Novel gene variants may predict risk for co-occurring Parkinson’s disease, IBD

Key takeaways:

• Researchers analyzed more than 7,600 individuals with Parkinson’s, inflammatory bowel disease or healthy controls.
• G2019S and N2081D variants may contribute to increased or decreased risk for co-occurring PD, IBD.

Novel forms of a rare genetic variant may contribute to the risk for co-occurring Parkinson’s disease and inflammatory bowel disease, according to research presented in Genome Medicine.

“Inflammatory bowel disease comprises a group of chronic inflammatory diseases that primarily affect the gastrointestinal tract. Parkinson’s disease is one of the most common neurodegenerative disorders,” Meltem Ece Kars, MD, PhD, a postdoctoral researcher at The Charles Bronfman Institute for Personalized Medicine at Icahn School of Medicine at Mount Sinai, and colleagues wrote.

“Emerging evidence suggests a link between these two apparently unrelated disorders, indicating shared risk factors and underlying pathophysiology.”

The gene variant LRRK2 has been implicated as playing a role in both Parkinson’s disease (PD) and inflammatory bowel disease (IBD), Kars and colleagues wrote. The researchers aimed to explore the genetic basis for a connection between the two to facilitate the identification of shared genetic factors.

Their study analyzed whole exomes from the BioMe BioBank and U.K. Biobank, as well as whole genomes from the Danish National Biobank (DNB) to examine the effects of LRRK2 missense variants on IBD, PD and their co-occurrence.

From the BioMe and Biobank cohort, a total of 231 individuals with PD, 387 with IBD and 800 controls were included. From the U.K. Biobank, 661 individuals with PD, 2,081 with IBD and 3,000 controls were identified, while 67 individuals with IBD-PD and 426 controls were identified from the DNB.

Researchers 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, prioritizing by biological relatedness approaches.

They additionally conducted phenome-wide association studies employing BioMe BioBank and U.K. Biobank whole exomes to estimate the genetic relevance of the 14 prioritized genes to IBD-PD.

Analysis of LRRK2 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 risk for co-occurring conditions.

SKAT-O identified two significant genes, LRRK2 and IL10RA, while NHC identified six significant gene clusters that are biologically relevant to IBD-PD.

Kars and colleagues additionally observed prominent overlaps between the enriched pathways in the known IBD, PD and candidate IBD-PD gene sets and detected significantly enriched pathways unique to IBD-PD, including MAPK signaling, LPS/IL-1 mediated inhibition of RXR function and NAD signaling.

“We've found that [inflammatory bowel disease] 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 in a related release. “This could dramatically change our approach to these diseases, allowing for therapies that target both conditions simultaneously."

Reference:

Mount Sinai Study Identifies Genetic Link Between Inflammatory Bowel Disease and Parkinson’s Disease. https://www.mountsinai.org/about/newsroom/2024/mount-sinai-study-identifies-genetic-link-between-inflammatory-bowel-disease-and-parkinsons-disease. Published May 13, 2024. Accessed May 14, 2024.