Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease.
Rannikmäe K., Davies G., Thomson PA., Bevan S., Devan WJ., Falcone GJ., Traylor M., Anderson CD., Battey TW., Radmanesh F., Deka R., Woo JG., Martin LJ., Jimenez-Conde J., Selim M., Brown DL., Silliman SL., Kidwell CS., Montaner J., Langefeld CD., Slowik A., Hansen BM., Lindgren AG., Meschia JF., Fornage M., Bis JC., Debette S., Ikram MA., Longstreth WT., Schmidt R., Zhang CR., Yang Q., Sharma P., Kittner SJ., Mitchell BD., Holliday EG., Levi CR., Attia J., Rothwell PM., Poole DL., Boncoraglio GB., Psaty BM., Malik R., Rost N., Worrall BB., Dichgans M., Van Agtmael T., Woo D., Markus HS., Seshadri S., Rosand J., Sudlow CL., METASTROKE Consortium None., CHARGE WMH Group None., ISGC ICH GWAS Study Collaboration None., WMH in Ischemic Stroke GWAS Study Collaboration None., International Stroke Genetics Consortium None.
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.