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.