Attention-mediated genetic influences on psychotic symptomatology in adolescence

Abstract

Attention problems are among the earliest precursors of schizophrenia. In this longitudinal cohort study, we examine relationships between cognitive and neuropsychiatric polygenic scores (PGSs), psychosis-spectrum symptoms and attention-related phenotypes in adolescence (ABCD; n = 11,855; mean baseline age 9.93 ± 0.6). 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 PGSs were associated with greater PLE severity (R2 = 0.026–0.035) and greater attentional variability (R2 = 0.100–0.109). Notably, the effect of broad neurodevelopmental PGS on PLEs weakened over time, whereas schizophrenia PGS did not. Attentional variability partially mediated relationships between multiple PGSs and PLEs, explaining 4–16% of these associations. Finally, PGSs parsed by developmental coexpression modules were significantly associated with PLE severity, though effect sizes were larger for genome-wide PGSs. Findings implicate broad neurodevelopmental liability in the pathophysiology of psychosis-spectrum symptomatology in adolescence; attentional variability may link risk variants to symptoms. Using data from the Adolescent Brain Cognitive Development Study, the authors find an association between neuropsychiatric and cognitive polygenic scores and psychotic-like experience severity, and reveal a mediating role of attentional variability.