COL4A2 is associated with lacunar ischemic stroke and deep ICH: Meta-analyses among 21,500 cases and 40,600 controls

Kristiina Rannikmäe, Vhinoth Sivakumaran, Henry Millar, Rainer Malik, Christopher D Anderson, Mike Chong, Tushar Dave, Guido J Falcone, Israel Fernandez-Cadenas, Jordi Jimenez-Conde, Arne Lindgren, Joan Montaner, Martin O'Donnell, Guillaume Paré, Farid Radmanesh, Natalia S Rost, Agnieszka Slowik, Martin Söderholm, Matthew Traylor, Sara L Pulit & 10 others Sudha Seshadri, Brad B Worrall, Daniel Woo, Hugh S Markus, Braxton D Mitchell, Martin Dichgans, Jonathan Rosand, Cathie L M Sudlow, Stroke Genetics Network (SiGN), METASTROKE Collaboration, and International Stroke Genetics Consortium (ISGC), Simon Koblar

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

OBJECTIVE: To determine whether common variants in familial cerebral small vessel disease (SVD) genes confer risk of sporadic cerebral SVD.

METHODS: We meta-analyzed genotype data from individuals of European ancestry to determine associations of common single nucleotide polymorphisms (SNPs) in 6 familial cerebral SVD genes (COL4A1, COL4A2, NOTCH3, HTRA1, TREX1, and CECR1) with intracerebral hemorrhage (ICH) (deep, lobar, all; 1,878 cases, 2,830 controls) and ischemic stroke (IS) (lacunar, cardioembolic, large vessel disease, all; 19,569 cases, 37,853 controls). We applied data quality filters and set statistical significance thresholds accounting for linkage disequilibrium and multiple testing.

RESULTS: A locus in COL4A2 was associated (significance threshold p < 3.5 × 10-4) with both lacunar IS (lead SNP rs9515201: odds ratio [OR] 1.17, 95% confidence interval [CI] 1.11-1.24, p = 6.62 × 10-8) and deep ICH (lead SNP rs4771674: OR 1.28, 95% CI 1.13-1.44, p = 5.76 × 10-5). A SNP in HTRA1 was associated (significance threshold p < 5.5 × 10-4) with lacunar IS (rs79043147: OR 1.23, 95% CI 1.10-1.37, p = 1.90 × 10-4) and less robustly with deep ICH. There was no clear evidence for association of common variants in either COL4A2 or HTRA1 with non-SVD strokes or in any of the other genes with any stroke phenotype.

CONCLUSIONS: These results provide evidence of shared genetic determinants and suggest common pathophysiologic mechanisms of distinct ischemic and hemorrhagic cerebral SVD stroke phenotypes, offering new insights into the causal mechanisms of cerebral SVD.

LanguageEnglish
Pages1829-1839
Number of pages11
JournalNeurology
Volume89
Issue number17
DOIs
Publication statusPublished - 24 Oct 2017

Keywords

  • Cerebral Hemorrhage
  • Collagen Type IV
  • Europe
  • Genetic Association Studies
  • Humans
  • Polymorphism, Single Nucleotide
  • Stroke, Lacunar
  • Journal Article
  • Meta-Analysis

Cite this

Rannikmäe, Kristiina ; Sivakumaran, Vhinoth ; Millar, Henry ; Malik, Rainer ; Anderson, Christopher D ; Chong, Mike ; Dave, Tushar ; Falcone, Guido J ; Fernandez-Cadenas, Israel ; Jimenez-Conde, Jordi ; Lindgren, Arne ; Montaner, Joan ; O'Donnell, Martin ; Paré, Guillaume ; Radmanesh, Farid ; Rost, Natalia S ; Slowik, Agnieszka ; Söderholm, Martin ; Traylor, Matthew ; Pulit, Sara L ; Seshadri, Sudha ; Worrall, Brad B ; Woo, Daniel ; Markus, Hugh S ; Mitchell, Braxton D ; Dichgans, Martin ; Rosand, Jonathan ; Sudlow, Cathie L M ; Stroke Genetics Network (SiGN), METASTROKE Collaboration, and International Stroke Genetics Consortium (ISGC) ; Koblar, Simon. / COL4A2 is associated with lacunar ischemic stroke and deep ICH : Meta-analyses among 21,500 cases and 40,600 controls. In: Neurology. 2017 ; Vol. 89, No. 17. pp. 1829-1839.
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title = "COL4A2 is associated with lacunar ischemic stroke and deep ICH: Meta-analyses among 21,500 cases and 40,600 controls",
abstract = "OBJECTIVE: To determine whether common variants in familial cerebral small vessel disease (SVD) genes confer risk of sporadic cerebral SVD.METHODS: We meta-analyzed genotype data from individuals of European ancestry to determine associations of common single nucleotide polymorphisms (SNPs) in 6 familial cerebral SVD genes (COL4A1, COL4A2, NOTCH3, HTRA1, TREX1, and CECR1) with intracerebral hemorrhage (ICH) (deep, lobar, all; 1,878 cases, 2,830 controls) and ischemic stroke (IS) (lacunar, cardioembolic, large vessel disease, all; 19,569 cases, 37,853 controls). We applied data quality filters and set statistical significance thresholds accounting for linkage disequilibrium and multiple testing.RESULTS: A locus in COL4A2 was associated (significance threshold p < 3.5 × 10-4) with both lacunar IS (lead SNP rs9515201: odds ratio [OR] 1.17, 95{\%} confidence interval [CI] 1.11-1.24, p = 6.62 × 10-8) and deep ICH (lead SNP rs4771674: OR 1.28, 95{\%} CI 1.13-1.44, p = 5.76 × 10-5). A SNP in HTRA1 was associated (significance threshold p < 5.5 × 10-4) with lacunar IS (rs79043147: OR 1.23, 95{\%} CI 1.10-1.37, p = 1.90 × 10-4) and less robustly with deep ICH. There was no clear evidence for association of common variants in either COL4A2 or HTRA1 with non-SVD strokes or in any of the other genes with any stroke phenotype.CONCLUSIONS: These results provide evidence of shared genetic determinants and suggest common pathophysiologic mechanisms of distinct ischemic and hemorrhagic cerebral SVD stroke phenotypes, offering new insights into the causal mechanisms of cerebral SVD.",
keywords = "Cerebral Hemorrhage, Collagen Type IV, Europe, Genetic Association Studies, Humans, Polymorphism, Single Nucleotide, Stroke, Lacunar, Journal Article, Meta-Analysis",
author = "Kristiina Rannikm{\"a}e and Vhinoth Sivakumaran and Henry Millar and Rainer Malik and Anderson, {Christopher D} and Mike Chong and Tushar Dave and Falcone, {Guido J} and Israel Fernandez-Cadenas and Jordi Jimenez-Conde and Arne Lindgren and Joan Montaner and Martin O'Donnell and Guillaume Par{\'e} and Farid Radmanesh and Rost, {Natalia S} and Agnieszka Slowik and Martin S{\"o}derholm and Matthew Traylor and Pulit, {Sara L} and Sudha Seshadri and Worrall, {Brad B} and Daniel Woo and Markus, {Hugh S} and Mitchell, {Braxton D} and Martin Dichgans and Jonathan Rosand and Sudlow, {Cathie L M} and {Stroke Genetics Network (SiGN), METASTROKE Collaboration, and International Stroke Genetics Consortium (ISGC)} and Simon Koblar",
note = "{\circledC} 2017 American Academy of Neurology.",
year = "2017",
month = "10",
day = "24",
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language = "English",
volume = "89",
pages = "1829--1839",
journal = "Neurology",
issn = "0028-3878",
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Rannikmäe, K, Sivakumaran, V, Millar, H, Malik, R, Anderson, CD, Chong, M, Dave, T, Falcone, GJ, Fernandez-Cadenas, I, Jimenez-Conde, J, Lindgren, A, Montaner, J, O'Donnell, M, Paré, G, Radmanesh, F, Rost, NS, Slowik, A, Söderholm, M, Traylor, M, Pulit, SL, Seshadri, S, Worrall, BB, Woo, D, Markus, HS, Mitchell, BD, Dichgans, M, Rosand, J, Sudlow, CLM, Stroke Genetics Network (SiGN), METASTROKE Collaboration, and International Stroke Genetics Consortium (ISGC) & Koblar, S 2017, 'COL4A2 is associated with lacunar ischemic stroke and deep ICH: Meta-analyses among 21,500 cases and 40,600 controls', Neurology, vol. 89, no. 17, pp. 1829-1839. https://doi.org/10.1212/WNL.0000000000004560

COL4A2 is associated with lacunar ischemic stroke and deep ICH : Meta-analyses among 21,500 cases and 40,600 controls. / Rannikmäe, Kristiina; Sivakumaran, Vhinoth; Millar, Henry; Malik, Rainer; Anderson, Christopher D; Chong, Mike; Dave, Tushar; Falcone, Guido J; Fernandez-Cadenas, Israel; Jimenez-Conde, Jordi; Lindgren, Arne; Montaner, Joan; O'Donnell, Martin; Paré, Guillaume; Radmanesh, Farid; Rost, Natalia S; Slowik, Agnieszka; Söderholm, Martin; Traylor, Matthew; Pulit, Sara L; Seshadri, Sudha; Worrall, Brad B; Woo, Daniel; Markus, Hugh S; Mitchell, Braxton D; Dichgans, Martin; Rosand, Jonathan; Sudlow, Cathie L M; Stroke Genetics Network (SiGN), METASTROKE Collaboration, and International Stroke Genetics Consortium (ISGC) ; Koblar, Simon.

In: Neurology, Vol. 89, No. 17, 24.10.2017, p. 1829-1839.

Research output: Contribution to journalArticle

TY - JOUR

T1 - COL4A2 is associated with lacunar ischemic stroke and deep ICH

T2 - Neurology

AU - Rannikmäe, Kristiina

AU - Sivakumaran, Vhinoth

AU - Millar, Henry

AU - Malik, Rainer

AU - Anderson, Christopher D

AU - Chong, Mike

AU - Dave, Tushar

AU - Falcone, Guido J

AU - Fernandez-Cadenas, Israel

AU - Jimenez-Conde, Jordi

AU - Lindgren, Arne

AU - Montaner, Joan

AU - O'Donnell, Martin

AU - Paré, Guillaume

AU - Radmanesh, Farid

AU - Rost, Natalia S

AU - Slowik, Agnieszka

AU - Söderholm, Martin

AU - Traylor, Matthew

AU - Pulit, Sara L

AU - Seshadri, Sudha

AU - Worrall, Brad B

AU - Woo, Daniel

AU - Markus, Hugh S

AU - Mitchell, Braxton D

AU - Dichgans, Martin

AU - Rosand, Jonathan

AU - Sudlow, Cathie L M

AU - Stroke Genetics Network (SiGN), METASTROKE Collaboration, and International Stroke Genetics Consortium (ISGC)

AU - Koblar, Simon

N1 - © 2017 American Academy of Neurology.

PY - 2017/10/24

Y1 - 2017/10/24

N2 - OBJECTIVE: To determine whether common variants in familial cerebral small vessel disease (SVD) genes confer risk of sporadic cerebral SVD.METHODS: We meta-analyzed genotype data from individuals of European ancestry to determine associations of common single nucleotide polymorphisms (SNPs) in 6 familial cerebral SVD genes (COL4A1, COL4A2, NOTCH3, HTRA1, TREX1, and CECR1) with intracerebral hemorrhage (ICH) (deep, lobar, all; 1,878 cases, 2,830 controls) and ischemic stroke (IS) (lacunar, cardioembolic, large vessel disease, all; 19,569 cases, 37,853 controls). We applied data quality filters and set statistical significance thresholds accounting for linkage disequilibrium and multiple testing.RESULTS: A locus in COL4A2 was associated (significance threshold p < 3.5 × 10-4) with both lacunar IS (lead SNP rs9515201: odds ratio [OR] 1.17, 95% confidence interval [CI] 1.11-1.24, p = 6.62 × 10-8) and deep ICH (lead SNP rs4771674: OR 1.28, 95% CI 1.13-1.44, p = 5.76 × 10-5). A SNP in HTRA1 was associated (significance threshold p < 5.5 × 10-4) with lacunar IS (rs79043147: OR 1.23, 95% CI 1.10-1.37, p = 1.90 × 10-4) and less robustly with deep ICH. There was no clear evidence for association of common variants in either COL4A2 or HTRA1 with non-SVD strokes or in any of the other genes with any stroke phenotype.CONCLUSIONS: These results provide evidence of shared genetic determinants and suggest common pathophysiologic mechanisms of distinct ischemic and hemorrhagic cerebral SVD stroke phenotypes, offering new insights into the causal mechanisms of cerebral SVD.

AB - OBJECTIVE: To determine whether common variants in familial cerebral small vessel disease (SVD) genes confer risk of sporadic cerebral SVD.METHODS: We meta-analyzed genotype data from individuals of European ancestry to determine associations of common single nucleotide polymorphisms (SNPs) in 6 familial cerebral SVD genes (COL4A1, COL4A2, NOTCH3, HTRA1, TREX1, and CECR1) with intracerebral hemorrhage (ICH) (deep, lobar, all; 1,878 cases, 2,830 controls) and ischemic stroke (IS) (lacunar, cardioembolic, large vessel disease, all; 19,569 cases, 37,853 controls). We applied data quality filters and set statistical significance thresholds accounting for linkage disequilibrium and multiple testing.RESULTS: A locus in COL4A2 was associated (significance threshold p < 3.5 × 10-4) with both lacunar IS (lead SNP rs9515201: odds ratio [OR] 1.17, 95% confidence interval [CI] 1.11-1.24, p = 6.62 × 10-8) and deep ICH (lead SNP rs4771674: OR 1.28, 95% CI 1.13-1.44, p = 5.76 × 10-5). A SNP in HTRA1 was associated (significance threshold p < 5.5 × 10-4) with lacunar IS (rs79043147: OR 1.23, 95% CI 1.10-1.37, p = 1.90 × 10-4) and less robustly with deep ICH. There was no clear evidence for association of common variants in either COL4A2 or HTRA1 with non-SVD strokes or in any of the other genes with any stroke phenotype.CONCLUSIONS: These results provide evidence of shared genetic determinants and suggest common pathophysiologic mechanisms of distinct ischemic and hemorrhagic cerebral SVD stroke phenotypes, offering new insights into the causal mechanisms of cerebral SVD.

KW - Cerebral Hemorrhage

KW - Collagen Type IV

KW - Europe

KW - Genetic Association Studies

KW - Humans

KW - Polymorphism, Single Nucleotide

KW - Stroke, Lacunar

KW - Journal Article

KW - Meta-Analysis

U2 - 10.1212/WNL.0000000000004560

DO - 10.1212/WNL.0000000000004560

M3 - Article

VL - 89

SP - 1829

EP - 1839

JO - Neurology

JF - Neurology

SN - 0028-3878

IS - 17

ER -