Independent and joint effects of genomic and exposomic loads for schizophrenia on distressing and persisting psychotic experiences in adolescence

Abstract 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 past-month 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. Competing Interest Statement 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. Funding Statement 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]) Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: 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 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present study are available upon reasonable request to the authors.