NEW YORK (GenomeWeb) – A gene behind Parkinson's disease can also influence an individual's chances of developing Crohn's disease, according to research by an international team of investigators.
The researchers began by using exome sequencing and genotyping to search for Crohn's disease-associated genetic variants in nearly 5,700 individuals of Ashkenazi Jewish ancestry — a population at enhanced risk of developing the inflammatory bowel disease. As they reported in Science Translational Medicine today, the search led to risky and protective variants in LRRK2, a gene that has been linked to Parkinson's disease in Ashkenazi and non-Ashkenazi populations.
Through a series of follow-up experiments, including targeted LRRK2 analyses involving tens of thousands of individuals, the team found evidence of pleiotropy between Crohn's and Parkinson's disease. While a variant that protected against Crohn's disease appeared to deactivate LRRK2, for example, LRRK2 variants associated with enhanced Crohn's and Parkinson's risk seemed to ramp up the kinase enzyme activity of the protein encoded by LRRK2.
"We identified independent coding [Crohn's disease] risk and protective alleles in LRRK2, a large multifunctional gene that confers the greatest genetic effects reported thus far in Parkinson's disease," Mount Sinai genetics and genomic researchers Inga Peter and Judy Cho, the study's co-corresponding authors, and their colleagues wrote.
Although hundreds of genetic loci have been implicated in inflammatory bowel disease in past studies, the team noted that effective, long-term treatments are still lacking for many affected individuals, particularly for those with Crohn's disease. Consequently, the authors set out to find more rare genetic contributors to Crohn's disease in a population that's prone to the condition.
Based on exome sequence data for 50 Crohn's disease-affected Ashkenazi Jewish individuals, the researchers identified almost 4,300 new mutations. They were subsequently stitched into a custom HumanExome BeadChip array, which was used to genotype 1,477 unrelated Ashkenazi Jewish individuals with the inflammatory bowel disease and 2,614 without.
In these individuals, the team narrowed in on three suspicious non-synonymous variants that were subsequently analyzed in an independent group of 589 Crohn's disease cases and 1,019 controls. Two of these alleles — in the NOD2 and IL23R genes — had been linked to the condition in the past. A third locus involved risky or protective variants in and around LRRK2 and SLC2A13 that prompted further scrutiny in Crohn's cases and beyond.
The researchers' analyses indicated that the latter signal stemmed from variants in LRRK2, a gene implicated in both sporadic and familial forms of Parkinson's disease in the past. They noted that one of the risky LRRK2 variants was over-represented in individuals with earlier Crohn's disease onset.
Using gene expression profiles from hundreds of intestinal biopsy samples, the team saw signs that LRRK2 belongs to a network of genes expressed in Crohn's-affected samples.
And when they looked at LRRK2 variants in another 6,538 individuals with Crohn's disease, 5,570 individuals with Parkinson's disease, and 12,607 unaffected controls, from both Ashkenazi Jewish and non-Ashkenazi backgrounds, the authors saw overlapping effects for the alleles associated with Crohn's and Parkinson's.
The team went on to explore this overlap in a series of cell line and patient-derived cell culture experiments, characterizing the consequences of the protective and risky LRRK2 variants on the kinase enzyme activity and other functional features of the resulting protein.
"The presence of shared alleles in [Crohn's disease] and [Parkinson's disease] provides refined insight into disease mechanisms," the authors wrote, "and may have major implications for the treatment of these two seemingly unrelated diseases."