Exploring Genetic and Biological Interconnections Between Neuroticism, Psychological Distress, Insomnia, and C‐Reactive Protein: Insights From the UK Biobank

ABSTRACT Psychobehavioral and physical health traits often co‐occur. Although previous studies have identified associations between neuroticism, psychological distress, insomnia, and inflammatory biomarkers such as C‐reactive protein (CRP), it remains unclear whether there is a genetic basis to these associations, and which biological pathways are involved. This study aimed to explore pleiotropy between psychobehavioural and physical traits and examine underlying biological pathways. To identify shared SNPs, we applied CPASSOC SHet and genomic SEM to GWAS summary statistics from the UK Biobank (Neale Lab; N neuroticism = 293,006; N doctor visits for distress = 358,693; N insomnia = 360,738; N CRP = 358,693). Pathway enrichment analyses were done to explore relevant biological pathways based on positional and eQTL annotations. We used colocalization data to evaluate sharing of genetic signals between pairs of traits. Genetic correlations were moderate to high among neuroticism, distress visits, and insomnia, but low between CRP and each psychobehavioral trait. In the multitrait analyses, we did not observe any genomic region with genome‐wide significant variants for all traits, although we identified a few regions with markers that reached genome‐wide significance in the cross‐trait analysis and had p ‐values < 0.001 for all traits. Enrichment analysis highlighted 8p23.1, a polymorphic inversion region enriched for immune and developmental genes. Colocalization supported multiple shared causal variants among psychobehavioral traits, with limited sharing with CRP. These findings suggest that co‐occurrence between psychobehavioral and systemic inflammation traits is only weakly explained by shared common‐variant genetics, emphasizing nongenetic mechanisms.