Neuroticism and cerebral small vessel disease: A genetic correlation and Mendelian randomization analysis

The association of neuroticism and cerebral small vessel disease (CSVD) development remains unclear. In this study, we used Mendelian randomization (MR) to explore the potential role of neuroticism in CSVD development.

We collected data on ischemic stroke (IS); small vessel stroke (SVS); three neuroimaging markers altered in CSVD, including white matter hyperintensity (WMH), fractional anisotropy (FA), and mean diffusivity (MD); and three neuroticism clusters, including depressed affect, worry, sensitivity to environmental stress and adversity (SESA), from large-scale genome-wide association studies (GWAS). Bidirectional MR analyses were used to evaluate the association between neuroticism and CSVD, primarily estimated using the inverse variance weighted (IVW) method. The linkage disequilibrium score (LDSC) regression was employed to assess the association between various phenotypes.

LDSC analysis unveiled a noteworthy genetic correlation between depressed affect and IS (rg = 0.111, p = 0.001) as well as between worry and SVS (rg = -0.111, p = 0.032). Our study revealed a causal correlation between SESA and FA using both forward and reverse MR analyses (SESA on FA, odds ratio (OR) = 0.186 (0.071 to 0.483), p = 5.50 × 10^-4; FA on SESA, OR = 0.996 (0.9916 to 0.9997), p = 0.035). Meanwhile, FA also exerted a statistical causal influence on depressed affect cluster (OR = 0.992 (0.987 to 0.997), p = 0.001).

This research suggests a potential correlation between certain aspects of neuroticism and CSVD, with further studies needed to better understand the causal relationship and its implications for patient intervention.