Penetrance of Parkinson disease LRRK2 G2385R‐associated variant in the Chinese population

Abstract Background and purpose Penetrance estimates of the leucine‐rich repeat kinase 2 ( LRRK2 ) variants for Parkinson disease (PD) vary widely. G2385R is one of the most common LRRK2 variants in Asian populations, and its penetrance is currently unknown. We aimed to estimate the penetrance of G2385R in the Chinese population. Methods The G2385R variant was tested by Sanger sequencing in 6386 participants older than 50 years, all from the community cohort established by Shanghai Ruijin Hospital in 2009–2011. G2385R carriers and matched noncarriers underwent a brief questionnaire survey (including sex, current age, PD diagnosis, and age at onset) and face‐to‐face PD assessment during 2020–2021. The penetrance of PD was estimated by the Kaplan–Meier method. Results A total of 396 G2385R carriers and 415 noncarriers were included, after excluding those with a baseline diagnosis of PD or unwilling to participate. In G2385R carriers, the penetrance of PD was 1.64% at 70 years, 10.26% at 80 years, and 18.49% at 90 years, and reached 25.90% at 95 years. The penetrance of PD in G2385R carriers was higher than in noncarriers ( p = 0.0071). In noncarriers, only 0%, 3.72%, and 9.66% developed parkinsonism by 70, 80, and 90 years of age. Among carriers and noncarriers, there were no statistically significant differences in penetrance comparisons between males and females, or between urban and rural. Conclusions The lifetime penetrance of LRRK2 G2385R in the Chinese population was 25.9%. The penetrance modifier of G2385R in our study was age‐related. Further investigation of genetic and environmental modifiers affecting G2385R penetrance is warranted.