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

Rannikmaee, Kristiina; Davies, Gail; Thomson, Pippa A.; Bevan, Steve; Devan, William J.; Falcone, Guido J.; Traylor, Matthew; Anderson, Christopher D.; Battey, Thomas W. K. and Radmanesh, Farid, et al. (2015) In Neurology 84(9). p.918-926
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... (More)
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. (Less)
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Neurology
volume
84
issue
9
pages
918 - 926
publisher
American Academy of Neurology
external identifiers
  • wos:000350576700015
  • scopus:84924093050
ISSN
1526-632X
DOI
10.1212/WNL.0000000000001309
language
English
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yes
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265e7a04-fcec-4888-bb45-ae749ceb077b (old id 5296975)
date added to LUP
2015-05-04 08:31:33
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2017-11-05 04:01:28
@article{265e7a04-fcec-4888-bb45-ae749ceb077b,
  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 &lt; 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) &gt; 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.},
  author       = {Rannikmaee, Kristiina and Davies, Gail and Thomson, Pippa A. and Bevan, Steve and Devan, William J. and Falcone, Guido J. and Traylor, Matthew and Anderson, Christopher D. and Battey, Thomas W. K. and Radmanesh, Farid and Deka, Ranjan and Woo, Jessica G. and Martin, Lisa J. and Jimenez-Conde, Jordi and Selim, Magdy and Brown, Devin L. and Silliman, Scott L. and Kidwell, Chelsea S. and Montaner, Joan and Langefeld, Carl D. and Slowik, Agnieszka and Hansen, Björn and Lindgren, Arne and Meschia, James F. and Fornage, Myriam and Bis, Joshua C. and Debette, Stephanie and Ikram, Mohammad A. and Longstreth, Will T. and Schmidt, Reinhold and Zhang, Cathy R. and Yang, Qiong and Sharma, Pankaj and Kittner, Steven J. and Mitchell, Braxton D. and Holliday, Elizabeth G. and Levi, Christopher R. and Attia, John and Rothwell, Peter M. and Poole, Deborah L. and Boncoraglio, Giorgio B. and Psaty, Bruce M. and Malik, Rainer and Rost, Natalia and Worrall, Bradford B. and Dichgans, Martin and Van Agtmael, Tom and Woo, Daniel and Markus, Hugh S. and Seshadri, Sudha and Rosand, Jonathan and Sudlow, Cathie L. M.},
  issn         = {1526-632X},
  language     = {eng},
  number       = {9},
  pages        = {918--926},
  publisher    = {American Academy of Neurology},
  series       = {Neurology},
  title        = {Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease},
  url          = {http://dx.doi.org/10.1212/WNL.0000000000001309},
  volume       = {84},
  year         = {2015},
}