Polygenic Risk Underlies Youth Psychopathology and Personalized Functional Brain Network Topography

Abstract Importance Functional brain networks are associated with both behavior and genetic factors. To uncover clinically translatable 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 relationship between transdiagnostic polygenic risk scores (PRSs), personalized functional brain networks (PFNs), and overall psychopathology (p-factor) during early adolescence. Design The Adolescent Brain Cognitive Development (ABCD) Study⍰ is an ongoing longitudinal cohort study of 21 collection sites across the United States. Here, we conduct a cross-sectional analysis of ABCD baseline data, collected 2017-2018. Setting The ABCD Study ® is a multi-site community-based study. Participants The sample is largely recruited through school systems. 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. 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 (1) P-factor derived from bifactor models of youth- and parent-reported mental health assessments. (2) Person-specific functional brain network topography derived from functional magnetic resonance imaging (fMRI) scans. Results Total participants included 11,873 youths ages 9-10 years old; 5,678 (47.8%) were female, and the mean (SD) age was 9.92 (0.62) years. PFN topography was found to be heritable ( N =7,459, 57.06% of vertices h 2 p FDR <0.05, mean h 2 =0.35). PRS-F1 was associated with p-factor ( N =5,815, r =0.12, 95% CI 0.09–0.15, p<0.001). Interindividual differences in functional network topography were associated with p-factor ( N =7,459, mean r =0.12), PRS-F1 ( N =3,982, mean r =0.05), and PRS-F2 ( N =3,982, mean r =0.08). Cortical maps of p-factor and PRS-F1 regression coefficients were highly correlated ( r =0.7, p =0.003). Conclusions and Relevance Polygenic risk for transdiagnostic adulthood psychopathology is associated with both p-factor and heritable PFN topography during early adolescence. These results advance our understanding of the developmental drivers of psychopathology. Key Points Question What is the relationship between transdiagnostic polygenic risk scores (PRSs), personalized functional brain networks (PFNs), and overall psychopathology (p-factor) during early adolescence? Findings In this cross-sectional analysis of the Adolescent Brain Cognitive Development (ABCD) Study⍰ ( N =11,873, ages 9-10), we found that a PRS of common psychopathology in adulthood (PRS-F1) was associated with p-factor during early adolescence. Interindividual differences in p-factor, PRS-F1, and PRS-F2 (capturing rarer psychopathology in adulthood) were all robustly associated with PFN topography. Meaning Polygenic risk for transdiagnostic adulthood psychopathology is associated with both p-factor and PFN topography during early adolescence.