Genetic liability plays a critical role in shaping mental health outcomes, with polygenic risk scores (PRS) increasingly used to quantify inherited predispositions. Mental health disorders such as depression, anxiety, and schizophrenia are not only major contributors to morbidity but are also linked to elevated risks of premature mortality. While observational studies suggest strong associations between mental illness and both all-cause and cause-specific mortality, it remains unclear to what extent genetic predisposition to poor mental health contributes to these risks independent of environmental and behavioral factors. Leveraging the large-scale, deeply phenotyped UK Biobank cohort, this project aims to address this knowledge gap.
We will use existing PRS or construct PRS for multiple mental health conditions (e.g., depression, schizophrenia, bipolar disorder, ADHD) using the latest genome-wide association studies. These PRS will be evaluated in relation to all-cause mortality and major categories of cause-specific mortality, such as cardiovascular disease, cancer, respiratory disease, and suicide-related deaths. Cox proportional hazards models and competing risks regression will be applied, adjusting for key covariates including age, sex, socioeconomic status, and lifestyle factors. Stratified analyses will explore effect modification by sex and other demographic factors, and mediation analyses will assess the extent to which lifestyle and comorbidity profiles explain the observed associations.
This project will provide novel insights into the genetic underpinnings of mortality risks associated with mental health predispositions. By disentangling the contribution of inherited liability from other social and behavioral determinants, the findings will deepen our understanding of how genetic susceptibility to mental health disorders translates into long-term health consequences.
