Genome-wide association study links COL6A6 and PIK3R4 to delayed cerebral ischaemia
Joan Jiménez-Balado1, Marc Arreaza-Baena1, Mark K Bakker2
1Neurovascular Research Lab, Hospital del Mar Research Institute, 08003, Barcelona, Spain.
Insights
A genome-wide study identified a significant genetic variant, rs7636350, associated with increased risk of delayed cerebral ischaemia (DCI) after aneurysmal subarachnoid haemorrhage (aSAH). This finding implicates COL6A6 and PIK3R4 genes in DCI pathophysiology.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Delayed cerebral ischaemia (DCI) is a significant complication following aneurysmal subarachnoid haemorrhage (aSAH), leading to poor clinical outcomes.
- The precise mechanisms underlying DCI remain incompletely understood, necessitating further genetic investigation.
Purpose of the Study:
- To conduct a genome-wide association study (GWAS) to identify genetic variants associated with DCI in aSAH patients.
- To explore the functional implications of identified variants, including gene expression (eQTLs) and DNA methylation (mQTLs).
- To investigate potential genetic overlaps between DCI, ischaemic stroke, and intracranial aneurysms.
Main Methods:
- A two-stage, multicentre GWAS was performed on European ancestry aSAH patients with and without DCI.
- Meta-analysis combined data from both stages.
- Post-GWAS analyses included eQTL and mQTL analyses, methylation validation, and genetic correlation with stroke and aneurysm GWAS data.
Main Results:
- One genome-wide significant variant, rs7636350, was associated with an increased risk of DCI (P=4.47×10⁻⁸).
- This variant is located near the COL6A6 and PIK3R4 genes.
- Functional analyses revealed an eQTL for PIK3R4 and an mQTL for cg23181900 within COL6A6; hypermethylation at cg23181900 correlated with DCI.
- Genetic correlation analyses indicated links with ischaemic stroke and intracranial aneurysm.
Conclusions:
- A novel genome-wide significant locus implicating COL6A6 and PIK3R4 was identified for DCI risk after aSAH.
- Evidence suggests a regulatory role for DNA methylation at cg23181900.
- These findings advance the understanding of DCI pathophysiology and may guide future therapeutic strategies.
Abstract:
Delayed cerebral ischaemia (DCI) is a major determinant of poor clinical outcome after aneurysmal subarachnoid haemorrhage (aSAH), but its underlying mechanisms are not fully understood. We aimed to perform a genome-wide association study (GWAS) in aSAH patients with and without DCI. We conducted a multicentre study of European ancestry within the International Stroke Genetics Consortium with two stages: Stage 1 (n = 1,085; four centres) and Stage 2 (n = 801; one centre). A GWAS meta-analysis was performed across both stages. We then examined whether variants associated with DCI were linked to differences in gene expression (expression quantitative trait loci, eQTLs) or DNA methylation (methylation quantitative trait loci, mQTLs) and validated the methylation findings in an aSAH cohort with available DNA methylation data (n = 344). We performed complementary postGWAS analysis in order to promote biological interpretation of the genome-wide findings, including the genetic overlap with ischaemic stroke and intracranial aneurysm (ruptured and unruptured) using publicly available published GWAS summary statistics. Among 1,879 patients with DCI data, the prevalence of DCI was 22.8% (428/1,879). In the meta-analysis across both stages, we identified one genome-wide significant variant, rs7636350 (Chr3:130328911:T:C), associated with an increased risk of DCI (additive OR 1.75 [95% CI 1.43-2.13], P=4.47×10⁻⁸). This variant mapped near the COL6A6 and PIK3R4 genes. Functional annotation revealed one significant eQTL for PIK3R4 and one mQTL for cg23181900, located within COL6A6. Hypermethylation at cg23181900 was associated with DCI in a cohort with DNA methylation data (logFC=0.016, 95% CI 0.002-0.032; P=0.0317). Genetic correlation analyses showed a marginal correlation with ischaemic stroke due to large artery atherosclerosis (r=0.172; P=0.0508) and a higher correlation with intracranial aneurysm (r=0.341; P=0.002). We identified a genome-wide significant locus associated with DCI after aSAH, implicating COL6A6 and PIK3R4. We additionally identified an mQTL at cg23181900, suggesting a regulatory link at this locus. These findings enhance our understanding of DCI pathophysiology and support further studies to clarify causality and determine whether these pathways may inform future therapeutic strategies.
