PATJ low frequency variants are associated with worse ischemic stroke functional outcome: a genome-wide meta-analysis

Abstract

Background: Ischemic stroke (IS) is one of the leading causes of disability in adults. Part of the great variability in functional outcome after stroke has been attributed to genetic factors. To date, no locus has been identified consistently with stroke outcome. The GODS project (Genetic contribution to functional Outcome and Disability after Stroke) was created to identify genes influencing the recovery process by undertaking an accurate phenotyping and producing the largest genome-wide association study (GWAS) in IS recovery to date. Methods: A 12 cohorts meta-analysis of GWAS was conducted (n=2,482). IS cases were included by selecting patients functionally independent before the stroke, with an anterior territory stroke, and an initial neurological severity with NIHSS≥4. A VEGAS gene-based burden test and a gene expression analysis were performed afterwards. Functional outcome at 3 months was recorded with modified Rankin Scale (mRS). Cohorts with functional outcome recorded at timepoints other than 3 months or incomplete data of previous functional status were excluded in the stringent analyses (remaining 7 cohorts, n=1,791). Analyses of association with mRS were adjusted for NIHSS, stroke subtype, age, gender, smoking status and principal components. Findings: We identified and replicated a novel locus in PATJ (rs76221407, discovery p=1.08x10-8; joint p=1.7x10-9), strongly associated with functional outcome after stroke. The gene-based analysis also revealed the PATJ locus as significantly associated with outcome. In addition, RNA-expression of PATJ at 3 months after stroke correlated significantly with the 3-month mRS score. Interpretation: Our results identify a gene associated to 3-month functional outcome after IS at genome-wide significance level. Future studies should consider stringent phenotyping to enrich the information captured to identify additional novel outcome loci.