Phenome-wide Investigation of Behavioral, Environmental, and Neural Associations with Cross-Disorder Genetic Liability in Youth of European Ancestry

Abstract

Etiologic insights into psychopathology may be gained by using hypothesis-free methods to identify associations between genetic risk for broad psychopathology and phenotypes measured during adolescence, including both markers of child psychopathology and intermediate phenotypes such as neural structure that may link genetic risk with outcomes. We conducted a phenome-wide association study (phenotype n=1,269-1,694) of polygenic risk scores (PRS) for broad spectrum psychopathology (i.e., Compulsive, Psychotic, Neurodevelopmental, and Internalizing) in youth of PCA-selected European ancestry (n=5,556; ages 9-13) who completed the baseline and/or two-year follow-up of the ongoing Adolescent Brain Cognitive DevelopmentSM (ABCD) Study. We found that Neurodevelopmental and Internalizing PRS were significantly associated with a host of proximal as well as distal phenotypes (Neurodevelopmental: 187 and 211; Internalizing: 122 and 173 phenotypes at baseline and two-year follow-up, respectively), whereas Compulsive and Psychotic PRS showed zero and one significant associations, respectively, after Bonferroni correction. Neurodevelopmental PRS were further associated with brain structure metrics (e.g., total volume, mean right hemisphere cortical thickness), with only cortical volume indirectly linking Neurodevelopmental PRS to grades in school. Genetic variation influencing risk to psychopathology manifests broadly as behaviors, psychopathology symptoms, and related risk factors in middle childhood and early adolescence. Keywords: Phenome-wide Association Study (PheWAS), polygenic risk scores, Neurodevelopmental, Internalizing

Genetic Insights into Externalizing and Internalizing Traits through Integration of the Research Domain Criteria and Hierarchical Taxonomy of Psychopathology

“…Based on previous GWAS of externalizing and internalizing 14,15,83 and existing theory, 7,9 we considered a total of 18 externalizing and internalizing traits for inclusion in the analyses (Supplementary Figure 1). We excluded two traits (automobile speeding propensity and anorexia nervosa) that were weakly associated with the others in the model (mean r g < 0.20).…”

Combining Transdiagnostic and Disorder-Level GWAS Enhances Precision of Psychiatric Genetic Risk Profiles in a Multi-Ancestry Sample

“…Additionally, across ancestries, common genetic risk partially accounted for the shared features of BD and SCZ. Other gSEM studies have also showed that SCZ and BD load onto the same genetic factor, 18,[70][71][72] highlighting their strong shared etiology despite belonging to different diagnostic classes. Although smaller samples and greater genetic diversity limited statistical power to replicate the EUR factor structure in AFR individuals, there were significant commonalities across genetic ancestry groups.…”