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; 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

doi:10.1212/WNL.0000000000001309

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. LangefeldAgnieszka 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 journal › Article › Research › peer-review

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Abstract

© 2015 American Academy of Neurology. 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 language	English
Pages (from-to)	918-926
Journal	Neurology
Volume	84
Issue number	9
DOIs	https://doi.org/10.1212/WNL.0000000000001309
Publication status	Published - 3 Mar 2015

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Rannikmäe, K., Davies, G., Thomson, P. A., Bevan, S., Devan, W. J., Falcone, G. J., Traylor, M., Anderson, C. D., Battey, T. W. K., Radmanesh, F., Deka, R., Woo, J. G., Martin, L. J., Jimenez-Conde, J., Selim, M., Brown, D. L., Silliman, S. L., Kidwell, C. S., Montaner, 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

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.

@article{11bcde4d07324ad0b8065cb7061c0d3f,

title = "Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease",

abstract = "{\textcopyright} 2015 American Academy of Neurology. 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 = mar,

day = "3",

doi = "10.1212/WNL.0000000000001309",

language = "English",

volume = "84",

pages = "918--926",

journal = "Neurology",

issn = "0028-3878",

publisher = "Lippincott Williams and Wilkins",

number = "9",

}

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

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 journal › Article › Research › peer-review

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 - © 2015 American Academy of Neurology. 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 - © 2015 American Academy of Neurology. 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.

U2 - 10.1212/WNL.0000000000001309

DO - 10.1212/WNL.0000000000001309

M3 - Article

VL - 84

SP - 918

EP - 926

JO - Neurology

JF - Neurology

SN - 0028-3878

IS - 9

ER -

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

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