Objective: To investigate the frequency of multiple LRRK2 variants in Parkinson’s disease (PD) cohort, and to explore the effect of LRRK2 variants on the occurrence and development of PD.

Background: LRRK2 gene is the most common genetic factor in PD. More than 200 variants in LRRK2 have been identified, but the known pathogenic mutations are rare and have significant regional characteristics. The role of most LRRK2 variants in PD are still unclear.

Method: PD patients who underwent whole genome sequencing were categorized into three groups: early-onset PD (EOPD), sporadic late-onset PD (sLOPD), and familial late-onset PD (fLOPD). The frequencies of different LRRK2 gene variants in each group were summarized and compared with 200 healthy controls (HC). Risk loci with significantly increased frequencies in the PD cohort were selected(table 1-2). After excluding patients carrying other pathogenic variants and other risk loci, cross-sectional clinical characteristics and longitudinal disease progression were analyzed in genetically-undefined PD patients (GU-PD)(table 3-4). Pedigree-based clinical and imaging characteristics were analyzed for pathogenic mutations, while descriptive and gene burden analyses were conducted for low-frequency rare variants.

Results: A total of 58 LRRK2 exonic variants were identified in the PD cohort, including pathogenic mutations N1437D and R1441C. Significant risk loci included G2385R, R1628P, and R1067Q, with G2385R frequencies significantly higher in EOPD, sLOPD, and fLOPD compared to healthy controls. We specifically investigated the clinical characteristics and disease progression of G2385R carriers, finding that EOPD patients had higher baseline GDS scores (p=0.034), indicating increased depressive tendencies. Disease progression analysis revealed faster cognitive decline in G2385R EOPD patients. In the sLOPD group, G2385R carriers exhibited milder baseline motor symptoms (p=0.032). However, there was no significant difference in the progression of motor and non-motor symptoms between G2385R carriers and genotype-negative patients in both EOPD and sLOPD groups. Additionally, some low-frequency rare variants and partial protective variants were identified.

Conclusion: The impact of LRRK2 gene variants on Parkinson’s disease risk varies. In-depth research into the frequencies and functions of different LRRK2 loci will enhance our understanding of the pathogenesis of Parkinson’s disease.

Study flow chart

Significance of risk loci

Clinical manifestation at baseline

Disease progression of LRRK2 G2385R-PD

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MDS Abstracts - https://www.mdsabstracts.org/abstract/analysis-of-lrrk2-exonic-variants-in-parkinsons-disease-in-chinese-population/