To assess the longitudinal associations of genomic and exposomic liabilities for schizophrenia, both independently and jointly, 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=5,122). The primary outcome was past-month distressing PEs at 3-year follow-up. Secondary outcomes were lifetime distressing PEs defined at varying cutoffs of persistence (from ≥ 1-4 waves). Multilevel logistic regression models were used to test the independent and joint associations of the binary modes (risk-category defined as above 75th percentile) of polygenic risk score for schizophrenia (PRS-SCZ75) and exposome score for schizophrenia (ES-SCZ75) on the outcomes. The relative excess risk due to interaction (RERI) was determined using the delta method to indicate departure additive interaction. PRS-SCZ75 was statistically significantly associated with lifetime distressing PEs (≥ 1 wave) (OR 1.29 [95% CI 1.08, 1.53]) and repeating distressing PEs ≥ 2 waves (OR 1.34 [95% CI 1.08, 1.65]) but not with pastmonth distressing PEs or repeating distressing PEs at a higher cutoff of persistence. ES-SCZ75 was consistently associated with past-month and repeating distressing PEs at all cutoffs, 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]). There was evidence for additive interaction between ES-SCZ75 and PRS-SCZ75 for lifetime distressing PEs (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, as well as their persistence in early adolescence

J. van Os and S. Guloksuz are supported by the Ophelia research project, ZonMw grant 636340001. B. Rutten was funded by a Vidi award (91718336) from the Netherlands Scientific Organisation. J. van Os, S.Guloksuz, B. Rutten, L. K. Pries and A. G. Arias Magnasco are supported by the YOUTH-GEMs project, funded by the European Union Horizon Europe program under the grant agreement number: 101057182. R. Barzilay serves on the scientific Advisory Board and holds equity in Taliaz Health, with no relevance to the current study. M. Di Vincenzo, T. Prachason, G. Sampogna, B. D. Lin and A. Fiorillo report no financial relationships with commercial interests.

This work was supported by the National Institute of Health (Grant No. U01DA041120 [to DMB]; Grant Nos. K23MH121792 and L30MH120574 [to NRK]; Grant Nos. MH109532 and DA032573 [to AA]; Grant No. F32AA027435 [to ECJ]; Grant No. T32-DA007261 [to ASH]; and Grant Nos. R01-AG045231, R01- HD083614, R01-AG052564, R21-AA027827, and R01-DA046224 [to RB])

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The Adolescent Brain Cognitive Development (ABCD) Study, from which data were used in this work, received ethical approval from the Centralized Institutional Review Board (IRB) of the University of California-San Diego and local research site IRBs

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