Independent versus joint effects of polygenic or family-based schizophrenia risk in diverse ancestry youth in the ABCD study.
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| 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
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| Journal | Psychological medicine
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| Volume | 55
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| Pages | e327
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| Date Published | 10/2025
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| ISSN | 1469-8978
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| DOI | 10.1017/S0033291725102304
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| PubMed ID | 41165094
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