Neurology. 2023 Oct 9:10.1212/WNL.0000000000207716. doi: 10.1212/WNL.0000000000207716. Online ahead of print.
ABSTRACT
BACKGROUND AND OBJECTIVES: Despite notable advances in genetic understanding of stroke recovery, most studies focus only on candidate genes. To date, only two genome-wide association studies (GWAS) have focused on stroke outcomes but they were limited to the modified Rankin Scale (mRS). The mRS maps poorly to biological processes. Therefore, we performed a GWAS to discover single nucleotide polymorphisms (SNPs) associated with motor recovery post-stroke.
METHODS: We used the Vitamin Intervention for Stroke Prevention (VISP) dataset of 2,100 genotyped participants with non-disabling stroke. We included only participants that had motor impairment at randomization. Participants with a recurrent stroke during the trial were excluded. Genotyped data underwent strict quality control and imputation. The GWAS utilized logistic regression models with generalized estimating equations (GEE) to leverage the repeated NIH Stroke Scale (NIHSS) motor score measurements spanning six time points over 24 months. The primary outcome was a decrease in the motor drift score of ≥1 vs <1 at each time point. Our model estimated the odds ratio of motor improvement for each SNP after adjusting for age, sex, race, days from stroke to visit, initial motor score, VISP treatment arm, and principal components.
RESULTS: A total of 488 (64%) participants with a mean (SD) age of 66 +/- 11 years were included in the GWAS. Although no associations reached genome-wide significance (p<5×10-8), our analysis detected 115 suggestive associations (p<5×10-6). Notably, we found multiple SNP clusters near genes with plausible neuronal repair biology mechanisms. The CLDN23 gene had the most convincing association with rs1268196-T as its most significant SNP (odds ratio 0.32; 95% CI 0.21, 0.48; pvalue 6.19×10-7). CLDN23 affects blood-brain barrier integrity, neurodevelopment, and immune cell transmigration.
CONCLUSION: We identified novel suggestive genetic associations with the first-ever motor-specific post-stroke recovery GWAS. The results seem to describe a distinct stroke recovery phenotype compared to prior genetic stroke outcome studies that use outcome measures, like the mRS. Replication and further mechanistic investigation are warranted. Additionally, this study demonstrated a proof-of-principle approach to optimize statistical efficiency with longitudinal datasets for genetic discovery.
PMID:37813584 | DOI:10.1212/WNL.0000000000207716