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Unhealthy Behaviours and Parkinsons Disease: A Mendelian Randomisation Study

By Karl Heilbron, Melanie P. Jensen, Sara Bandres-Ciga, Pierre Fontanillas, The 23andMe Research Team, Cornelis Blauwendraat, Mike A Nalls, Andrew B Singleton, George Davey Smith, Paul Cannon, Alastair Noyce

Posted 27 Mar 2020
medRxiv DOI: 10.1101/2020.03.25.20039230

ObjectiveTobacco smoking, alcohol intake, and high BMI have been identified in observational studies as potentially protective factors against developing Parkinsons disease (PD). Because of the possibility of residual confounding and reverse causation, it is unclear whether such epidemiological associations are causal. Mendelian randomisation (MR) uses genetic variants to explore causal effects of exposures on outcomes; minimising these sources of bias. Using MR, this study sought to determine the causal relationship between tobacco smoking, alcohol intake, and high BMI, and the risk of PD. MethodsWe performed genome-wide association studies to identify single nucleotide polymorphisms associated with the exposures. MR analysis of the relationship between each exposure and PD was undertaken using a split-sample design. The inverse variance weighted (IVW) method was used to combine SNP-specific effect estimates. ResultsEver-smoking causally reduced risk of PD (OR 0.955; 95% confidence interval [CI] 0.921-0.991; p=0.013). An increase in daily alcohol intake causally increased risk of PD (OR 1.125, 95% CI 1.025-1.235; p=0.013) and a 1 kg/m2 BMI causally reduced risk of PD (OR 0.988, 95% CI 0.979-0.997; p=0.008). Sensitivity analyses did not suggest bias from horizontal pleiotropy or invalid instruments. InterpretationUsing split-sample MR in over 2.4 million participants, we observed a protective effect of smoking on risk of PD, warranting the prioritisation of related therapeutic targets, such as nicotinic agonists, in prevention trials. In contrast to observational data, alcohol consumption causally increased risk of PD. Higher BMI had a protective effect on PD, but the effect was small.

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