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Pathogenic missense variants in the  leucine-rich repeat kinase 2  ( LRRK2 ) gene have been identified through linkage analysis in familial Parkinson disease (PD). Subsequently, other missense variants with lower effect sizes on PD risk have emerged, as well as non-coding polymorphisms (e.g. rs76904798) enriched in PD cases in genome-wide association studies. Here we leverage recent whole-genome sequences from the Accelerating Medicines Partnership-Parkinson’s Disease (AMP-PD) and the Genome Aggregation (gnomAD) databases to characterize novel missense variants in  LRRK2  and explore their relationships with known pathogenic and PD-linked missense variants. Using a computational prediction tool that successfully classifies known pathogenic  LRRK2  missense variants, we describe an online web-based resource that catalogs characteristics of over 1200  LRRK2  missense variants of unknown significance. Novel high-pathogenicity scoring variants, some identified exclusively in PD cases, tightly cluster within the ROC-COR-Kinase domains. Structure–function predictions support that some of these variants exert gain-of-function effects with respect to LRRK2 kinase activity. In AMP-PD participants, all p.R1441G carriers ( N  = 89) are also carriers of the more common PD-linked variant p.M1646T. In addition, nearly all carriers of the PD-linked p.N2081D missense variant are also carriers of the  LRRK2  PD-risk variant rs76904798. These results provide a compendium of  LRRK2  missense variants and how they associate with one another. While the pathogenic p.G2019S variant is by far the most frequent high-pathogenicity scoring variant, our results suggest that ultra-rare missense variants may have an important cumulative impact in increasing the number of individuals with  LRRK2 -linked PD.

Identification of LRRK2 missense variants in the accelerating medicines partnership Parkinson’s disease cohort