Social Isolation, Social Interaction, and Neuroticism: A Mendelian Randomization Study

Objective Neuroticism, as a fundamental personality trait marked by emotional instability, anxiety, and a propensity for negative emotions, presents difficulties in elucidating its developmental underpinnings, especially in the context of its association with social factors. Concurrently, observational studies in this domain encounter various hurdles, such as confounding variables and the issue of reverse causality. This study employed Two-sample Mendelian Randomization (TSMR) to explore the genetic basis of the causal relationship between social isolation, social interaction, and neuroticism. Methods Single nucleotide polymorphisms (SNPs) associated with social isolation and social interaction were extracted from an aggregated Genome-Wide Association Study (GWAS) dataset. Instrumental variables conforming to predetermined criteria were selected. The primary TSMR analysis was conducted using the Inverse Variance-Weighted (IVW) method, complemented by robustness checks through the Weighted Median, Weighted Mode, and MR Egger methods. Heterogeneity and pleiotropy tests were performed, along with sensitivity analyses, to enhance the precision and robustness of the results. Results Among five social engagement types analyzed, loneliness (IVW Odds Ratio per Standard Deviation change: 4.230; 95% Confidence Interval: 2.081–8.599; p <0.001) and loneliness (MTAG) (IVW Odds Ratio per Standard Deviation change: 1.670; 95% Confidence Interval: 1.314–2.122; p <0.001) demonstrated a statistically significant association with increased neuroticism risk. The remaining three social engagement types showed no significant association with neuroticism risk. Conclusion The findings suggest a causal relationship between loneliness and loneliness (MTAG) and a heightened risk of neuroticism, warranting further research to understand the underlying mechanisms.