Analysis of LRRK2 G2019S carriers in the All of Us research program database

The LRRK2 G2019S variant is a major genetic cause of Parkinson’s disease (PD), yet its lifetime penetrance remains uncertain. We used the All of Us (AoU) database to investigate G2019S penetrance and modifiers of disease manifestation. We analyzed LRRK2 G2019S carriers from the AoU v8 whole-genome sequencing dataset and stratified participants into manifesting and non-manifesting groups based on phenotypic data. We evaluated associations between family history, smoking, genetic modifiers and PD risk. Lifetime penetrance was estimated at 38%. Family history of PD was threefold more frequent among manifesting carriers, whereas no asymptomatic carriers older than 80 years reported such a history. Smoking showed a non-significant inverse association with disease risk. The protective LRRK2 N551K-R1398H-K1423K haplotype was enriched among elderly non-manifesting carriers and was associated with reduced LRRK2 kinase activity (pThr73-Rab10) in control subjects. We also replicated a nominal association between the KALRN rs145611031-C intronic variant and PD risk among LRRK2 G2019S carriers. In this large community-based cohort, lifetime penetrance of the LRRK2 G2019S variant was substantially lower than estimates reported in many family-based studies. Family history emerged as a major determinant of disease risk, while smoking and genetic modifiers may further influence clinical manifestation.