Genetics of NLRP3 suggests lack of involvement and inefficient druggability in Parkinson's disease

Activation of the NLRP3-inflammasome has been implicated in Parkinsons disease based on in vitro and in vivo studies. Clinical trials targeting the NLRP3-inflammasome in Parkinsons disease are ongoing. However, the evidence supporting NLRP3s involvement in Parkinsons disease from human genetics data is limited. In this study, we conducted analyses of common and rare variants in NLRP3-inflammasome related genes in Parkinsons disease cohorts. We performed pathway-specific analyses using polygenic risk scores and studied potential causal associations using Mendelian randomization with the NLRP3 components and the cytokines IL-1{beta} and IL-18. Our findings showed no associations of common or rare variants, nor of the pathway polygenic risk score with Parkinsons disease. Mendelian randomization suggests that altering the expression of the NLRP3-inflammasome, IL-1{beta} or IL-18, does not affect Parkinsons disease risk or progression. Therefore, our results do not support a role for the NLRP3-inflammasome in Parkinsons disease pathogenesis or as a target for drug development.