Newly reported research indicates that genetic variants associated with Parkinson’s disease (PD) are more common than scientists had previously believed. Investigators for the Parkinson’s Foundation-backed PD GENEration (PD GENE) study—which reached its goal of 15,000 participants ahead of schedule earlier in 2024—found that 13% of study participants have a genetic form of PD. This is a significant observation when compared with long-standing estimates.
Lead principal investigator for PD GENEration, Roy Alcalay, MD, MS, at Tel Aviv Medical Center, Israel, and the Department of Neurology, Columbia University Irving Medical Center, reported data from the first 3.5 years of the study, which examined a broad North American cohort, in Brain. Their paper is titled “Parkinson’s disease variant detection and disclosure: PD GENEration, a North American study.”
Variants in seven genes (LRRK2, GBA1, PRKN, SNCA, PINK1, PARK7, and VPS35) have been formally acknowledged as causal contributors to Parkinson’s disease, the authors wrote. “Prior studies have identified pathogenic variants in Parkinson’s disease-linked genes in about 5–10% of people with Parkinson’s disease in the United States and Europe.” However, individuals with Parkinson’s disease are often unaware of their genetic status since clinical testing is infrequently offered,” they continued. “ … only a small fraction of people with Parkinson’s disease receive genetic testing due to lack of awareness among clinicians and patients, cost issues and lack of clinician confidence in providing results to patients … As a result, genetic information is not incorporated into clinical care, and variant-targeted precision medicine trials struggle to enroll people with Parkinson’s disease.”
PD GENEration, which tests for clinically relevant Parkinson’s-related genes, has been offered by the Parkinson’s Foundation since 2019 to any person with a confirmed PD diagnosis. The study is the first of its kind to return results at scale via live genetic counseling in English or Spanish. This enables participants and physicians to make more informed decisions about their care, including enrollment in gene-specific clinical trials.
Newly reported results from the PD GENEration study found that 7.7% of participants carried a GBA1 genetic mutation, 2.1% of participants carried a PRKN genetic mutation, and 2.4% of participants carried a LRRK2 genetic mutation. All participants were informed about their genetic status through the genetic counseling component of the program.
The positivity rate for a genetic variant is significantly higher for individuals with high risk, the analysis found. Those with age at onset (AAO), high-risk ancestry (such as Ashkenazi Jewish, Spanish Basque, or North African Berber), or a first-degree relative affected with the disease had an 18% positivity rate. The positivity rate for individuals without one of those risk factors was nearly 10%. The authors stated, “In summary, this large study of genetic testing for Parkinson’s disease in North America and Caribbean sites confirms a relatively high rate of positive (abnormal) results, approximately 13% for reportable or disease-relevant variants. Positive results were observed in up to 18% in people with genetic risk factors such as early AAO, high-risk ancestry, or an affected first-degree relative, but also 9% in people lacking any of these risk factors.”
The researchers suggest that many of these participants may qualify for precision medicine trials, showing the feasibility and importance of broadly offering genetic testing. “Our findings show that there are many previously unidentified people with Parkinson’s disease who could qualify for precision medicine trials, especially ones focused on GBA1 (approaching 10% of all participants) and, to a lesser extent, LRRK2,” they wrote. Alcalay added, “We did not anticipate the high positivity rate for genetic mutations, specifically the nearly 10% having a positive result even without any known genetic risk factors. Further, the speed at which participants enrolled in PD GENEration is a testament to the interest of people with PD to obtain data on their genetic status. Taken together, the positivity rate and the high interest in getting genotyped will hopefully translate to increased participation in observational studies and clinical trials toward therapies targeting these genes, simplifying precision medicine clinical trials in PD.”
The authors say the PD GENE study has attempted to reduce previously identified barriers to genetic testing in Parkinson’s disease, including cost, physician knowledge and comfort with genetics (through training materials and coursework), the perceived low yield of genetic testing, and patient awareness. The team also noted some trial weaknesses, and stated, “In the future, we plan to enhance our ongoing efforts to enroll underrepresented populations and to help improve the understanding of Parkinson’s disease gene variants in these groups.”
Commented Lola Cook, MS, CGC, Department of Medical and Molecular Genetics at Indiana University, first author of the report in Brain, and one of six genetic counselors involved in the study to date, “PD GENEration stands at the forefront of precision medicine and the potential for tailored treatments. In large part, this is because the Parkinson’s Foundation has recognized the importance of including genetic counseling in a research study that discloses genetic results. As we’ve seen from the study’s enrollment numbers and survey results, there is a strong interest among people with PD to push the research effort forward. This includes understanding the disease’s genetics, generally and individually. It’s the idea that we are all doing our part to move toward improved treatments and a cure.”
PD GENEration is continuing into its next phase with support from the Global Parkinson’s Genetics Program (GP2), a program of the Aligning Science Across Parkinson’s (ASAP) initiative. ASAP’s funding allows the Parkinson’s Foundation to accelerate the study’s impact by focusing on those who have been historically underrepresented in research. Such enhanced wide-scale recruitment is reaching a larger and more diverse community in the United States, Canada, and Latin America. The Parkinson’s Foundation aims to enroll an additional 8,000 participants, including 2,400 in Latin America, during the next phase of the study. “Several strategies are underway to enhance the recruitment of other underserved populations into the last third of the study’s planned cohort,” the investigators wrote.
James Beck, PhD, senior vice president and CSO of the Parkinson’s Foundation, added, “PD GENEration is designed to be inclusive and accessible to all populations, with the goal of improving clinical outcomes for everyone. We are proud that the data we have collected through PD GENEration reflects the largest and most diverse North American cohort ever tested—and even though we reached our initial recruitment goal of 15,000 this spring, bigger things are on the horizon … Our partnership with ASAP and GP2 allows us to reach significantly more people, further increasing the diversity of participants. Being able to understand the genetics that people with PD have in common across different populations could reveal biological secrets of the disease, with the potential to lead to new treatments.”
In their paper, the authors further noted, “As trials of gene-specific potentially disease-modifying treatments have begun, and genetic results may impact disease prognosis, possibly for management, and with certainty and clarity related to familial risks, we believe that clinical genetic testing should be offered to all people with Parkinson’s disease to empower them to act upon their genetic findings.”
