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

Psychological medicine
Authors
Keywords
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 ( = 0.05, FDR- = 0.02) and subthreshold psychotic symptoms ( = 0.46, FDR- = 0.01) in European youth, higher CBCL scores ( range = 0.36-0.6, FDR- < 0.001), and higher odds of multiple internalizing and externalizing disorders (OR = 1.10-1.22, FDR- < 0.001) across ancestries. SCZ-PRS was associated with lower cognition across ancestries ( = -0.43, FDR- = 0.02), higher CBCL total problems, anxious/depressed, rule-breaking and aggressive behaviors in European youth ( range = 0.16-0.33, FDR- < 0.04), and depressive disorders in Admixed American youth (OR = 1.37, FDR- = 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.

Year of Publication
2025
Journal
Psychological medicine
Volume
55
Pages
e327
Date Published
10/2025
ISSN
1469-8978
DOI
10.1017/S0033291725102304
PubMed ID
41165094
Links