The landscape of rare genetic variation associated with inflammatory bowel disease and Parkinson's disease comorbidity

Abstract

Background: Inflammatory bowel disease (IBD) and Parkinson's disease (PD) are chronic disorders that have been suggested to share common pathophysiological processes. LRRK2 has been implicated as playing a role in both diseases. Exploring the genetic basis of the IBD-PD comorbidity through studying high-impact rare genetic variants can facilitate the identification of the novel shared genetic factors underlying this comorbidity.

Methods: We analyzed whole exomes from the BioMe BioBank and UK Biobank, and whole genomes from a cohort of 67 European patients diagnosed with both IBD and PD to examine the effects of LRRK2 missense variants on IBD, PD and their co-occurrence (IBD-PD). We performed optimized sequence kernel association test (SKAT-O) and network-based heterogeneity clustering (NHC) analyses using high-impact rare variants in the IBD-PD cohort to identify novel candidate genes, which we further prioritized by biological relatedness approaches. We conducted phenome-wide association studies (PheWAS) employing BioMe BioBank and UK Biobank whole exomes to estimate the genetic relevance of the 14 prioritized genes to IBD-PD.

Results: The analysis of LRRK2 missense variants revealed significant associations of the G2019S and N2081D variants with IBD-PD in addition to several other variants as potential contributors to increased or decreased IBD-PD risk. SKAT-O identified two significant genes, LRRK2 and IL10RA, and NHC identified 6 significant gene clusters that are biologically relevant to IBD-PD. We observed prominent overlaps between the enriched pathways in the known IBD, PD, and candidate IBD-PD gene sets. Additionally, we detected significantly enriched pathways unique to the IBD-PD, including MAPK signaling, LPS/IL-1 mediated inhibition of RXR function, and NAD signaling. Fourteen final candidate IBD-PD genes were prioritized by biological relatedness methods. The biological importance scores estimated by protein-protein interaction networks and pathway and ontology enrichment analyses indicated the involvement of genes related to immunity, inflammation, and autophagy in IBD-PD. Additionally, PheWAS provided support for the associations of candidate genes with IBD and PD.

Conclusions: Our study confirms and uncovers new LRRK2 associations in IBD-PD. The identification of novel inflammation and autophagy-related genes supports and expands previous findings related to IBD-PD pathogenesis, and underscores the significance of therapeutic interventions for reducing systemic inflammation.

Keywords: Crohn’s disease; Genetic pleiotropy; Inflammatory bowel disease; Parkinson’s disease; Ulcerative colitis; Whole genome sequencing.

Fig. 1

Study workflow. Parkinson’s disease (PD) and inflammatory bowel disease (IBD) cases were identified based on ICD-10 codes in the UK Biobank and BioMe BioBank. The IBD-PD cohort comprised 67 individuals diagnosed with both PD and IBD and 426 healthy controls from the 1000 Genomes Project (1KGP). Variant-level association testing was performed separately in each cohort using LRRK2 variants observed in the whole exome (UK Biobank and BioMe BioBank) and whole genome sequencing (IBD-PD cohort) data (upper panel). Discovery of novel candidate genes was performed using the sequence kernel association test (SKAT-O) and network-based heterogeneity clustering (NHC) methods; the genes were further prioritized using pathway enrichment and biological relatedness methods. Fourteen prioritized candidate genes were then investigated in the BioMe BioBank and UK Biobank using phenome-wide association analysis (PheWAS) to validate identified associations (lower panel)

Fig. 2

LRRK2-centered and genome-wide analysis of the IBD-PD comorbidity. A PCA plot demonstrating the distribution of IBD-PD cases among 1000 Genomes Project (1KGP) superpopulations. B Correlogram displaying the associations of LRRK2 missense variants with Parkinson’s disease (PD), inflammatory bowel disease (IBD), Crohn’s disease (CD), and ulcerative colitis (UC) in the Danish Registry, BioMe BioBank, and UK Biobank (UKBB) cohorts. The colors indicate odds ratios (ORs), whereas asterisks denote the significance level of the P values (* P < 0.05, ** P < 0.01, ***P < 0.001). Empty cells indicate that the variant had a minor allele count (MAC) < 3 in the respective cohort or MAC < 1 in cases, and hence the association could not be assessed. C Manhattan plot displaying the results of the SKAT-O analysis. The two genes that passed the level of genome-wide significance (LRRK2 and 1L10RA) are highlighted in red. The dashed line denotes the genome-wide significance level. D STRING protein–protein interaction (PPI) network generated using genes identified in the most significant cluster (cluster 7) in the NHC analysis (in red). The size of the nodes is proportional to the number of variant carriers. Known IBD-associated genes in the extended PPI network are highlighted in blue

Fig. 3

Candidate gene prioritization and validation using a phenotype-wide association study (PheWAS). A Density plots displaying the distribution of the average distances of 120 random genes (D_random) to known inflammatory bowel disease (IBD, in purple) and known Parkinson’s disease (PD, in green) genes obtained from 10,000 resampling iterations. Dashed lines represent the average distance of the candidate gene set (D_candidate, n = 120) to known IBD and PD genes. B Circos plot showing the candidate genes identified by four complementary pathway and biological relatedness approaches. Final candidate genes that were identified by all four methods are highlighted in orange. C Heatmap of the combined biological importance scores of the IBD-PD candidate genes. A higher score indicates a higher number of shared pathways, ontologies, or modules with known IBD and PD genes. The colors represent the magnitude of the scaled scores calculated by each method. The highest-scaled scores are depicted in red, whereas the lowest scores are shown in blue. The top 40 genes are shown in the plot

Fig. 4

Gene-level PheWAS of 14 candidate genes in A BioMe BioBank and B UK Biobank. The red dashed lines denote the study-wide significance levels