Attention-mediated genetic influences on psychotic symptomatology in adolescence

Attention problems are among the earliest precursors of schizophrenia (SCZ). Here we examine relationships between multi-trait polygenic scores (PGS), psychotic spectrum symptoms, and attention-related phenotypes in an adolescent cohort (ABCD; n=11,855, mean baseline age: 9.93). Across three biennial visits, greater attentional variability and altered functional connectivity were associated with severity of psychotic-like experiences (PLEs). In European ancestry youth, neuropsychiatric and cognitive PGS were associated with greater PLE severity and greater attentional variability; notably, the effect of multi-trait PGS on PLEs weakened over time. Attentional variability partially mediated relationships between multi-trait PGS and PLEs, explaining 4-16% of these associations. Lastly, multi-trait PGS parsed by developmental co-expression patterns were significantly associated with greater PLE severity, though effect sizes were larger for genome-wide PGS. Findings suggest that broad neurodevelopmental liability is implicated in pathophysiology of psychotic spectrum symptomatology in adolescence, and attentional variability may act as an intermediate between risk variants and symptom expression. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the National Institute of Mental Health (K23 MH121792-01 to NRK, K01 1K01MH135289-01 to LMH, R01MH124694 to JLR, K08MH118577 to JKF, R01MH129858 to CEB). The ABCD Study is supported by the National Institutes of Health and additional federal partners via the following awards: U01DA041048, U01DA050989, U01DA051016, U01DA041022, U01DA051018, U01DA051037, U01DA050987, U01DA041174, U01DA041106, U01DA041117, U01DA041028, U01DA041134, U01DA050988, U01DA051039, U01DA041156, U01DA041025, U01DA041120, U01DA051038, U01DA041148, U01DA041093, U01DA041089, U24DA041123 and U24DA041147. ### 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 Institutional Review Board at the University of California, Los Angeles, gave ethical approval for this work. 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 The ABCD measures used in this article can be found at . The GWAS summary statistics for major psychiatric disorders are available through the Psychiatric Genomics Consortium site: . Those for cognitive performance are available through the Social Science Genetic Association Consortium site: .