Mendelian Randomisation Study of Smoking, Alcohol, and Coffee Drinking in Relation to Parkinson’s Disease
Authors: Domenighetti Cloé ,   on behalf of the Comprehensive Unbiaised Risk Factor Assessment for Genetics and Environment in Parkinson’s Disease (Courage-PD) consortium, Sugier Pierre-Emmanuel , Sreelatha Ashwin Ashok Kumar , Schulte Claudia , Grover Sandeep , Mohamed Océane , Portugal Berta , May Patrick , Bobbili Dheeraj R. , Radivojkov-Blagojevic Milena , Lichtner Peter , Singleton Andrew B. , Hernandez Dena G. , Edsall Connor , Mellick George D. , Zimprich Alexander , Pirker Walter , Rogaeva Ekaterina , Lang Anthony E. , Koks Sulev , Taba Pille , Lesage Suzanne , Brice Alexis , Corvol Jean-Christophe , Chartier-Harlin Marie-Christine , Mutez Eugénie , Brockmann Kathrin , Deutschländer Angela B. , Hadjigeorgiou Georges M. , Dardiotis Efthimos , Stefanis Leonidas , Simitsi Athina Maria , Valente Enza Maria , Petrucci Simona , Duga Stefano , Straniero Letizia , Zecchinelli Anna , Pezzoli Gianni , Brighina Laura , Ferrarese Carlo , Annesi Grazia , Quattrone Andrea , Gagliardi Monica , Matsuo Hirotaka , Kawamura Yusuke , Hattori Nobutaka , Nishioka Kenya , Chung Sun Ju , Kim Yun Joong , Kolber Pierre , van de Warrenburg Bart PC , Bloem Bastiaan R. , Aasly Jan , Toft Mathias , Pihlstrøm Lasse , Guedes Leonor Correia , Ferreira Joaquim J. , Bardien Soraya , Carr Jonathan , Tolosa Eduardo , Ezquerra Mario , Pastor Pau , Diez-Fairen Monica , Wirdefeldt Karin , Pedersen Nancy L. , Ran Caroline , Belin Andrea C. , Puschmann Andreas , Hellberg Clara , Clarke Carl E. , Morrison Karen E. , Tan Manuela , Krainc Dimitri , Burbulla Lena F. , Farrer Matt J. , Krüger Rejko , Gasser Thomas , Sharma Manu , Elbaz Alexis 
Published: October 2021

Background: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson’s disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. Objective: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. Methods: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). Results: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60–0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. Conclusion: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.