Enlarged Perivascular Spaces (EPVS) and the Risk of Amyotrophic Lateral Sclerosis (ALS): Evidence for Overlapping Genetic Signals in White Matter Without Causal Links

<b>Background/Objectives</b>: Emerging evidence suggests that enlarged perivascular spaces (EPVS), which play a significant role in brain fluid exchange and waste removal, may be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). In this study, we aimed to explore the shared genetic link and causal effect between EPVS and ALS. <b>Methods</b>: This study used publicly available summary data from the largest and most recent genome-wide association studies (GWAS) on EPVS (<i>n</i> = 40,095) and ALS (<i>n</i> = 138,086) in European populations. EPVS were assessed in the hippocampus (EPVS-HIP), basal ganglia (EPVS-BG), and white matter (EPVS-WM). We used linkage disequilibrium score regression (LDSC) to investigate the genetic correlation. Multi-trait analysis of GWAS (MTAG), Cross-Phenotype Association (CPASSOC) analysis, and genetic colocalization analysis were performed to identify shared risk loci. Bidirectional Mendelian randomization analysis was used to investigate the causal relationship. <b>Results</b>: A negative genetic correlation was observed between EPVS-WM and ALS after Bonferroni correction (rg = -0.24, <i>p</i> < 0.01). No significant correlations were observed between ALS and EPVS-HIP (rg = -0.03, <i>p</i> = 0.79) or EPVS-BG (rg = 0.01, <i>p</i> = 0.91). Four significant loci including rs113247976 in <i>KIF5A</i> and rs118082508 in <i>SDR9C7</i> were identified as potential pleiotropic loci of the relationship. None of these loci demonstrated evidence of genetic colocalization. Furthermore, Mendelian randomization analysis revealed no causative effect in either direction. <b>Conclusions</b>: EPVS-WM and ALS may share part of their genetic architecture, but no evidence for a causal relationship was observed. Future research is needed to further refine these relationships.