Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease

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./n© 2015 American Academy of Neurology. Kristiina Rannikmäe is supported by the Edinburgh and Lothians Health Foundation REMIND Fund and Stroke Research and Amenities Endowments Fund; Cathie Sudlow is supported by the Scottish Funding Council; Gail Davies is supported by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1), BBSRC and Medical Research Council (MSRC). Tom Van Agtmael is supported by the Kidney Research UK project grant RP19/2012. Details of funding for the studies contributing to the ICH GWAS can be found in: Woo D, Falcone GJ, Devan WJ, et al. Meta-analysis of genome-wide association studies identifies 1q22 as a novel susceptibility locus for intracerebral hemorrhage. American Journal of Human Genetics 2014;pii: S0002-9297(14)00070-6. doi:10.1016/j.ajhg.2014.02.012. [Epub ahead of print]. Details of funding for the studies contributing to the ischaemic stroke GWAS can be found in: Traylor M, Farrall M, Holliday EG, et al. Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies. Lancet Neurology 2012;11:951-962. Details of funding for the studies contributing to the WMH in ischaemic stroke GWAS can be found in: Adib-Samii P, Rost N, Traylor M, et al. 17q25 Locus Is Associated With White Matter Hyperintensity Volume in Ischaemic Stroke, But Not With Lacunar Stroke Status. Stroke 2013;44:1609-1615. Details of funding for the studies contributing to the WMH in population GWAS can be found in: Fornage M, Debette S, Bis JC, et al. Genome-Wide Association Studies of Cerebral White Matter Lesion Burden: The CHARGE Consortium. Annals of Neurology 2011;69:928-939. Martin Dichgans is supported by the Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain); Guido J Falcone is supported by the NIH / NINDS grant P50NS061343; Chistopher D Anderson is supported by the American Brain Foundation Clinical Research Training Fellowship, NIH-NINDS K23NS086873, Massachusetts General Hospital Institute for Heart, Vascular, and Stroke Care SPARK award; Jonathan Rosand is supported by the NIH / NINDS grant R01NS059727.