The Parkinson’s Phenome: Traits Associated with Parkinson’s Disease in a Large and Deeply Phenotyped Cohort

Background Observational studies have begun to characterize the wide spectrum of phenotypes associated with Parkinson’s disease (PD), but recruiting large numbers of PD cases and assaying a diversity of phenotypes has often been difficult. Here, we set out to systematically describe the PD phenome using a cross-sectional case-control design in a large database. Methods We analyzed the association between PD and 840 phenotypes derived from online surveys. For each phenotype, we ran a logistic regression using an average of 5,141 PD cases and 65,459 age- and sex-matched controls. We selected uncorrelated phenotypes, determined statistical significance after correcting for multiple testing, and systematically assessed the novelty of each significant association. We tested whether significant phenotypes were also associated with disease duration in PD cases. Findings PD diagnosis was associated with 149 independent phenotypes. We replicated 32 known associations and discovered 49 associations that have not previously been reported. We found that migraine, obsessive-compulsive disorder, seasonal allergies, and anemia were associated with PD, but were not significantly associated with PD duration, and tend to occur decades before the average age of diagnosis for PD. Further work is needed to determine whether these phenotypes are PD risk factors or whether they share common disease mechanisms. Interpretation We used a systematic approach in a single large dataset to assess the spectrum of traits that were associated with PD. Some of these traits may be risk factors for PD, features of the pre-diagnostic phase of disease, or manifestations of PD pathology. The model outputs from all 840 logistic regressions are available to the research community and may be used to generate hypotheses regarding PD etiology. Funding The Michael J. Fox Foundation, Parkinson’s UK, Barts Charity, National Institute on Aging, and 23andMe, Inc. Research in Context Evidence before this study We used PubMed to perform a MEDLINE database search for review articles published up to January 21 st , 2018 that contained the keywords “Parkinson” and “epidemiology” in the title or abstract. We performed additional MEDLINE searches for each phenotype that was significantly associated with PD. Although dozens of phenotypes have been tested for an association with PD, only a few associations have been consistently repeatable ( e.g. pesticide exposure, coffee consumption). Added value of this study We systematically tested for an association between PD and 840 phenotypes using up to 13,546 cases and 1·3 million controls, making this one of the largest PD epidemiology studies ever conducted. We discovered 49 novel associations that will need to be replicated or validated. We found 44 associations for phenotypes that have previously been studied in relation to PD, but for which an association has not been consistently demonstrated. Implications of all the available evidence Taken together with results from previous studies, this series of case-control analyses adds evidence for associations between PD and many phenotypes that are not currently thought to be part of the canonical PD phenome. This work paves the way for future studies to assess whether any of these phenotypes represent PD risk factors and whether any of these risk factors are modifiable.