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

Kristiina Rannikmäe, Gail Davies, Pippa A. Thomson, Steve Bevan, William J. Devan, Guido J. Falcone, Matthew Traylor, Christopher D. Anderson, Thomas W K Battey, Farid Radmanesh, Ranjan Deka, Jessica G. Woo, Lisa J. Martin, Jordi Jimenez-Conde, Magdy Selim, Devin L. Brown, Scott L. Silliman, Chelsea S. Kidwell, Joan Montaner, Carl D. Langefeld & 32 others Agnieszka Slowik, Björn M. Hansen, Arne G. Lindgren, James F. Meschia, Myriam Fornage, Joshua C. Bis, Stéphanie Debette, Mohammad A. Ikram, Will T. Longstreth, Reinhold Schmidt, Cathy R. Zhang, Qiong Yang, Pankaj Sharma, Steven J. Kittner, Braxton D. Mitchell, Elizabeth G. Holliday, Christopher R. Levi, John Attia, Peter M. Rothwell, Deborah L. Poole, Giorgio B. Boncoraglio, Bruce M. Psaty, Rainer Malik, Natalia Rost, Bradford B. Worrall, Martin Dichgans, Tom Van Agtmael, Daniel Woo, Hugh S. Markus, Sudha Seshadri, Jonathan Rosand, Cathie L M Sudlow

Research output: Contribution to journalArticle

48 Citations (Scopus)

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; 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.

Original languageEnglish
Pages (from-to)918-926
Number of pages9
JournalNeurology
Volume84
Issue number9
DOIs
Publication statusPublished - Mar 3 2015

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Cerebral Small Vessel Diseases
Single Nucleotide Polymorphism
Cerebral Hemorrhage
Stroke
Lacunar Stroke
Cerebrovascular Disorders
Linkage Disequilibrium
Ethnic Groups
Population
Genes
Meta-Analysis
Collagen
Genotype
Phenotype
Brain

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Rannikmäe, K., Davies, G., Thomson, P. A., Bevan, S., Devan, W. J., Falcone, G. J., ... Sudlow, C. L. M. (2015). Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Neurology, 84(9), 918-926. https://doi.org/10.1212/WNL.0000000000001309

Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. / Rannikmäe, Kristiina; Davies, Gail; Thomson, Pippa A.; Bevan, Steve; Devan, William J.; Falcone, Guido J.; Traylor, Matthew; Anderson, Christopher D.; Battey, Thomas W K; Radmanesh, Farid; Deka, Ranjan; Woo, Jessica G.; Martin, Lisa J.; Jimenez-Conde, Jordi; Selim, Magdy; Brown, Devin L.; Silliman, Scott L.; Kidwell, Chelsea S.; Montaner, Joan; Langefeld, Carl D.; Slowik, Agnieszka; Hansen, Björn M.; Lindgren, Arne G.; Meschia, James F.; Fornage, Myriam; Bis, Joshua C.; Debette, Stéphanie; Ikram, Mohammad A.; Longstreth, Will T.; Schmidt, Reinhold; Zhang, Cathy R.; Yang, Qiong; Sharma, Pankaj; Kittner, Steven J.; Mitchell, Braxton D.; Holliday, Elizabeth G.; Levi, Christopher R.; Attia, John; Rothwell, Peter M.; Poole, Deborah L.; Boncoraglio, Giorgio B.; Psaty, Bruce M.; Malik, Rainer; Rost, Natalia; Worrall, Bradford B.; Dichgans, Martin; Van Agtmael, Tom; Woo, Daniel; Markus, Hugh S.; Seshadri, Sudha; Rosand, Jonathan; Sudlow, Cathie L M.

In: Neurology, Vol. 84, No. 9, 03.03.2015, p. 918-926.

Research output: Contribution to journalArticle

Rannikmäe, K, Davies, G, Thomson, PA, Bevan, S, Devan, WJ, Falcone, GJ, Traylor, M, Anderson, CD, Battey, TWK, 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, CLM 2015, 'Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease', Neurology, vol. 84, no. 9, pp. 918-926. https://doi.org/10.1212/WNL.0000000000001309
Rannikmäe K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ et al. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Neurology. 2015 Mar 3;84(9):918-926. https://doi.org/10.1212/WNL.0000000000001309
Rannikmäe, Kristiina ; Davies, Gail ; Thomson, Pippa A. ; Bevan, Steve ; Devan, William J. ; Falcone, Guido J. ; Traylor, Matthew ; Anderson, Christopher D. ; Battey, Thomas W K ; Radmanesh, Farid ; Deka, Ranjan ; Woo, Jessica G. ; Martin, Lisa J. ; Jimenez-Conde, Jordi ; Selim, Magdy ; Brown, Devin L. ; Silliman, Scott L. ; Kidwell, Chelsea S. ; Montaner, Joan ; Langefeld, Carl D. ; Slowik, Agnieszka ; Hansen, Björn M. ; Lindgren, Arne G. ; Meschia, James F. ; Fornage, Myriam ; Bis, Joshua C. ; Debette, Stéphanie ; Ikram, Mohammad A. ; Longstreth, Will T. ; Schmidt, Reinhold ; Zhang, Cathy R. ; Yang, Qiong ; Sharma, Pankaj ; Kittner, Steven J. ; Mitchell, Braxton D. ; Holliday, Elizabeth G. ; Levi, Christopher R. ; Attia, John ; Rothwell, Peter M. ; Poole, Deborah L. ; Boncoraglio, Giorgio B. ; Psaty, Bruce M. ; Malik, Rainer ; Rost, Natalia ; Worrall, Bradford B. ; Dichgans, Martin ; Van Agtmael, Tom ; Woo, Daniel ; Markus, Hugh S. ; Seshadri, Sudha ; Rosand, Jonathan ; Sudlow, Cathie L M. / Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. In: Neurology. 2015 ; Vol. 84, No. 9. pp. 918-926.
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title = "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; 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.",
author = "Kristiina Rannikm{\"a}e and Gail Davies and Thomson, {Pippa A.} and Steve Bevan and Devan, {William J.} and Falcone, {Guido J.} and Matthew Traylor and Anderson, {Christopher D.} and Battey, {Thomas W K} and Farid Radmanesh and Ranjan Deka and Woo, {Jessica G.} and Martin, {Lisa J.} and Jordi Jimenez-Conde and Magdy Selim and Brown, {Devin L.} and Silliman, {Scott L.} and Kidwell, {Chelsea S.} and Joan Montaner and Langefeld, {Carl D.} and Agnieszka Slowik and Hansen, {Bj{\"o}rn M.} and Lindgren, {Arne G.} and Meschia, {James F.} and Myriam Fornage and Bis, {Joshua C.} and St{\'e}phanie Debette and Ikram, {Mohammad A.} and Longstreth, {Will T.} and Reinhold Schmidt and Zhang, {Cathy R.} and Qiong Yang and Pankaj Sharma and Kittner, {Steven J.} and Mitchell, {Braxton D.} and Holliday, {Elizabeth G.} and Levi, {Christopher R.} and John Attia and Rothwell, {Peter M.} and Poole, {Deborah L.} and Boncoraglio, {Giorgio B.} and Psaty, {Bruce M.} and Rainer Malik and Natalia Rost and Worrall, {Bradford B.} and Martin Dichgans and {Van Agtmael}, Tom and Daniel Woo and Markus, {Hugh S.} and Sudha Seshadri and Jonathan Rosand and Sudlow, {Cathie L M}",
year = "2015",
month = "3",
day = "3",
doi = "10.1212/WNL.0000000000001309",
language = "English",
volume = "84",
pages = "918--926",
journal = "Neurology",
issn = "0028-3878",
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TY - JOUR

T1 - Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease

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

AU - Rosand, Jonathan

AU - Sudlow, Cathie L M

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.

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