Mutations in the leucine-rich repeat kinase 2 (LRRK2) have the largest known genetic influence on Parkinson's disease (PD).
Now, researchers have reported that mutations in LRRK2 also influenced the risk of Crohn's disease (CD). And as in PD, some variants they identified were protective, while others increased risk.
Corresponding author Inga Peter told BioWorld that her team did not go into the study looking for, or even considering, a possible link between the two disorders. "We were just screening for novel Crohn's disease genes," she said. "It was a totally unexpected finding."
Peter is a professor of genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai, and the corresponding author of the paper reporting the findings, which appeared in the Jan. 10, 2018, issue of Science Translational Medicine.
Beyond its specific findings on LRRK2, the study also illustrates both a strategy for and the possible payoffs of looking for rare mutations.
One of the unexpected challenges for wresting actionable findings from genomic studies has been that the genetic contributions to disease are often characterized by a pattern of many common variants, each of which has a small effect on disease risk.
Rare genetic variants that have a larger effect may exist for common diseases. But the sample sizes necessary to identify them with statistical confidence can be hard to come by.
To get around this problem, Peter and her team started by looking at individuals of Ashkenazi Jewish descent, even though they were ultimately looking for risk variants that affected the general population.
The Ashkenazi Jewish population has experienced several genetic bottlenecks, at one point consisting of only slightly more than 300 individuals.
In the millennia since, the population has been fruitful and multiplied. But genetically speaking, the past bottlenecks have left their mark. Certain rare mutations, Peter said, are "not so rare in this population."
The most famous examples are the BRCA genes. But Ashkenazi Jewish populations also have a high incidence of several lysosomal storage disorders, and their risk of CD is two to four times that of the general population.
In their experiments, Peter and her team looked for the genetic underpinnings of that risk by first sequencing the exomes of 50 individuals with CD. Collectively, the 50 had almost 4,000 new variants in their exomes. The team then genotyped both healthy individuals and individuals with Crohn's disease to see whether any of the variants in the exome cohort were associated with Crohn's risk in the larger cohort, and found both risk and protective variants in LRRK2, whose claim to fame to date has been its association with PD.
The team then replicated its association study in individuals that were not of Ashkenazi Jewish descent, and showed that although the mutations were (even) less common in this population, when they did occur, they had the same effect on CD risk.
"The mutations themselves were less common," Peter said. But when they did occur, "the effect size was the same."
How LRRK2 affects CD risk, and whether it affects the same underlying cellular processes in CD and PD, is still unclear. "The LRRK2 gene is linked to so many different processes that it's very difficult to pinpoint," Peter said, and beyond the involvement of very general mechanisms such as inflammation and autophagy, the diseases are not, on their surface, similar.
"We do believe that they are likely to have different substrates, and they may act in different tissues," she said. But "the whole idea of increased activity is the same."
Shared mechanisms or not, the findings could influence the clinical management of both CD and PD.
On the CD side, the scientists plan to test whether LRRK2 inhibition would be a useful therapeutic approach.
On the PD side, they want to test whether the shared genetic risk is accompanied by an epidemiological link between CD and PD.
"We are suspecting that people with CD will be more likely to develop PD, and possibly vice versa," Peter said.
The current consensus is that neurodegenerative diseases start damaging the brain decades before clinical symptoms are apparent, which makes it very challenging to identify future patients before the damage has become irreversible.
But the average onset of CD occurs decades before PD, and so if there is an epidemiological link between the two, it would provide an early way to identify at least one group of people who are at increased risk of PD. And with it, Peter said, "a window of opportunity of intervention . . . to prevent or postpone Parkinson's."