Hospital-treated infectious diseases, infection burden and risk of Parkinson disease: An observational and Mendelian randomization study.

• In the observational study, infectious diseases were associated with an increased short- and long-term risk of subsequent Parkinson disease (PD). • The greatest PD risk was observed in neurological/eye infection, with lower respiratory tract infection ranked second. • A dose–response relationship between infection burden and risk of incident PD was observed within each genetic risk score tertile. • We used Two-sample Mendelian randomization analyses to further confirm the causal association between infections and PD development. Experimental and cross-sectional evidence has suggested a potential role of infection in the ethology of Parkinson's disease (PD). We aim to examine the longitudinal association of infections with the incidence of PD and to explore whether the increased risk is limited to specific infection type rather than infection burden. Based on the UK Biobank, hospital-treated infectious diseases and incident PD were ascertained through record linkage to national hospital inpatient registers. Infection burden was defined as the sum of the number of infection episodes over time and the number of co-occurring infections. The polygenic risk score (PRS) for PD was calculated. The genome-wide association studies (GWAS) used in two-sample Mendelian Randomization (MR) were obtained from observational cohort participants of mostly European ancestry. Hospital-treated infectious diseases were associated with an increased risk of PD (adjusted HR [aHR] 1.35 [95 % CI 1.20–1.52]). This relationship persisted when analyzing new PD cases occurring more than 10 years post-infection (aHR 1.22 [95 % CI 1.04–1.43]). The greatest PD risk was observed in neurological/eye infection (aHR 1.72 [95 % CI 1.32–2.34]), with lower respiratory tract infection (aHR 1.43 [95 % CI 1.02–1.99]) ranked the second. A dose–response association was observed between infection burden and PD risk within each PD-PRS tertile (p-trend < 0.001). Multivariable MR showed that bacterial and viral infections increase the PD risk. Both observational and genetic analysis suggested a causal association between infections and the risk of developing PD. A dose–response relationship between infection burden and incident PD was revealed. [ABSTRACT FROM AUTHOR]