Category: Parkinson's Disease: Genetics
Objective: To study rare variant burden in different LRRK2 domains to investigate domain-based associations with Parkinson’s Disease (PD) and to identify functional variants in LRRK2.
Background: LRRK2 variants are a major cause of familial and sporadic PD. The LRRK2 protein consists of seven domains: Armadillo repeat (ARM), Ankyrin repeat (ANK), Leucine-rich repeat (LRR), Kinase, Ras-of-complex (Roc) GTPase in tandem with C-terminal of Roc (COR), and WD40 [figure1]. The catalytic Kinase domain and Roc-COR bidomain contain kinase and GTPase enzymes respectively and host variants known to be pathogenic to PD. The mechanism by which these variants influence PD pathogenesis is still unclear. However, it is known that the pathogenic variant p.G2019S in the LRRK2 Kinase domain, as well as other variants, are associated with an increased kinase activity.
Method: To study LRRK2 rare variants (minor allele frequency ≤ 0.01), protein-coding in six domain regions (Roc-COR bidomain counted as one), we performed burden analysis in six cohorts including a total of 9,405 PD patients and 22,356 controls via optimized sequence Kernel association test (SKAT-O), and METASKAT for the meta-analysis.
Results: The LRRK2 ARM, Roc-COR, and Kinase domains were found to be significantly associated with PD in the meta-analysis (P = 0.003; P = 0.013; P = 1.90 x 10-19). The association in LRRK2 Kinase was solely driven by p.G2019S as, without it, no association was observed. And, in one cohort, Roc-COR showed a significant association driven by a potentially protective p.Q1353K variant.
Conclusion: LRRK2 rare variants in ARM, Roc-COR, and Kinase domains are of interest in the study of PD as evidenced by domain-level associations. While the Kinase and Roc-COR domains have been extensively studied in PD, further functional studies are required to elucidate how variants in other LRRK2 domains might influence PD.
Overview of the LRRK2 domain structure
To cite this abstract in AMA style:
S. Parlar, K. Senkevich, E. Yu, J. Ruskey, J. Ahmad, F. Asayesh, D. Spiegelman, C. Waters, O. Monchi, Y. Dauvilliers, N. Dupré, L. Greenbaum, S. Hassin-Baer, I. Miliukhina, A. Timofeeva, A. Emelyanov, S. Pchelina, R. Alcalay, E. Fon, Z. Gan-Or. LRRK2 in Parkinson’s Disease: A per-domain rare-variant burden study [abstract]. Mov Disord. 2024; 39 (suppl 1). https://www.mdsabstracts.org/abstract/lrrk2-in-parkinsons-disease-a-per-domain-rare-variant-burden-study/. Accessed May 19, 2025.« Back to 2024 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/lrrk2-in-parkinsons-disease-a-per-domain-rare-variant-burden-study/