Genetic Testing for Patients with Parkinson’s Disease

By Andrea Yoo, MD

Synopsis: In this large scale, international study of Parkinson’s disease (PD) patients, approximately 15% of participants were found to have a positive PD-related genetic variant, most commonly in the GBA1 and LRRK2 genes.

Source: Westenberger A, Skrahina V, Usnich T, et al. Relevance of genetic testing in the gene-targeted trial era: The Rostock Parkinson’s disease study. Brain. 2024;147(8):2652-2667.

Parkinson’s disease (PD) is the second most common — and one of the fastest growing — neurodegenerative disorders worldwide. The number of patients with PD has doubled in the last 15 years and will affect 1% of the world’s population older than 65 years of age and 3% of the population older than 85 years of age.

The Rostock International Parkinson’s Disease Study (ROPAD) was an international observational study characterizing the frequency and variability of genetic variants in a large cohort of patients with PD. The authors looked for variants in 50 genes already known to be associated with PD or other disorders with PD-like phenotypical overlap, including other movement and neurocognitive disorders. The study consisted of 12,580 patients, age ≥ 18 years with the clinical diagnosis of PD from 16 different countries between April 2019 and May 2021.

The patients in the ROPAD study were predominantly male (62.3%), white (92%), and European (46%). Approximately 27% of participants reported a family history of PD. Overall, 1,864 (14.8%) participants had a positive PD-related genetic variant. Of the major previously reported PD-related genes, GBA1 and LRRK2 had the highest positivity rates at 10.4% and 2.9%, respectively, accounting for > 90% of results. The next two most common variants identified were PRKN (0.95%) and SNCA (0.2%), and 23 participants harbored both GBA1 and LRRK2 variants (0.18%).

Comparing the genetic variant-positive group to the genetic variant-negative group (identified as idiopathic PD [IPD]), the genetic variant-positive group was more likely to report a family history of PD (35.5% vs. 25.5%). Patients with a positive family history also were more likely to have a positive result (55%). The median age of onset was four years earlier in the genetic variant-positive group vs. the IPD group. Patients with an age of onset ≤ 50 years had higher rates of positivity (19.9%), which increased if there was concomitant family history (26.9%).

Assessing other associated genes, 37 participants had positive variants in non-PD genes related to parkinsonism-phenotype, with 24 of those patients with the GCH1 gene, which is classically categorized as a dystonia-parkinsonism disorder. Fifty-six patients returned positive results in genes associated with isolated dystonia disorders, such as TOR1A (0.07%) and SGCE (0.07%), or dementia syndromes, such as GRN (0.18%).

The authors do address several limitations of this study, potentially skewed by participant demographics. Approximately two-thirds of participants were recruited from tertiary care centers, which may bias and overestimate the presence of genetic PD. They highlight the relative lack of ethnic diversity, with > 90% of participants self-identifying as white.

Certain genes included for analysis but not seen in this study may reflect this lack of diversity, with the authors noting particularly low numbers of Asian participants (only 139).

Certain populations also were overrepresented, with participants from Israel accounting for 10% of the study but only with an estimated global representation of 0.1%. Certain subpopulations resulted in a higher percentage of positive results: Israel (19.5%) and Spain (18.2%), which likely was reflective of Ashkenazi Jewish and Berber heritage, respectively. These groups have known higher rates of GBA1 and LRRK2 variants, although adjusted analyses did not show any significant changes in results.

Commentary

The genetic landscape of PD is continuously expanding and likely far more complex than the current paradigm. In the accompanying scientific commentary by Gan-Or, referencing the ROPAD and PD GENEration studies, he makes the push for routine genetic testing.¹

As PD therapeutic clinical trials expand to disease-modifying therapies, several clinical trials targeting the two most common genetic variants, GBA1 and LRRK2, already are underway. These trials include genetic testing, but recruitment likely is skewed by those who already are known carriers. For example, GBA1 is routinely prescreened in certain European/Caucasian populations because of the risk of Gaucher disease. Gan-Or argues that routine genetic testing would allow for this “prescreening” to occur in a more heterogenous population.

However, this also comes with the increased need for appropriate genetic counseling, which is an additional resource-limiting factor in various parts of the world. Increasing availability of genetic testing without increasing access to counseling potentially could have other adverse effects.

Understanding PD genetics not only allows us to better understand the pathophysiology of the disease but also may give us a window into potentially understanding the variability in phenotypes and overall prognosis. Certain phenotypes, such as GBA1, are being studied for potentially earlier cognitive decline or poor outcomes with deep brain stimulation. Expanding our knowledge beyond the commonly known genes ultimately can aid in individualization of PD care with precision medicine.

Reference

1. Gan-Or Z. Clinical genetic testing in Parkinson’s disease should become part of routine patient care. Brain. 2024;147(8):2595-2597.

Andrea Yoo, MD, is Assistant Professor of Neurology, Weill Cornell Medicine.