Blauwendraat C, et al. - Whether LRRK1 and LRRK2 loss of function (LOF) variants contribute to the risk of developing Parkinson disease (PD) was investigated in this case-control cohort study. Researchers reported that haploinsufficiency of LRRK1 or LRRK2 was neither a cause of nor protective against PD. The results obtained from the study indicate that kinase inhibition or allele-specific targeting of mutant LRRK2 are still feasible therapeutic strategies in a subset of patients with PD.

Methods

• For this investigation, researchers analyzed next-generation sequencing data from a large case-control cohort (> 23,000 individuals) for LOF variants in LRRK1and LRRK2 to determine the prevailing mechanism of LRRK2-mediated disease in human populations.
• They generated data at five different sites and five different data sets, incorporating cases with clinically diagnosed PD and neurologically normal control individuals.
• Data were collected from 2012 through 2017.
• After that, frequencies of LRRK1 and LRRK2 LOF variants present in the general population and compared between cases and controls.

Results

• According to the findings, LRRK1 LOF variants were identified in 0.205% of cases and 0.139% of controls (odds ratio, 1.48; SE, 0.571; 95% CI, 0.45-4.44; P=.49) and LRRK2 LOF variants were found in 0.117% of cases and 0.087% of controls (odds ratio, 1.48; SE, 0.431; 95% CI, 0.63-3.50; P=.36) among 11,095 cases with PD and 12,615 controls.
• As per all association tests, lack of association was found between LRRK1 or LRRK2 variants and PD.
• Further analysis of lymphoblastoid cell lines from several heterozygous LOF variant carriers found that LRRK2 protein levels were decreased by approximately half vs wild-type alleles.