1 in 6 Parkinson’s cases linked to genetic variants: ROPAD data
Almost all are associated with LRRK2, GBA1 genes
About 15% of Parkinson’s disease cases are tied to genetic variants and nearly all are associated with the LRRK2 and GBA1 genes, initial data from the Rostock International Parkinson’s Disease (ROPAD) study indicates.
Launched by Centogene in collaboration with Denali Therapeutics in 2018, ROPAD (NCT03866603) is the world’s largest effort to characterize the genetic profile of people with Parkinson’s at more than 100 sites worldwide. Its goal is to better understand Parkinson’s disease diagnosis, progression, and treatment.
“Our collaborative work clearly shows how significant of a role genetics plays in Parkinson’s disease and underscores the need to integrate genetic testing in routine care of these patients,” Peter Bauer, MD, Centogene’s chief medical and genomic officer, said in a company press release. “This will not only enable access to potentially available treatments, but will de-risk and accelerate the development of gene-specific therapies, driving the future of Parkinson’s disease patient care.”
Data from ROPAD were published in Brain, in the study, “Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson’s disease study.”
While the causes of Parkinson’s remain poorly understood, it’s well established that genetics play a key role in influencing disease risk.
Still, estimates of the type and frequency of disease-related variants in different populations are limited. Moreover, many patients don’t know their genetic status, which makes it hard to include them in clinical trials that test therapeutics against genetic targets.
ROPAD data reviewed
The ROPAD study is an ongoing observational study to determine the frequency and type of genetic variants that contribute to Parkinson’s in a large international group.
“Over the past five years, Centogene and our more than 100 study sites around the world have worked together to diagnose Parkinson’s patients and accelerate treatment options,” Bauer said.
In this analysis, researchers investigated variants in 50 genes in 12,580 Parkinson’s patients from 16 countries. Among the adult participants, 62.3% were men, 92% were ethnically white, and 27.0% had a family history of the condition. DNA was extracted from dried blood spots and analyzed at Centogen.
Overall, 1,864 (14.8%) ROPAD participants had a positive Parkinson’s disease-relevant genetic test, or PDGT. Detected variants were related to the GBA1 gene (10.4%), LRRK2 gene (2.9%), PRKN gene (0.9%), SNCA gene (0.2%), or PINK1 gene (0.1%), or a combination of two genetic findings in two genes (about 0.2%).
About 90% of the patients with a positive PDGT had variants in the LRRK2 or GBA1 genes, “making these individuals potential candidates to be included in gene-targeted trials,” the researchers wrote.
Some variants accounted for a significantly higher percentage of familial versus sporadic Parkinson’s cases: LRRK2, 5.04% vs. 2.36%; GBA1, 7.04% vs. 4.84%; and PRKN, 1.68% vs. 0.72%.
Female patients were 22% more likely to have a positive PDGT and those with a family history were 55% more likely to be PDGT positive than those with a negative family history.
One patient out of five (19.9%) with an age of onset of 50 or younger (early onset) and 1 in 5 (19.5%) with a family history were identified with positive PDGTs. Among those with both an age of onset below 50 and a family history, about 1 in 4 (26.9%) were PDGT positive. These findings suggest “genetic testing might be offered preferentially to these patient groups,” the researchers wrote.
The age of onset, age at diagnosis, and age at ROPAD enrollment were all significantly four years younger in the positive PDGT group than in patients with idiopathic Parkinson’s disease, or that had an unknown cause. Furthermore, the likelihood of a positive PDGT decreased by 3% with every additional age of onset year.
When individual variants were compared, the proportion of participants with a family history was significantly higher among PDGT-positive patients with variants in the LRRK2-, PRKN/PINK1/PARK7-, and SNCA genes than in idiopathic patients.
The age of onset, diagnosis, and enrollment were significantly lower in patients with PRKN/PINK1/PARK7-related variants compared with the idiopathic group and all other genetic groups except for the SNCA-positive group. The age at onset, diagnosis, and enrollment was also younger in those with GBA1 variants than in the idiopathic group.
Finally, a small but considerable number of participants (about 0.8%) had a positive genetic test in genes related to parkinsonism, dystonia/dyskinesia (uncontrolled movements), or dementia, raising the possibility of shared underlying disease-causing mechanisms.
“The insights from the ROPAD study allow for data-driven, differential genetic counseling across the spectrum of different [age of onsets] and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD [Parkinson’s disease],” the researchers said.
Centogene and the Michael J. Fox Foundation (MJFF) teamed up recently to investigate genetic risk factors for Parkinson’s, with an emphasis on GBA1 gene variants. The company also launched a ROPAD Consortium to improve Parkinson’s research and treatment by connecting neurologists, nonprofits, and genetic testing programs for better data access and collaboration.
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