• Benjamin Meir Jacobs, Daniel Belete, Jonathan Bestwick, Cornelis Blauwendraat, Sara Bandres-Ciga, Karl Heilbron, Ruth Dobson, Mike A Nalls, Andrew Singleton, John Hardy, Gavin Giovannoni, Andrew John Lees, Anette-Eleonore Schrag, and Alastair J Noyce.
• Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine and Dentistry, London, UK.
• J. Neurol. Neurosurg. Psychiatr. 2020 Oct 1; 91 (10): 1046-1054.

ObjectiveTo systematically investigate the association of environmental risk factors and prodromal features with incident Parkinson's disease (PD) diagnosis and the interaction of genetic risk with these factors. To evaluate whether existing risk prediction algorithms are improved by the inclusion of genetic risk scores.MethodsWe identified individuals with an incident diagnosis of PD (n=1276) and controls (n=500 406) in UK Biobank. We determined the association of risk factors with incident PD using adjusted logistic regression models. We constructed polygenic risk scores (PRSs) using external weights and selected the best PRS from a subset of the cohort (30%). The PRS was used in a separate testing set (70%) to examine gene-environment interactions and compare predictive models for PD.ResultsStrong evidence of association (false discovery rate <0.05) was found between PD and a positive family history of PD, a positive family history of dementia, non-smoking, low alcohol consumption, depression, daytime somnolence, epilepsy and earlier menarche. Individuals with the highest 10% of PRSs had increased risk of PD (OR 3.37, 95% CI 2.41 to 4.70) compared with the lowest risk decile. A higher PRS was associated with earlier age at PD diagnosis and inclusion of the PRS in the PREDICT-PD algorithm led to a modest improvement in model performance. We found evidence of an interaction between the PRS and diabetes.InterpretationHere, we used UK Biobank data to reproduce several well-known associations with PD, to demonstrate the validity of a PRS and to demonstrate a novel gene-environment interaction, whereby the effect of diabetes on PD risk appears to depend on background genetic risk for PD.© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.

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