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

Abstract

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.

Figure 1. Regional association plot for deep ICH meta-analysis

Dots mark individual SNPs; y-axis: p value for association between each SNP and deep ICH; x-axis: position of SNPs. Most significantly associated SNP shown in purple; colors for other SNPs depend on linkage disequilibrium with this lead SNP (see r² color coding on figure). Recombination: exchange of a segment of DNA between 2 homologous chromosomes during meiosis leading to a novel combination of genetic material in the offspring. Recombination rate: measured as frequency of exchange per unit physical distance (centimorgan [cM]/mega base pair [Mb]). cM: unit of linkage that refers to the distance between 2 gene loci determined by the frequency with which recombination occurs between them. Two loci are said to be 1 cM apart if recombination is observed between them in 1% of meioses. Mb: a unit of length of nucleic acids, equal to 1 million base pairs. ICH = intracerebral hemorrhage; SNP = single nucleotide polymorphism.

Figure 2. Associations between the 3 SNPs significantly associated with deep ICH across all phenotypes

Figure represents pooled odds ratios across all cohorts. Significant or suggested associations in cerebral small vessel disease phenotypes are shown in red. Data for rs9521733 were unavailable in the WMH in population cohorts. CE = cardioembolic; CI = confidence interval; ICH = intracerebral hemorrhage; IS = ischemic stroke; LVD = large vessel disease; SNP = single nucleotide polymorphism; WMH = white matter hyperintensity.

Figure 3. Associations of significant single nucleotide polymorphisms across cohorts included in the meta-analysis of deep intracerebral hemorrhage

Heterogeneity: rs9521732: χ²_2df = 0.09, p = 0.9563, I² = 0%; rs9521733: χ²_2df = 0.02, p = 0.9903, I² = 0%; rs9515199: χ²_2df = 0.08, p = 0.9607, I² = 0%. CI = confidence interval; GERFHS = Genetic and Environmental Risk Factors for Hemorrhagic Stroke; GOCHA = Genetics of Cerebral Hemorrhage with Anticoagulation; ISGC = International Stroke Genetics Consortium.