New data suggests that LRRK2, the greatest known genetic contributor to Parkinson’s disease (PD), plays a role in the disease-causing mechanism of a larger percentage of people with PD than was previously believed. The findings, from lead investigator Owen Ross, PhD, of the Mayo Clinic’s Florida campus, were published online August 31 in Lancet Neurology. The study was supported with grants from The Michael J. Fox Foundation for Parkinson’s Research (MJFF), which has made the validation of LRRK2 as a potential disease-modifying target one of its key areas of research. Brian Fiske, PhD, director of research programs at MJFF, was a co-author of the paper.
Ross’ project, one of the largest to date in the study of the genetics of PD, found new variants in LRRK2 that suggest that the actual impact of the gene has been under-represented in the field of Parkinson’s research. It has already been shown that in some ethnic groups, mutations in LRRK2 increase the risk of developing Parkinson’s when compared to the general population. It is widely understood that LRRK2 mutations account for 15 to 20 percent of PD cases in Ashkenazi Jews and up to 40 percent of cases in North African Arab Berbers. Asians of Chinese descent also share common variants of LRRK2 which increases risk for PD. However, there remain a large number of LRRK2 variants that have yet to be investigated.
Ross’ work also found that mutations in LRRK2 can be protective against PD. He identified a common haplotype (a group of genetic variants that are inherited together) in both Caucasians and Asians that appears to lower an individual’s risk of developing the disease by as much as 20 percent. These findings likely suggest that this particular haplotype is common to most, if not all, ethnic populations, said Ross. The study also supports earlier work by Eng-King Tan, MD and colleagues that found that the genetic variation of LRRK2 may be protective against the development of PD in Chinese populations.
“It is important to recognize that there are good and bad variations in genetics, and that a combination of these work to determine whether or not someone might develop a particular disease,” said Ross. “We are now beginning to investigate how variations in LRRK2, some of them protective in nature, may affect an individual’s risk of PD.” In addition Ross adds that by “characterizing each patient’s individual ‘LRRK2 risk-profile’ future clinical trials can be conducted with those most likely to benefit from targeted LRRK2 therapeutics.”
Earlier funding from MJFF’s Edmond J. Safra Global Genetics Consortia supported the establishment of the Genetic Epidemiology of Parkinson’s Disease (GEO-PD) consortium which played a major role in the study. Investigators from 23 sites in 15 countries across five continents provided clinical samples from more than 15,000 individuals for the study.
MJFF continues to fund Ross to further investigate LRRK2 variants. He is working with Matthew Farrer, PhD, of the University of British Columbia, to implement a similar approach to look into genetically under-represented populations in areas such as South America, Africa, India and Indonesia to capture as much of the LRRK2-related genetic variation as possible.
“MJFF has a mission to help the global population of people with PD,” said Ross. “Many of the most populous countries in the world have yet to be investigated in terms of LRRK2’s influence on Parkinson’s. With the support of MJFF, we are beginning to tease out the full potential of LRRK2 as a genetic target that could lead the way to new therapies for PD.”
“MJFF is actively pursuing LRRK2 with the hope that it will allow us to study mechanisms underlying the onset and progression of PD,” added Fiske. “We are intent on capturing as much information as we can about LRRK2’s role in PD, and are always looking for ways to expand our data. Dr. Ross’ work is providing valuable information toward that goal.”