Category: Parkinson's Disease: Genetics
Objective: To examine whether smoking modifies the association between protective LRRK2 variants (N551K and R1398H) and the risk of Parkinson’s disease in a case-control cohort.
Background: Parkinson’s disease (PD) is a multifactorial neurodegenerative disorder shaped by both genetic and environmental influences. Variants in LRRK2, including N551K and R1398H, have been implicated in PD susceptibility, while cigarette smoking has consistently been associated with lower PD risk. It is unclear if smoking modifies the association between
protective LRRK2 variants and PD risk.
Method: We performed a case-control study to examine the joint association of smoking and LRRK2 variants (N551K and R1398H) with PD risk. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for age, sex, and family history of movement disorders. Interaction analyses were additionally explored using the relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (S).
Results: A total of 4,382 participants were included. Among smokers, carriers of the N551K CC genotype had significantly lower odds of PD than wildtype non-smokers (OR 0.762, 95%
CI 0.605–0.957; p = 0.0199), corresponding to approximately 24% lower odds. No significant association was observed for the N551K CG/GG genotype among smokers (p = 0.298). For R1398H, non-smoking carriers of the GG genotype showed lower odds of PD compared with the reference group (OR 0.777, 95% CI 0.619–0.975; p = 0.0301), whereas the AA/AG genotype was not significantly associated with PD (p = 0.0989). Interaction analyses suggested positive biological interaction, consistent with smoking attenuating LRRK2-associated risk.
Conclusion: Carriers of the LRRK2 (N551K) CC genotype had significantly lower odds of PD than wildtype non-smokers. Non-smoking carriers of the R1698H GG genotype
showed lower odds of PD compared with the smokers with AA/AG genotypes. Functional studies are needed to unravel the underlying mechanistic interactions.
To cite this abstract in AMA style:
JDJ. Wang, LL. Chan, E. Ng, KM. Prakash, L. Tan, EK. Tan. Association between Smoking and LRRK2 Variants on Parkinson’s Disease Risk [abstract]. Mov Disord. 2026; 41 (suppl 1). https://www.mdsabstracts.org/abstract/association-between-smoking-and-lrrk2-variants-on-parkinsons-disease-risk/. Accessed October 1, 2026.« Back to 2026 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/association-between-smoking-and-lrrk2-variants-on-parkinsons-disease-risk/