Background: Circadian rhythm may play a role in neurodegenerative diseases such as Parkinson disease (PD). Chronotype is the behavioural manifestation of circadian rhythm and Mendelian randomisation (MR) involves the use of genetic variants to explore causal effects of exposures on outcomes. This study aimed to explore a causal relationship between chronotype and coffee consumption on risk of PD. Methods: Two-sample MR was undertaken using publicly available GWAS data. Associations between genetic instrumental variables (IV) and 'morning person' (one extreme of chronotype) were obtained from the personal genetics company 23andMe, Inc., and UK Biobank, and consisted of the per-allele odds ratio of being a 'morning person' for 15 independent variants. The per-allele difference in log-odds of PD for each variant was estimated from a recent meta-analysis. The inverse variance weight method was used to estimate an odds ratio (OR) for the effect of being a 'morning person' on PD. Additional MR methods were used to check for bias in the IVW estimate, arising through violation of MR assumptions. The results were compared to analyses employing a genetic instrument of coffee consumption, because coffee consumption has been previously inversely linked to PD. Findings: Being a 'morning person' was causally linked with risk of PD (OR 1.27; 95% confidence interval 1.06-1.51; p=0.012). Sensitivity analyses did not suggest that invalid instruments were biasing the effect estimate and there was no evidence for a reverse causal relationship between liability for PD and chronotype. There was no robust evidence for a causal effect of high coffee consumption using IV analysis, but the effect was imprecisely estimated (OR 1.12; 95% CI 0.89-1.42; p=0.22). Interpretation: We observed causal evidence to support the notion that being a 'morning person', a phenotype driven by the circadian clock, is associated with a higher risk of PD. Further work on the mechanisms is warranted and may lead to novel therapeutic targets. Funding: No specific funding source.

Tendency towards being a "Morning person" increases risk of Parkinson's disease: evidence from Mendelian randomisation