Genetic testing for Parkinson's disease in Israel: Insights from the Rostock Parkinson's Disease (ROPAD) study, 2025, Saar Anis et al

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Mij

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Hightlights​

The study included 2699 Israeli Parkinson's disease patients, recruited to the Rostock Parkinson's Disease (ROPAD) study.
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The rate of positive PD-relevant genetic test (PDGT) was 19.0 %.
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Pathogenic LRRK2 variants were observed in 6.9 % of patients, and GBA1 risk factor variants in 10.5 %.
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A positive PDGT result due to variants in other genes was noted in only 1 % of participants.

Abstract​

Background​

We examined the yield of a large-scale genetic testing for patients with Parkinson's disease (PD) in Israel, where risk factor variants in GBA1 and/or the pathogenic p.Gly2019Ser variant in LRRK2 are prevalent among the Ashkenazi Jewish population.

Methods​

This study included data from all Israeli movement disorder clinics participating in the Rostock Parkinson's Disease (ROPAD) study. Patients were tested for variants in eight PD-related genes and 37 genes with possible phenotypic overlap.

Results​

The sample consisted of 2699 PD patients recruited in three phases (1702 [63.1 %] males, mean age at onset 59.2 ± 10.6 years, 718 [26.6 %] with a family history of PD). Positive PD-relevant genetic test (PDGT) results were obtained in 512 participants (19.0 %). Among 187 (6.9 %) patients the results were due to pathogenic variants only in LRRK2, in 283 (10.5 %) due to risk factor variants only in GBA1, and another 15 patients (0.6 %) were carriers of variants in both genes. Twenty-six subjects (1.0 %) had a positive PDGT based on findings in PRKN (n = 19), PINK1 (n = 4), PARK7, SNCA, or VPS35 (one in each gene), and an additional patient had dual findings (GBA1 and SNCA). The most prevalent variants were LRRK2 p.Gly2019Ser and GBA1 p.Asn409Ser, detected in 191 (7.1 %) and 173 (6.4 %) patients, respectively. Excluding patients harboring only LRRK2 and/or GBA1 variants, the yield was 27/2214 (1.2 %). Seven participants, including one with a positive PDGT, had positive testing findings in genes related to dystonia (GCH1 and TOR1A) and dementia (MAPT).

Conclusions​

Genetic testing for Israeli PD patients is beneficial, while the yield is primarily attributed to LRRK2 and GBA1 variants.
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New data from Israel’s participation in the ROPAD Parkinson genetics study raises big questions. Genetic testing across nearly 2700 Parkinson’s folks showed that only ~19% had a known genetic contributor. That leaves more than 80% of cases unexplained even among those w/ a family history. What are we missing? Spoiler alert: the environment.

Key Points:-
- Only ~19% of Israeli Parkinson’s folks had a positive genetic test result, mostly from LRRK2 or GBA1 variants.
- Even w/ family history, the genetic contribution was modest, highlighting the unexplained risk factors
- The majority of cases point us toward environmental exposures as critical drivers of the disease.

My take: The genetics are so important to our understanding of Parkinson's, however it is time to pivot more toward environmental causes. Here are 5 points that resonated w/ me from this paper.
1- Genes matter, but in this large Israeli study most people w/ Parkinson’s did not have a known genetic mutation.
2- Even if Parkinson’s runs in the family, genetics only explained about one in five cases.
3- What does this mean? We need to look beyond DNA alone. Environmental exposures like pesticides, chemicals, and pollutants are likely powerful contributors.
4- Understanding the mix of genes and environment will be the key to prevention and better treatments.
5-Parkinson’s is not just about heredity, it is a global health issue that demands we tackle both genetic risk and environmental causes.
 
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