Rare Variant Association Analysis Uncovers Involvement of VNN2 in Stroke Outcome

BACKGROUNDA strokes functional outcome presents vast variability among patients, which is influenced by age, sex, characteristics of the lesion, and genetic factors. However, there is very little knowledge about stroke recovery genetics. Recently, some GWAS (Genome-Wide Association Studies) have highlighted the involvement of common or low-frequency variants near or within PATJ, PPP1R21, PTCH1, NTN4 and TEK genes, whereas the role of rare variants is still unclear. This study aims to identify the genetic contributions to differences in stroke outcome analyzing the effect of rare variants. METHODSWe performed a pilot study analyzing 90 exomes of extreme good or bad recovery (modified Rankin Scale (mRS) at 3 months 0-1 vs 4-5) to select target genes involved in stroke recovery. To expand this study, 702 additional samples were sequenced by Targeted Next-Generation Sequencing capturing loci selected from the pilot study, GWAS studies and literature input. Here, we performed continuous (mRS 0-6) and dichotomous (mRS 0-1 vs 3-6) analyses, yielding one candidate gene. Protein structure and stability analysis were performed on selected variants. RESULTSOur work identified rare coding variants in VNN2 associated with patients with a better stroke recovery ({Delta}DIC > 10, equivalent to p-value < 0.001). Six rare variants were predicted to significantly affect protein stability ({Delta}{Delta}G > 1.6 kcal/mol), meanwhile, another variant, located in the active site, could affect the electrostatic surface. CONCLUSIONSVNN2 could play a role in post-stroke inflammation altering the cell adhesion and migration of neutrophils during recovery.