Polygenic Risk, Psychopathology, and Personalized Functional Brain Network Topography in Adolescence

Functional brain networks are associated with both behavior and genetic factors. To uncover biological mechanisms of psychopathology, it is critical to define how the spatial organization of these networks relates to genetic risk during development.

Objective

To determine the associations among transdiagnostic polygenic risk scores (PRSs), personalized functional brain networks (PFNs), and overall psychopathology (p-factor) during early adolescence.

Design, Setting, and Participants

The Adolescent Brain Cognitive Development (ABCD) Study is an ongoing longitudinal cohort study of 21 collection sites across the US. This cross-sectional analysis includes ABCD baseline data collected between September 2016 and October 2018. The ABCD Study is a multisite community-based study. The sample is largely recruited through school systems. ABCD exclusion criteria included severe sensory, intellectual, medical, or neurological issues that interfere with protocol and scanner contraindications. Split-half subsets were used for cross-validation, matched on age, ethnicity, family structure, handedness, parental education, site, sex, and anesthesia exposure. Data were analyzed from January 2023 to July 2024.

Exposures

Polygenic risk scores of transdiagnostic genetic factors F1 (PRS-F1) and F2 (PRS-F2) derived from adults in Psychiatric Genomic Consortium and UK Biobanks datasets. PRS-F1 indexes liability for common psychiatric symptoms and disorders related to mood disturbance; PRS-F2 indexes liability for rarer forms of mental illness characterized by mania and psychosis.

Main Outcomes and Measures

P-factor derived from bifactor models of youth- and parent-reported mental health assessments and person-specific functional brain network topography derived from functional magnetic resonance imaging scans.

Results

Total participants included 11 873 children aged 9 to 10 years; 5678 (47.8%) were female, and the mean (SD) age was 9.92 (0.62) years. PFN topography was found to be heritable (imaging subsample, n = 7459; 57.1% of vertices: mean h ² , 0.35; false discovery rate–corrected P  < .05). PRS-F1 was associated with p-factor (European ancestry subsample, n = 5815; r , 0.12; 95% CI, 0.09-0.15; P  < .001). Interindividual differences in functional network topography were associated with p-factor (imaging subsample, n = 7459; mean r , 0.12), PRS-F1 (imaging and European ancestry subsample, n = 3982; mean r , 0.05), and PRS-F2 (n = 3982; mean r , 0.08). Cortical maps of p-factor and PRS-F1 regression coefficients were correlated ( r , 0.70; P  = .003, permutation test, N = 1000).

Conclusions and Relevance

Polygenic risk for transdiagnostic adulthood psychopathology was associated with both p-factor and heritable PFN topography during early adolescence in this study. These results may advance our understanding of the developmental drivers of psychopathology.