The Changing Landscape of Genetic Risk: Age-Related Effects of Polygenic Scores for Suicidal Behaviors.

Suicidal thoughts and behaviors are a persistent public health challenge. Twin studies and genome-wide association studies (GWAS) have revealed moderate genetic influences. In exploratory analyses, we evaluated whether the impact of polygenic risk scores (PRSs) for suicide ideation (SI-PRS) and attempt (SA-PRS) varied across five waves of longitudinal data from the Add Health cohort, collected between 1994-1995 (Wave 1) and 2016-2018 (Wave 5), spanning ages 12 to 43 years. We used logistic regressions and Full-Information Maximum Likelihood structural equation modeling (SEM) in OpenMx to analyze associations between PRSs and measures of ideation and attempt while adjusting for sex, socioeconomic status, and ten ancestry principal components. Logistic regressions and the exploratory autoregressive SEM revealed modest but significant associations in later waves. Both approaches converged on the SI-PRS being associated with suicidal ideation at Wave 4 (ages 24-32) and the SA-PRS being associated with suicidal ideation at Wave 5 (ages 33-43). The SA-PRS was also associated with suicide attempts at Wave 5 in the SEM. There were no significant PRS-phenotype associations at Waves 1-3 (corresponding to adolescence and the transition to young adulthood). Our findings suggest that current PRSs, which are based primarily on adult GWAS samples, have stronger effect sizes during young adulthood and early mid-life rather than adolescence. Results highlight the need for expanded GWAS efforts that include age-stratified GWAS to capture developmental-specific genetic risks, which could better inform targeted prevention strategies.