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

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),; Maguire, J

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

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), Maguire, J

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Publisher:: Lippincott, Williams & Wilkins
Publication Type:: Journal Article
Citation:: Neurology, 2017, 89, (17), pp. 1829-1839
Issue Date:: 2017-10-24

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Field	Value	Language
dc.contributor.author	Rannikmäe, K
dc.contributor.author	Sivakumaran, V
dc.contributor.author	Millar, H
dc.contributor.author	Malik, R
dc.contributor.author	Anderson, CD
dc.contributor.author	Chong, M
dc.contributor.author	Dave, T
dc.contributor.author	Falcone, GJ
dc.contributor.author	Fernandez-Cadenas, I
dc.contributor.author	Jimenez-Conde, J
dc.contributor.author	Lindgren, A
dc.contributor.author	Montaner, J
dc.contributor.author	O'Donnell, M
dc.contributor.author	Paré, G
dc.contributor.author	Radmanesh, F
dc.contributor.author	Rost, NS
dc.contributor.author	Slowik, A
dc.contributor.author	Söderholm, M
dc.contributor.author	Traylor, M
dc.contributor.author	Pulit, SL
dc.contributor.author	Seshadri, S
dc.contributor.author	Worrall, BB
dc.contributor.author	Woo, D
dc.contributor.author	Markus, HS
dc.contributor.author	Mitchell, BD
dc.contributor.author	Dichgans, M
dc.contributor.author	Rosand, J
dc.contributor.author	Sudlow, CLM
dc.contributor.author	Stroke Genetics Network (SiGN), METASTROKE Collaboration, and International Stroke Genetics Consortium (ISGC),
dc.contributor.author	Maguire, J https://orcid.org/0000-0001-5722-8311
dc.date.accessioned	2022-08-02T05:41:31Z
dc.date.available	2017-07-31
dc.date.available	2022-08-02T05:41:31Z
dc.date.issued	2017-10-24
dc.identifier.citation	Neurology, 2017, 89, (17), pp. 1829-1839
dc.identifier.issn	0028-3878
dc.identifier.issn	1526-632X
dc.identifier.uri	http://hdl.handle.net/10453/159487
dc.description.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.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Lippincott, Williams & Wilkins
dc.relation.ispartof	Neurology
dc.relation.isbasedon	10.1212/WNL.0000000000004560
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	1103 Clinical Sciences, 1109 Neurosciences, 1702 Cognitive Sciences
dc.subject.classification	Neurology & Neurosurgery
dc.subject.mesh	Cerebral Hemorrhage
dc.subject.mesh	Collagen Type IV
dc.subject.mesh	Europe
dc.subject.mesh	Genetic Association Studies
dc.subject.mesh	Humans
dc.subject.mesh	Polymorphism, Single Nucleotide
dc.subject.mesh	Stroke, Lacunar
dc.subject.mesh	Cerebral Hemorrhage
dc.subject.mesh	Collagen Type IV
dc.subject.mesh	Europe
dc.subject.mesh	Genetic Association Studies
dc.subject.mesh	Humans
dc.subject.mesh	Polymorphism, Single Nucleotide
dc.subject.mesh	Stroke, Lacunar
dc.subject.mesh	Humans
dc.subject.mesh	Cerebral Hemorrhage
dc.subject.mesh	Collagen Type IV
dc.subject.mesh	Polymorphism, Single Nucleotide
dc.subject.mesh	Europe
dc.subject.mesh	Genetic Association Studies
dc.subject.mesh	Stroke, Lacunar
dc.title	COL4A2 is associated with lacunar ischemic stroke and deep ICH: Meta-analyses among 21,500 cases and 40,600 controls.
dc.type	Journal Article
utslib.citation.volume	89
utslib.location.activity	United States
utslib.for	1103 Clinical Sciences
utslib.for	1109 Neurosciences
utslib.for	1702 Cognitive Sciences
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Health
utslib.copyright.status	closed_access	*
pubs.consider-herdc	false
dc.date.updated	2022-08-02T05:41:30Z
pubs.issue	17
pubs.publication-status	Published
pubs.volume	89
utslib.citation.issue	17

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.

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http://hdl.handle.net/10453/159487