Polygenic risk scores for psychiatric, inflammatory, and cardio-metabolic traits and diseases highlight possible genetic overlaps with suicide attempt and treatment-emergent suicidal ideation

Suicide is the second leading cause of death among young people. Genetics may contribute to suicidal phenotypes and their co-occurrence in other psychiatric and medical conditions. Our study aimed to investigate the association of polygenic risk scores (PRSs) for 22 psychiatric, inflammatory, and cardio-metabolic traits and diseases with suicide attempt (SA) or treatment-worsening/emergent suicidal ideation (TWESI). PRSs were computed based on summary statistics of genome-wide association studies. Regression analyses were performed between PRSs and SA or TWESI in four clinical cohorts, including up to 3,834 individuals, and results were meta-analyzed across samples. Stratified genetic covariance analyses were performed to investigate the biology underlying cross-phenotype PRS associations. After Bonferroni correction, PRS for major depressive disorder (MDD) was positively associated with SA (p=1.7e-4). Nominal associations were shown between PRSs for coronary artery disease (CAD) (p=4.6e-3) or loneliness (p=0.009) and SA, PRSs for MDD or CAD and TWESI (p=0.033 and p=0.032, respectively). Genetic covariance between MDD and SA was shown in 35 gene sets related to drugs having anti-suicidal effects. A higher genetic liability for MDD may underlie a higher risk of SA. Further, but milder, possible modulatory factors are genetic risk for loneliness and CAD.