Introduction: White matter hyperintensity (WMH) is a prominent neuroimaging phenotype commonly detected in patients with stroke as well as genetic disorders like cerebral autosomal dominant arteriopathy with subcortical infarcts and leukencephalopathy (CADASIL). We sought to identify biologically connected pathways between the genetic loci associated with WMH burden in patients with CADASIL.
Methods: We investigated a published polygenetic risk score for WMH burden in 466 CADASIL patients. Sixty-one single nucleotide polymorphisms (SNPs) with p-values of p<10-4 comprised the score. We applied GRAIL (Gene Relationships Among Implicated Loci), a statistical text-mining software to assess shared biological pathways among these SNPs. The degree of relatedness to other genes was evaluated by mining PubMed abstracts. Identified related genes were ranked and scored based on inferred functional connections and investigated for association with WMH burden in 804 ischemic stroke patients.
Results: We identified four loci (CADM1, DPP6, GCNT1 and GCNT3) which were significantly more related to other genes in the network than expected by chance (p<0.05, Figure 1). There were 304 SNPs within these loci associated with WMH burden at p<0.05 in a meta-analysis of 804 patients with ischemic stroke. Among the identified keywords were: tyrosine, core, phosphorylation, cathepsin, channels, kinase, cancer, peptidase, suppressor, activated, tumor, fragile, channel, activation, mucin, adhesion, cell and domain.
Conclusion: Biological relationships between the four identified loci suggest putative molecular pathways associated with metabolic, enzymatic, and membrane channel-based activity mediating the effect of WMH burden in CADASIL. The role of biological pathways shared between CADASIL and ischemic stroke related WMH requires further investigation.