Abstract
Although psychiatric phenotypes are hypothesized to organize into a two-factor internalizing–externalizing structure, few studies have evaluated the structure of psychopathology in older adults, nor explored whether genome-wide polygenic scores (PGSs) are associated with psychopathology in a domain-specific manner. We used data from 6003 individuals of European ancestry from the Health and Retirement Study, a large population-based sample of older adults in the United States. Confirmatory factor analyses were applied to validated measures of psychopathology and PGSs were derived from well-powered genome-wide association studies (GWAS). Genomic SEM was implemented to construct latent PGSs for internalizing, externalizing, and general psychopathology. Phenotypically, the data were best characterized by a single general factor of psychopathology, a factor structure that was replicated across genders and age groups. Although externalizing PGSs (cannabis use, antisocial behavior, alcohol dependence, attention deficit hyperactivity disorder) were not associated with any phenotypes, PGSs for major depressive disorder, neuroticism, and anxiety disorders were associated with both internalizing and externalizing phenotypes. Moreover, the variance explained in the general factor of psychopathology increased by twofold (from 1% to 2%) using the latent internalizing or latent one-factor PGSs, derived using weights from Genomic Structural Equation Modeling (SEM), compared with any of the individual PGSs. Collectively, results suggest that genetic risk factors for and phenotypic markers of psychiatric disorders are transdiagnostic in older adults of European ancestry. Alternative explanations are discussed, including methodological limitations of GWAS and phenotypic measurement of psychiatric outcome in large-scale population-based studies.
Highlights
Psychiatric disorders impact health, wealth, and wellbeing across the life course[1,2,3]
polygenic scores (PGSs) associations with psychopathology To address a critical issue in the field, we evaluated polygenic specificity by examining the associations between each PGS and each phenotypic measure, controlling for the first 10 ancestry-specific principal components
The general factor of psychopathology was further equivalent across gender and age groupings as indicated by invariant factor structure and loadings, suggesting that the structure of psychiatric phenotypes in the Health and Retirement Study (HRS) is replicable across demographic groups
Summary
Psychiatric disorders impact health, wealth, and wellbeing across the life course[1,2,3]. Psychiatric disorders have pronounced effects on physical health and mortality[2,5]. A robust literature suggests that this comorbidity may be explained by an overarching phenotypic meta-structure that includes separate but correlated internalizing (e.g., depression, anxiety) and externalizing (e.g., substance use, attention deficit hyperactivity disorder [ADHD]) factors[10]. These comorbidity patterns align with phenotypic differences between
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