Independent and joint effects of genomic and exposomic loads for schizophrenia on psychotic experiences in adolescents of European ancestry

This study aimed to assess the independent and joint associations of genomic and exposomic liabilities for schizophrenia with distressing psychotic experiences (PEs) and their persistence in early adolescence. The Adolescent Brain and Cognitive Development Study data from children with European ancestry were used (N = 5122). The primary outcome was past-month distressing PEs at the 3-year follow-up. Secondary outcomes were distressing PEs at varying cutoffs of persistence. Multilevel logistic regression models were used to test the associations of binary modes (>75th percentile) of polygenic risk score for schizophrenia (PRS-SCZ₇₅) and exposome score for schizophrenia (ES-SCZ₇₅) on the outcomes. Relative excess risk due to interaction (RERI) calculation indicated additive interaction. When analyzed independently, PRS-SCZ₇₅ was not significantly associated with past-month distressing PEs but with lifetime (OR 1.29 [95% CI 1.08, 1.53]) and repeating distressing PEs ≥2 waves (OR 1.34 [95% CI 1.08, 1.65]); whereas, ES-SCZ₇₅ was consistently associated with all outcomes, with increasing strength of association as a function of PEs persistence (one wave: OR 2.77 [95% CI 2.31, 3.31]; two waves: OR 3.16 [95% CI 2.54, 3.93]; three waves: OR 3.93 [95% CI 2.86, 5.40]; four waves: OR 3.65 [95% CI 2.34, 5.70]). When considered jointly, ES-SCZ₇₅ and PRS-SCZ₇₅ did not additively interact to predict past-month distressing PEs but showed significant additive interactions for lifetime (RERI = 1.26 [95%CI 0.14, 2.38]) and repeating distressing PEs ≥2 waves (RERI = 1.79 [95%CI 0.35, 3.23]). Genomic and exposomic liabilities for schizophrenia were independently and jointly associated with distressing PEs and their persistence in early adolescence.