Genetic link identified between inflammatory bowel disease and Parkinson's disease

By Dr. Liji Thomas, MDMay 15 2024Reviewed by Danielle Ellis, B.Sc.

Both inflammatory bowel disease (IBD) and Parkinson’s disease (PD) are chronic inflammatory conditions, and some scientists hypothesize a common pathway for both involving the leucine-rich repeat kinase 2 (LRRK2) gene. A recent study published in Genome Medicine examined rare gene variants found in people with both these conditions in a bid to identify the genetic underpinnings common to both.

About IBD and PD

IBD refers to a cluster of gastrointestinal diseases, including Crohn’s disease (CD) and ulcerative colitis (UC), characterized by chronic inflammatory damage of various segments of the gut. PD is a highly prevalent neurodegenerative disorder where the individual develops slowness of movement, rigidity, resting tremor, and unstable posture due to the loss of dopaminergic neurons in specific brain regions.

These two conditions are now suggested to share a common set of risk factors and to evolve through common pathways, though they impact apparently remote organs. This may be due to chronic systemic inflammation, perhaps driven by the gut-brain axis, in individuals at risk due to any of the multiple gene variants that increase their vulnerability to neurodegeneration.

A large recent meta-analysis involving 12 million patients seems to underline the plausibility of this hypothesis by demonstrating that IBD patients have a higher risk of being diagnosed with PD, especially after the age of 65. Conversely, the use of anti-inflammatory drugs such as TNF-α inhibitors is associated with a marked drop in PD risk. These reports indicate the possibility that IBD and PD are both triggered in some way by inflammation, shared genes, or both.

LRRK2 is the best-studied gene to show associations with IBD-PD since gene variants with increased activity have been linked with a higher risk of both CD and PD. Yet each of these is linked to a specific gene variant, like G2019S for PD and N2081D for CD.

The current study sought to analyze patients with both co-occurring conditions to provide more comprehensive insights into the common mechanisms underlying them, focusing on LRRK2 missense variants. The investigators looked at how such variants affected the risk of PD, CD, UC, IBD, and IBD-PD.

About the study

The researchers used genomic data from a set of 67 European patients who had both PD and IBD, as well as whole exomes from the BioMe BioBank and UK Biobank. The aim was to find how non-functional variants of LRRK2 affected either condition or the odds of their occurring together.

They examined networks of correlations between high-impact rare variants so as to identify novel candidate genes. These were further tested for relative importance on the basis of the degree to which they were biologically related. Phenome-wide association studies (PheWAS) were also carried out with whole exomes in an attempt to clarify how relevant the prioritized genes were in the individuals with co-occurring IBD and PD.

What did the study show?

The study showed that some missense variants of LRRK2 were linked to the co-occurrence of IBD and PD, namely, G2019S and N2081D. Moreover, others were identified as having the potential to increase or decrease the risk of such co-occurrence.

For instance, G2019S was more frequent in both PD and IBD, while N2081D was linked to increased risk for PD and CD. The P1542S variant was found to be associated with a higher risk of IBD-PD only. In contrast, R1398H, N551K, and I723V variants were protective against IBD-PD.

Further association analysis showed that both LRRK2 and IL10RA were significantly associated with IBD-PD. Prior research has suggested that the genes encoding IL10 and IL10 receptors are important in countering inflammation. Their variants are linked to very early onset IBD, as well as in neurodegenerative disease.

The results also showed six gene clusters with biologically relevant associations to IBD-PD. Two were genes that had earlier been associated with PD, and four were associated with other pathways that may be involved in the pathogenesis of neurodegenerative disease in general, PD in particular, or IBD.

Some pathways were found to be enriched in the gene sets related to IBD, PD, and putative IBD-PD. Some others were identified as being uniquely enriched in IBD-PD gene sets alone. The genes associated with IBD-PD were compared to those known to be associated with either IBD or PD and found to be more often related than expected by random chance.

The biological relatedness analysis identified 14 genes as of the highest priority for IBD-PD. The candidate genes were related to immunity, inflammation, and autophagy, indicating their potential role in the initiation and progression of IBD-PD. The PheWAS results provided more support for the hypothesis that these genes were functionally important in the appearance of broad-ranging symptoms and signs.

The current study looked at rare rather than common gene variants contributing to the pathogenesis of IBD-PD comorbidity on the postulate that common variants account for only a small fraction of cases. Other cases may be traceable to chronic inflammation and environmental triggers.

Conclusions

The researchers found, as expected from prior studies that LRRK2 is associated with IBD-PD and discovered new associations as well. Their ability to identify new genes involved in autophagy and inflammation pathways in the IBD-PD networks extends what is known about the origin of IBD-PD. Moreover, it emphasizes the need to counter systemic inflammation while treating these co-occurring conditions.

 “It will be crucial to continue investigating the genetic determinants of IBD-PD comorbidity to gain a comprehensive understanding of the underlying pathogenesis and develop effective risk stratification and personalized treatment strategies.”

Larger studies using a case-control design and assessing both common and rare variants will be necessary to evaluate the identified candidate genes, which may not produce symptoms or signs in every case.