Dysfunctional Alternative Polyadenylation Modifies the Penetrance of LRRK2 Variants in Parkinson's Disease

Abstract Background Pathogenic variants in the LRRK2 gene are the most common genetic cause of Parkinson's disease (PD), but incomplete penetrance results in variable PD onset among carriers. The molecular modifiers underlying this variability remain poorly understood. Objective To investigate whether dysfunctional alternative polyadenylation (APA), a key post‐transcriptional regulatory process, modulates the penetrance of LRRK2 variants in PD. Methods Using RNA‐seq data from 905 participants in the Parkinson's Progression Markers Initiative (PPMI), we quantified dysfunctional APA based on the percentage of distal polyadenylation site usage index (PDUI). Dysfunctional APA associated with LRRK2 variants was assessed in healthy controls (HCs) and PD patients, with a focus on PD‐specific APA. We further identified dysfunctional APA that distinguishes symptomatic from asymptomatic LRRK2 variant carriers and evaluated its associations with immune cell composition and symptom severity. A sensitivity analysis using an APA‐based score was conducted to assess whether the G2019S variant drives dysfunctional APA in LRRK2 carriers. Results PD patients exhibited over twice the number of dysfunctional APA events associated with LRRK2 variants compared with HCs. PD‐specific APA events were involved in immune disorders, amyloid fiber formation, and ubiquitin‐specific processing proteases, all implicated in PD pathogenesis. Fourteen dysfunctional APA events distinguished symptomatic from asymptomatic LRRK2 carriers, correlated with immune cell composition, and were associated with PD symptom severity. The G2019S variant largely recapitulates the global dysfunctional APA pattern observed in LRRK2 variant carriers and validated in an independent replication cohort. Conclusions Dysfunctional APA is a potential modifier of LRRK2 variant penetrance, contributing to PD onset. © 2025 International Parkinson and Movement Disorder Society.