Independent versus joint effects of polygenic or family-based schizophrenia risk in diverse ancestry youth in the ABCD study

Psychol Med. 2025 Oct 30;55:e327. doi: 10.1017/S0033291725102304.

ABSTRACT

BACKGROUND: Subtle behavioral and cognitive symptoms precede schizophrenia (SCZ) and appear in individuals with elevated risk based on polygenic risk scores (SCZ-PRS) and family history of psychosis (SCZ-FH). However, most SCZ-PRS studies focus on European ancestry youth, limiting generalizability. Furthermore, it remains unclear whether SCZ-FH reflects common-variant polygenic risk or broader SCZ liability.

METHODS: Using baseline data from the Adolescent Brain Cognitive Development (ABCD) study, we investigated associations of SCZ-FH and SCZ-PRS with cognitive, behavioral, and emotional measures from NIH-Toolbox, Child Behavior Checklist (CBCL), and Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS) for 9,636 children (mean age = 9.92 yrs, 47.4% female), specifically, 5,636 European, 2,093 African, and 1,477 Admixed American ancestry individuals.

RESULTS: SCZ-FH was associated with SCZ-PRS (b = 0.05, FDR-p = 0.02) and subthreshold psychotic symptoms (b = 0.46, FDR-p = 0.01) in European youth, higher CBCL scores (b range = 0.36-0.6, FDR-p < 0.001), and higher odds of multiple internalizing and externalizing disorders (OR = 1.10-1.22, FDR-p < 0.001) across ancestries. SCZ-PRS was associated with lower cognition across ancestries (b = -0.43, FDR-p = 0.02), higher CBCL total problems, anxious/depressed, rule-breaking and aggressive behaviors in European youth (b range = 0.16-0.33, FDR-p < 0.04), and depressive disorders in Admixed American youth (OR = 1.37, FDR-p = 0.02). Results remained consistent when SCZ-PRS and SCZ-FH were jointly modeled. Some SCZ-FH associations weakened when income-to-needs was accounted for, suggesting that SCZ-FH may capture both genetic and environmental influences.

CONCLUSIONS: SCZ-FH showed associations with broad psychopathology, while SCZ-PRS was associated with cognition and specific symptoms in European youth. Findings highlight their complementary role in SCZ risk assessment and the need to improve PRS utility across ancestries.

PMID:41165094 | DOI:10.1017/S0033291725102304