Associations between disease-specific polygenic risk scores and disease-specific causes of death in the UK Biobank cohort

1.Disease-specific Polygenic Risk Scores (PRS) are usually evaluated against the incidence of diseases they were derived for. Individuals may be more interested in how these PRS influence their probable cause of death. Using UK Biobank data, we examined the top 10 causes of death among individuals in the highest quintile of disease-specific PRS for Alzheimers disease, bowel cancer, cardiovascular disease, coronary artery disease, ischaemic stroke, breast cancer, epithelial ovarian cancer, and prostate cancer. Analyses were stratified by sex, age at death, and smoking status (never, past, current). We also assessed varying PRS percentile thresholds to identify when the target disease became the leading cause of death, and evaluated the impact of each disease-specific PRS on all-cause mortality using Cox proportional hazards models. For most disease-specific PRS, individuals in the high-risk group were more likely to die from other common diseases. The leading causes of death varied according to demographic and behavioural subgroup: breast cancer in women, ischaemic heart disease in men, dementia in the oldest age groups, and lung cancer among smokers. For instance, while prostate cancer was the leading cause of death among older never-smoking men in the highest quintile of the prostate cancer PRS; in other age and smoking status categories, ischaemic heart disease or lung cancer were more common. While a high PRS is predictive of disease diagnosis, most individuals die from other common conditions, depending on their demographic and behavioural subgroups. These findings highlight the importance of contextualising PRS results in clinical settings and risk communication. 2. Key messagesO_LIWhat is already known on this topic: C_LI Disease-specific PRS have been investigated for their ability to predict incidence, not death, from the specific target disease. O_LIWhat this study adds: C_LI We evaluated PRS for the most common diseases against death from the target disease, as well as other common causes of death. O_LIHow this study might affect research, practice or policy: C_LI Providing the probabilities of death from each target disease, and from other diseases, to the probability of PRS-specific incidence may help contextualise communication of risks associated with high disease-specific PRS.