Category: Parkinson's Disease: Genetics
Objective: To identify genetic risk modifiers for LRRK2 variant carriers of European ancestry.
Background: The LRRK2 p.G2019S variant is associated with substantially elevated risk for Parkinson’s disease, yet the incomplete penetrance of this variant indicates that additional factors modulate disease risk, including PD polygenic risk scores (PRS), as previously shown1. Additionally, several other more common LRRK2 variants (p.M1646T, rs76904798, rs17443099) are associated with more modest disease risk. The genetic modifiers that influence disease risk in the context of these variants remain poorly characterized and represent an important area for further investigation.
Method: Leveraging data from the Global Parkinson’s Genetics Program, the International Parkinson’s Disease Genomics Consortium, the UK Biobank, and the Fox Insight Genetics Study, we performed stratified autosomal meta-analyses by variant type: rare, high risk variants (p.G2019S, p.R1441G) and common, lower risk variants (p.M1646T, rs76904798, rs17443099) in European and Ashkenazi Jewish ancestries.
Results: We identified several regions where the risk of PD among common LRRK2 variant carriers is influenced by specific variants at loci that are known to be associated more generally with PD risk. To continue our investigation, we will formally test gene-gene interaction effects, characterize dual LRRK2 and GBA1 carriers, and leverage whole-genome sequencing to validate rare variants.
Conclusion: The risk of PD in common LRRK2 risk variant carriers is influenced by variants at known PD loci, most notably RAB29, SNCA, TMEM175, and MAPT. We anticipate that this analysis will help in understanding the complex interplay of genetic modifiers that influence the phenotype and progression of PD among carriers of LRRK2 variants.
References: 1. Iwaki, H. et al. Penetrance of Parkinson’s disease in LRRK2 p.G2019S carriers is modified by a polygenic risk score. Mov. Disord. 35, 774–780 (2020).
To cite this abstract in AMA style:
H. Leonard, L. Lange, M. Makarious, Z. Fang, C. Blauwendraat, A. Singleton. Genome-wide Discovery of Genetic Modifiers of LRRK2 risk in Parkinson’s Disease Carriers across European Populations [abstract]. Mov Disord. 2026; 41 (suppl 1). https://www.mdsabstracts.org/abstract/genome-wide-discovery-of-genetic-modifiers-of-lrrk2-risk-in-parkinsons-disease-carriers-across-european-populations/. Accessed October 1, 2026.« Back to 2026 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/genome-wide-discovery-of-genetic-modifiers-of-lrrk2-risk-in-parkinsons-disease-carriers-across-european-populations/