LRRK2 Gene Involved in Pathogenesis of IBD and Parkinson Disease Comorbidity

Leucine-rich repeat kinase 2 (LRRK2) is found to be the most significant gene in the pathogenesis of inflammatory bowel disease (IBD) and Parkinson disease (PD) comorbidity, according to study findings published in the journal Genome Medicine.

Previous studies have suggested the role of LRRK2 in IBD and PD pathogenesis, which share common pathophysiologic processes.

Using data from the Danish National Patient Registry, Mount Sinai BioMe Biobank, and the UK Biobank, researchers determined the genetic basis of IBD-PD comorbidity.

The whole genomes of European patients with both IBD and PD, as well as the whole exomes of patients with IBD or PD, were analyzed for association testing of LRRK2 missense gene variants. For the identification of novel candidate genes in this cohort, optimized sequence kernel association test (SKAT-O) and network-based heterogeneity clustering (NHC) were performed, followed by gene prioritization using biological relatedness methods.

A total of 20,158,023 variants across 67 patients with both IBD and PD and 426 control participants were included in the analysis. The majority of the study population was men.

From the 9 LRRK2 missense variants identified in the IBD-PD dataset, as well as 14 variants from the BioMe Biobank cohort and 28 from the UK Biobank cohort, G2019S was significantly associated with IBD-PD comorbidity (P =1.59×10^-4). The presence of G2019S showed an increased risk for PD in both the Biobank cohorts (P =6.56 × 10^-5 and P =7.66 × 10^-3, respectively). The researchers observed that N2081D was also associated with IBD-PD comorbidity (P =.027). In addition, increased risk for the IBD-PD phenotype was seen with L119P, P1542S, and M2397T.

Based on SKAT-O analyses, LRRK2, IL10RA, and DHRS2 were found to be associated with both IBD and PD (P =7.41×10^-7, P =1.11×10^-6, and P =1.85×10^-5, respectively), with LRRK2 noted to be the most significant gene and IL10RA and DHRS2 as candidate genes.

Results of the NHC showed 6 significant gene clusters that were significantly associated with IBD-PD.

To compare IBD-PD-associated genes with established IBD and PD genes, the researchers combined the results of SKAT-O and NHC analyses. They found that 5.83% overlapped with known IBD genes and 3.33% with known PD genes.

Further, findings from a pathway enrichment analysis showed 6 pathways that were enriched in all 3 gene sets; 75 pathways were shared between IBD-PD and known IBD gene sets, and 4 pathways between IBD-PD and known PD gene sets.

Using biological relatedness methods, 14 candidate IBD-PD genes were prioritized that were involved in immunity, inflammation, and autophagy in IBD-PD.

Limitations of the analysis included lack of detailed clinical data for patients with both IBD and PD; the lack of generalizability to more racially and ethnically diverse populations; and the use of data from a relatively small cohort. However, the researchers concluded, “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.”