Independent Versus Joint Effects of Polygenic or Family-Based Schizophrenia Risk in Diverse Ancestry Youth in the ABCD Study
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Background
Subtle behavioral and cognitive symptoms often precede schizophrenia (SCZ) onset and are found in individuals with elevated risk for SCZ based on family history (SCZ-FH) and polygenic risk scores (SCZ-PRS). 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.
Method
Using baseline data from the Adolescent Brain Cognitive Development (ABCD) study, we investigated associations of a continuous SCZ-FH measure and SCZ-PRS, derived using PRS-CSx, with cognitive, behavioral and emotional measures derived from the 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 elevated SCZ-PRS (b=0.39, FDR-p=0.02) and subthreshold psychotic symptom severity (b=3.74, FDR-p=0.01) in European youth, higher CBCL scores across ancestries (b range=2.90-4.81, FDR-p<0.001), and higher odds of depression, anxiety, conduct disorder, post-traumatic stress disorder, and attention-deficit/hyperactivity disorder (OR=2.17-5.09, FDR-p<0.001) across ancestries. SCZ-PRS was associated with lower cognitive functioning across ancestries (b=-0.43, FDR-p=0.023), 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.
Conclusion
SCZ-FH showed stronger associations with broad psychopathology, while SCZ-PRS was associated with cognitive functioning and specific emotional and behavioral symptoms in European youth. These findings highlight their complementary role in early SCZ risk assessment and underscore the need to improve PRS utility across ancestries.
