Functional and molecular characterization of suicidality factors using phenotypic and genome-wide data

Genome-wide association studies (GWAS) of suicidal thoughts and behaviors support the existence of genetic contributions. Continuous measures of psychiatric disorder symptom severity can sometimes model polygenic risk better than binarized definitions. We compared two severity measures of suicidal thoughts and behaviors at the molecular and functional levels using genome-wide data. We used summary association data from GWAS of four traits analyzed in 122,935 individuals of European ancestry: thought life was not worth living (TLNWL), thoughts of self-harm, actual self-harm, and attempted suicide. The fifth trait, suicidality, was constructed with phenotypically as an aggregate of these four traits and genetically using Genomic Structural Equation modeling. Suicidality and S-factor were compared at the level of SNP-heritability (h2), genetic correlation, partitioned h2, effect size distribution, transcriptomic effects in the brain, and cross-population polygenic scoring (PGS). The S-factor had good model fit ({chi}2=0.21, AIC=16.21, CFI=1.00, SRMR=0.024). Suicidality (h2=7.6%) had higher h2 than the S-factor (h2=2.54, Pdiff =4.78x10-13). Although the S-factor had a larger number of non-null susceptibility loci ({pi}c=0.010), these loci had small effect sizes compared to those influencing suicidality ({pi}c =0.005, Pdiff =0.045). The h2 of both traits was enrichment for conserved biological pathways. The rg and{rho} GE support highly overlapping genetic and transcriptomic features between suicidality and the S-factor. PGS using European-ancestry SNP effect sizes strongly associated with TLNWL in Admixed Americans: Nagelkerkes R2=8.56%, P=0.009 (PGSsuicidality) and Nagelkerkes R2=7.48%, P=0.045 (PGSS-factor). An aggregate suicidality phenotype was statistically more heritable than the S-factor across all analyses and may be more informative for future study genetic designs than individual suicidality indicator traits.