The effect of LRRK2 loss-of-function variants in humans

Area of Science:

• Genetics
• Neuroscience
• Pharmacology

Background:

• Human genetic variants causing protein loss-of-function (pLoF) serve as in vivo models for gene function and drug toxicity.
• Gain-of-kinase-function variants in LRRK2 are linked to increased Parkinson's disease risk, making LRRK2 inhibition a potential therapeutic strategy.
• Preclinical studies suggest on-target toxicity concerns for LRRK2 inhibitors, but human data on LRRK2 inhibition consequences are limited.

Purpose of the Study:

• To investigate the biological consequences of LRRK2 inhibition in humans by analyzing loss-of-function variants.
• To assess the association between LRRK2 loss-of-function variants and specific phenotypes or disease states.
• To evaluate the utility of large-scale genomic databases and human loss-of-function data for drug discovery target validation.

Main Methods:

• Systematic analysis of LRRK2 pLoF variants across large-scale genomic datasets (gnomAD, UK Biobank, 23andMe).
• Identification and curation of high-confidence LRRK2 pLoF variants in over 1,400 individuals.
• Experimental validation of variant effects on protein levels and correlation with phenotypic data.

Main Results:

• Identified 1,455 individuals with high-confidence heterozygous pLoF variants in LRRK2.
• Confirmed reduced LRRK2 protein levels in 82.5% of analyzed variants.
• Found no strong association between heterozygous LRRK2 pLoF variants and specific phenotypes or disease states.

Conclusions:

• Heterozygous loss-of-function variants in LRRK2 reduce protein levels but do not appear to be strongly associated with adverse phenotypes in humans.
• Large-scale human genetic data and phenotyping are valuable for validating drug targets, including LRRK2 for Parkinson's disease.
• This study provides crucial human in vivo data on the consequences of LRRK2 inactivation, informing therapeutic strategies and safety assessments.