Identifying novel modifiable risk factors for ischemic stroke through phenome-wide association study and Mendelian randomization analyses in a large-scale prospective cohort.

Despite extensive research, significant uncertainty remains regarding the associations between various risk factors and ischemic stroke (IS). This study aimed to systematically identify and validate a broad range of potential modifiable risk factors for IS. Utilizing genetic and phenotypic data from the UK Biobank (UKB; N = 418,236), we conducted a phenome-wide association study (PheWAS) and Cox regression analysis to identify modifiable factors across sociodemographics, physical measures, lifestyles, medical history, mental health, and biological assays associated with both polygenic risk scores for IS (IS-PRS) and incident IS. To assess potential causal relationships, two-sample Mendelian randomization (MR) analysis was further performed. Among the 1,023 modifiable factors examined, 145 were significantly associated with both IS-PRS and incident IS. Notably, better lung function and more computer use were associated with decreased IS risk, whereas more summer outdoor exposure, sleep-related factors, mental health factor, and facial ageing were linked to increased IS risk. The strongest association was observed for pneumonitis due to solids and liquids, with a hazard ratio (HR) and 95% confidence interval (CI) of 7.65 (7.06- 8.28). MR analysis provided further causal evidence supporting 31 of the identified risk factors and confirmed the casual associations of worse lung function, greater summer outdoor exposure and longer daytime napping with increased IS risk. The study comprehensively identified a wide range of novel modifiable risk factors for IS, including physical, lifestyle, and mental health indicators. These findings may contribute to the development of more targeted and effective prevention strategies for IS.