GENETICALLY INFORMED ARCHETYPES OF COGNITION AND MENTAL HEALTH TO STUDY VULNERABILITY AND RESILIENCE ACROSS THE ADULT LIFESPAN

Mental health and related functional outcomes vary widely across adulthood, yet conventional diagnostic categories and single risk scores provide limited insight into the multidimensional structure underlying vulnerability, resilience, comorbidity, and long-term outcomes. Large population cohorts offer new opportunities to move beyond these reductions, but scalable and interpretable analytical frameworks remain limited.
Here, we propose archetypal analysis using data from the UK Biobank as a framework for deriving continuous, interpretable profiles (“archetypes”) that integrate cognitive function, dimensional mental health measures, personality traits, and functional outcomes. Using a top-down approach, phenotype-based archetypes are derived from harmonized cognitive and mental health measures, and archetype scores are treated as quantitative traits for genetic analyses, including genome-wide association studies, heritability estimation, and genetic correlation.
In parallel, archetypal analysis is applied to high-dimensional polygenic score profiles to define genetics-derived archetypes representing distinct configurations of cognitive and psychiatric liability. These genetics-based archetypes are then characterized with respect to cognitive performance, mental health phenotypes, and longitudinal outcomes, enabling a bottom-up examination of how genetic liability relates to preserved function, vulnerability, or resilience.
By combining scalable, interpretable phenotyping with genetic discovery and longitudinal follow-up, this work seeks to establish biologically informed constructs of vulnerability and resilience with relevance for psychiatric and neurological outcomes across the adult lifespan.