Despite notable advances in genetic understanding of stroke recovery, most studies focus only on candidate genes. To date, only 2 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 poststroke.

We used the Vitamin Intervention for Stroke Prevention (VISP) data set of 2,100 genotyped participants with nondisabling stroke. We included only participants who 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 used logistic regression models with generalized estimating equations to leverage the repeated NIH Stroke Scale motor score measurements spanning 6 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 (OR) 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.

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 x 10^–8), our analysis detected 115 suggestive associations (p < 5 x 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 (OR 0.32; 95% CI 0.21–0.48; p value 6.19 x 10^–7). CLDN23 affects blood-brain barrier integrity, neurodevelopment, and immune cell transmigration.

We identified novel suggestive genetic associations with the first-ever motor-specific poststroke recovery GWAS. The results seem to describe a distinct stroke recovery phenotype compared with prior genetic stroke outcome studies that use outcome measures, such as the mRS. Replication and further mechanistic investigation are warranted. In addition, this study demonstrated a proof-of-principle approach to optimize statistical efficiency with longitudinal data sets for genetic discovery.

尽管对中风恢复的遗传学理解取得了显着进展，但大多数研究仅关注候选基因。迄今为止，只有 2 项全基因组关联研究 (GWAS) 关注卒中结果，但仅限于改良 Rankin 量表 (mRS)。mRS 很难映射到生物过程。因此，我们进行了 GWAS 来发现与中风后运动恢复相关的单核苷酸多态性 (SNP)。

我们使用了预防中风的维生素干预 (VISP) 数据集，该数据集包含 2,100 名患有非致残性中风的基因型参与者。我们随机分组时仅纳入有运动障碍的参与者。试验期间复发性中风的参与者被排除在外。基因分型数据经过严格的质量控制和估算。GWAS 使用具有广义估计方程的逻辑回归模型来利用 24 个月内 6 个时间点重复的 NIH 中风量表运动评分测量结果。主要结果是每个时间点运动漂移评分降低 ≥1 与 <1。我们的模型在调整年龄、性别、种族、中风到就诊的天数、初始运动评分、VISP 治疗组和主要成分后，估计了每个 SNP 运动改善的优势比 (OR)。

GWAS 共纳入了 488 名 (64%) 参与者，平均 (SD) 年龄为 66 ± 11 岁。尽管没有关联达到全基因组显着性 ( p < 5 x 10 ^–8 )，但我们的分析检测到 115 个暗示性关联 ( p < 5 x 10 ^–6 )。值得注意的是，我们在具有合理神经元修复生物学机制的基因附近发现了多个 SNP 簇。CLDN23基因与 rs1268196-T 作为其最显着的 SNP 具有最令人信服的关联（OR 0.32；95% CI 0.21–0.48；p值6.19 x 10 ^–7）。CLDN23影响血脑屏障完整性、神经发育和免疫细胞迁移。

我们发现了与首个运动特异性中风后恢复 GWAS 之间新的暗示性遗传关联。与之前使用 mRS 等结果测量的遗传性中风结果研究相比，结果似乎描述了一种独特的中风恢复表型。有必要进行复制和进一步的机制研究。此外，这项研究还展示了一种原理验证方法，可利用纵向数据集优化统计效率以进行遗传发现。