LRRK2, other gene mutations shared by IBD, Parkinson’s: Study

Findings could pave way for treating root cause of both conditions

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by Andrea Lobo |

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Researchers at the Icahn School of Medicine at Mount Sinai have identified LRRK2 gene mutations as a common element in both inflammatory bowel disease (IBD), an umbrella name for disorders marked by prolonged inflammation of the digestive tract, and Parkinson’s disease.

The study also identified genes involved in inflammation and autophagy — the cells’ recycling system — as likely involved in the mechanisms underlying both conditions.

The findings highlight the importance of developing therapeutic strategies for reducing systemic inflammation in people with coexistent IBD and Parkinson’s disease.

“Our research not only links these two diseases genetically but also sets the stage for new forms of treatment, and potentially prevention strategies, that could lessen the burden of these diseases on patients,” Meltem Ece Kars, MD, PhD, postdoctoral researcher at Mount Sinai’s Charles Bronfman Institute for Personalized Medicine, said in a press release from the institution.

The study, “The landscape of rare genetic variation associated with inflammatory bowel disease and Parkinson’s disease comorbidity,” was published in Genome Medicine.

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Inflammatory bowel disease (IBD) covers two main disorders — ulcerative colitis and Crohn’s disease — characterized by imbalanced immune responses that trigger chronic inflammation of the digestive tract. IBD has been associated with an increased risk of developing Parkinson’s disease.

Most cases of Parkinson’s are sporadic. However, about 15% of patients have a family history of the disease, or familial Parkinson’s, commonly associated with mutations in the LRRK2 gene.

Previous studies that examined the genetic correlations between IBD and Parkinson’s have used data from separate analyses of both conditions. “Conducting a joint analysis of individuals affected by both IBD and [Parkinson’s] would provide important insights into the underlying mechanisms shared by these two conditions,” the researchers wrote.

The team used advanced genomic analysis techniques to investigate the genetic overlap between the two conditions. They analyzed data from the Mount Sinai BioMe BioBank and the U.K. Biobank, which contained data on patients with only IBD or Parkinson’s, as well as 67 patients with both IBD and Parkinson’s from the Danish National Biobank.

The researchers assessed the impact of nine LRRK2 mutations identified in patients with both IBD and Parkinson’s. They also examined the associations of 14 LRRK2 mutations from the BioMe biobank and 28 from the U.K. biobank with Parkinson’s, IBD, Crohn’s disease and ulcerative colitis.

They identified G2019S, a well-known LRRK2 variant associated with Crohn’s and Parkinson’s, and the N2081D variant as being significantly associated with the coexistence of both IBD and Parkinson’s.

“Overall, these results provide further evidence in support of the role of LRRK2 variants in the [disease mechanisms] of IBD-[Parkinson’s] comorbidity,” the researchers wrote.

Then, using the IBD-Parkinson’s database, they confirmed the LRRK2 gene as the most significant gene associated with the coexistence of both conditions and identified IL10RA and DHRS2 as two candidate genes.

A network-based analysis, a type of analysis more effective at identifying genes in small groups of patients, revealed six biologically relevant clusters of genes – genes that share similar functions — involved in both conditions.

Further analysis revealed the involvement of genes related to immunity, inflammation, and autophagy that overlapped in both conditions. Researchers could identify 14 candidate genes, all reported to be associated with the mechanisms underlying IBD and Parkinson’s, supporting a connection between immune dysregulation, gut inflammation, and Parkinson’s motor symptoms.

“We’ve found that IBD and [Parkinson’s disease] are caused by certain shared genetic factors, including variants in LRRK2 and other genes previously unknown for this combined condition,” Kars said. “By pinpointing the genetic underpinnings common to both IBD and [Parkinson’s], we pave the way for innovative treatments, whether through the development of novel drug targets or the repurposing of existing drugs, that could potentially tackle the root causes of these conditions,” Kars added.

The findings could lead to a more integrated approach to studying diseases that may share common genetic pathways, the Icahn School of Medicine said.