Danish SaleheenHuman loss-of-function variants suggest that partial LRRK2 inhibition is a safe therapeutic strategy for Parkinson's disease

Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation, and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes^1,2. Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson's disease^3,4, suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. While preclinical studies in model organisms have raised some on-target toxicity concerns⁵-⁸, the biological consequences of LRRK2 inhibition have not been wellcharacterized in humans. Here we systematically analyse pLoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD)9, 49,960 exome sequenced individuals from the UK Biobank, and over 4 million participants in the 23andMe genotyped dataset. After stringent variant curation, we identify 1,455 individuals with high-confidence pLoF variants in LRRK2, 82.5% with experimental validation. We show that heterozygous pLoF variants in LRRK2 reduce LRRK2 protein levels but are not strongly associated with reduced life expectancy, or with any specific phenotype or disease state. These data suggest that therapeutics that partially downregulate LRRK2 levels or kinase activity are unlikely to have major on-target safety liabilities. Our results demonstrate the value of largescale genomic databases and phenotyping of human LoF carriers for target validation in drug discovery.