Importance Parkinson disease (PD) and inflammatory bowel disease (IBD) have been associated, implying shared pathophysiology. Characterizing genetic pleiotropy between the two conditions aids the exploration of common etiology. Objective To estimate the genetic correlation between PD and IBD and to identify specific loci influencing both conditions. Design Genetic study with applications of high definition likelihood and conditional false discovery rate (FDR) framework. Setting The study was based on summary statistics of genome-wide association studies (GWAS). Participants The PD GWAS comprised 37,688 cases and 981,372 controls, and the IBD GWAS included 25,042 cases and 34,915 controls. Participants were of mixed ethnicity. Exposures None. Main Outcomes and Measures The main outcomes were a set of single nucleotide polymorphisms (SNPs) identified by conditional FDR analysis as jointly associated with PD and IBD. Results Weak but statistically significant genetic correlations were detected for PD with both Crohn's disease (CD) and ulcerative colitis (UC), the two main subtypes of IBD. A total of 1333 SNPs in 28 genomic loci and 1915 SNPs in 22 loci were jointly associated with PD-CD and PD-UC, respectively, at conjunctional FDR under 0.01. The pleiotropic loci appeared distinctive for PD-CD and PD-UC, are mostly novel and comprise loci with either same or opposing genetic effects on the two phenotypes. Positional and eQTL mapping prioritized 316 PD-CD and 303 PD-UC genes, among which only <10% are differentially expressed in both colon and substantia nigra. The KEGG pathways enriched by all prioritized genes were highly concordant between PD-CD and PD-UC, with the majority being related to immune and/or autoimmune dysfunction. Conclusions and Relevance Overall, we found robust evidence for a genetic link between PD and each subtype of IBD. The identified genetic overlap is complex at the locus and gene levels, indicating the presence of both common etiology and antagonistic pleiotropy. At the functional level, our results highlighted a central role of host immunity and/or autoimmunity in the PD-IBD relationship.

Dr. Ludvigsson coordinates a study on behalf of the Swedish IBD quality register (SWIBREG). The study has received funding from Janssen corporation. Other authors declare no competing interest.

The study is funded by Swedish Research Council (grant No. 2017-02175). Dylan M. Williams is funded by the United Kingdom's Medical Research Council (MC_UU_00019/2).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study involved only publicly available summary statistics of multiple GWAS data. Full summary statistics of GWAS on IBD are publicly available at GWAS Catalog: genetic associations with CD can be downloaded at https://www.ebi.ac.uk/gwas/studies/GCST004132 and for UC at https://www.ebi.ac.uk/gwas/studies/GCST004133. Summary statistics of PD GWAS can be obtained via research project applications to 23andMe and the IPDGC. For 23andMe, the full GWAS summary statistics for the discovery data set will be made available through 23andMe to qualified researchers under an agreement with 23andMe that protects the privacy of the 23andMe participants. Please visit research.23andme.com/collaborate/ for more information and to apply to access the data.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

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All data analyzed in the present study are publicly available summary statistics of multiple GWAS data. Full summary statistics of GWAS on IBD are publicly available at GWAS Catalog: genetic associations with CD can be downloaded at https://www.ebi.ac.uk/gwas/studies/GCST004132 and for UC at https://www.ebi.ac.uk/gwas/studies/GCST004133. Summary statistics of PD GWAS can be obtained via research project applications to 23andMe and the IPDGC. For 23andMe, the full GWAS summary statistics for the discovery data set will be made available through 23andMe to qualified researchers under an agreement with 23andMe that protects the privacy of the 23andMe participants. Please visit research.23andme.com/collaborate/ for more information and to apply to access the data.