TY - JOUR
T1 - Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease
AU - METASTROKE Consortium
AU - CHARGE WMH Group
AU - ISGC ICH GWAS Study Collaboration
AU - WMH in Ischemic Stroke GWAS Study Collaboration
AU - International Stroke Genetics Consortium
AU - Rannikmäe, Kristiina
AU - Davies, Gail
AU - Thomson, Pippa A.
AU - Bevan, Steve
AU - Devan, William J.
AU - Falcone, Guido J.
AU - Traylor, Matthew
AU - Anderson, Christopher D.
AU - Battey, Thomas W.K.
AU - Radmanesh, Farid
AU - Deka, Ranjan
AU - Woo, Jessica G.
AU - Martin, Lisa J.
AU - Jimenez-Conde, Jordi
AU - Selim, Magdy
AU - Brown, Devin L.
AU - Silliman, Scott L.
AU - Kidwell, Chelsea S.
AU - Montaner, Joan
AU - Langefeld, Carl D.
AU - Slowik, Agnieszka
AU - Hansen, Björn M.
AU - Lindgren, Arne G.
AU - Meschia, James F.
AU - Fornage, Myriam
AU - Bis, Joshua C.
AU - Debette, Stéphanie
AU - Ikram, Mohammad A.
AU - Longstreth, Will T.
AU - Schmidt, Reinhold
AU - Zhang, Cathy R.
AU - Yang, Qiong
AU - Sharma, Pankaj
AU - Kittner, Steven J.
AU - Mitchell, Braxton D.
AU - Holliday, Elizabeth G.
AU - Levi, Christopher R.
AU - Attia, John
AU - Rothwell, Peter M.
AU - Poole, Deborah L.
AU - Boncoraglio, Giorgio B.
AU - Psaty, Bruce M.
AU - Malik, Rainer
AU - Rost, Natalia
AU - Worrall, Bradford B.
AU - Dichgans, Martin
AU - Van Agtmael, Tom
AU - Woo, Daniel
AU - Markus, Hugh S.
AU - Seshadri, Sudha
N1 - Publisher Copyright:
© 2015 American Academy of Neurology.
PY - 2015/3/3
Y1 - 2015/3/3
N2 - 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; r2 > 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.
AB - 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; r2 > 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.
UR - https://www.scopus.com/pages/publications/84924093050
U2 - 10.1212/WNL.0000000000001309
DO - 10.1212/WNL.0000000000001309
M3 - Article
C2 - 25653287
AN - SCOPUS:84924093050
SN - 0028-3878
VL - 84
SP - 918
EP - 926
JO - Neurology
JF - Neurology
IS - 9
ER -