) and deep ICH (lead SNP rs4771674: OR 1.28, 95%CI 1.13-1.44, p 55.76 3 1025). A SNP in HTRA1 was associated (significance threshold p , 5.5 3 1024) with lacunar IS (rs79043147: OR 1.23, 95%CI 1.10-1.37, p 5 1.90 3 1024) 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.
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U2 - 10.1212/WNL.0000000000004560
DO - 10.1212/WNL.0000000000004560
M3 - Article
C2 - 28954878
AN - SCOPUS:85031410982
VL - 89
SP - 1829
EP - 1839
JO - Neurology
JF - Neurology
SN - 0028-3878
IS - 17
ER -