RGD Reference Report - COL4A2 is associated with lacunar ischemic stroke and deep ICH: Meta-analyses among 21,500 cases and 40,600 controls. - Rat Genome Database

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

Authors: 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 
Citation: Rannikmäe K, etal., Neurology. 2017 Oct 24;89(17):1829-1839. doi: 10.1212/WNL.0000000000004560. Epub 2017 Sep 27.
RGD ID: 13450933
Pubmed: PMID:28954878   (View Abstract at PubMed)
PMCID: PMC5664302   (View Article at PubMed Central)
DOI: DOI:10.1212/WNL.0000000000004560   (Journal Full-text)


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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Cerebral Hemorrhage susceptibilityIAGP 13450933DNA:SNPs::RGD 
Cerebral Hemorrhage susceptibilityISOCOL4A2 (Homo sapiens)13450933; 13450933DNA:SNPs::RGD 
Lacunar Strokes susceptibilityIAGP 13450933DNA:SNPs::RGD 
Lacunar Strokes susceptibilityISOCOL4A2 (Homo sapiens)13450933; 13450933DNA:SNPs::RGD 

Objects Annotated

Genes (Rattus norvegicus)
Col4a2  (collagen type IV alpha 2 chain)

Genes (Mus musculus)
Col4a2  (collagen, type IV, alpha 2)

Genes (Homo sapiens)
COL4A2  (collagen type IV alpha 2 chain)


Additional Information