パーキンソン病の進化する遺伝的風景：世界的な有病率、表現型相関、そして精密医療の必要性

Highlights

• Large-scale global studies (ROPAD and PD GENEration) report a genetic diagnostic yield of 13%–19% in Parkinson’s disease (PD) populations, predominantly driven by GBA1 and LRRK2 variants.
• The GBA1 gene represents the most frequent risk factor globally, with distinct ethnic distributions: p.N409S dominates in Ashkenazi Jewish and White populations, while p.L483P is more prevalent in Asian and Hispanic cohorts.
• Genetic testing yields significant results even in patients without traditional risk factors (e.g., late onset or negative family history), supporting a shift toward universal clinical genetic screening.
• Emerging evidence links adaptive immune response genes, such as P2RX7, with PD risk and age at onset, suggesting a complex interplay between genetics and neuroinflammation.

Background

Historically, Parkinson’s disease (PD) was viewed as a predominantly idiopathic condition. However, the last two decades have seen a paradigm shift toward a genetic understanding of the disease. With the advent of gene-targeted therapeutic trials—specifically targeting glucocerebrosidase (GBA) and leucine-rich repeat kinase 2 (LRRK2) pathways—identifying a patient’s genetic status has transitioned from a research interest to a clinical necessity. Despite this, many patients remain unaware of their genetic profile due to limited access to testing and a lack of standardized disclosure protocols. This synthesis integrates high-impact data from major international cohorts to redefine the genetic architecture of PD and its clinical implications.

Key Content

Global Prevalence and Diagnostic Yield of Genetic Testing

Recent multi-center observational studies have clarified the expected yield of genetic testing in diverse populations. The international Rostock Parkinson’s Disease (ROPAD) study, evaluating 12,580 patients across 16 countries, identified a positive PD-relevant genetic test (PDGT) in 14.8% of participants. This yield was significantly higher in specific subsets, such as those with an age at onset (AAO) ≤ 50 years (19.9%) or a positive family history (19.5%). Notably, in Israel—a population with a high density of Ashkenazi Jews—the yield rose to 19.0%, with LRRK2 p.Gly2019Ser and GBA1 p.Asn409Ser accounting for the vast majority of cases (Anis et al., 2025; Westenberger et al., 2024).

In North America, the PD GENEration study (n=10,510) reported a 13% overall yield. Crucially, 9.1% of patients with no known risk factors (late onset, no family history, no high-risk ancestry) carried reportable variants. This finding challenges current restrictive testing guidelines and suggests that relying solely on clinical red flags may miss nearly 10% of genetically-defined PD cases (Cook et al., 2024).

GBA1: The Major Genetic Driver and Phenotypic Modifier

Variants in GBA1, encoding the lysosomal enzyme glucocerebrosidase, are now recognized as the most common genetic risk factors for PD. The MDSGene systematic review, covering over 27,000 GBA1 variant carriers, identified a clear genotype-phenotype relationship. Patients carrying “severe” variants (e.g., those associated with neuronopathic Gaucher disease) experience more rapid motor progression and a higher burden of non-motor symptoms compared to those with “mild” or “risk” variants (Rossi et al., 2025).

Geographic and ethnic disparities are pronounced: the p.N409S variant is the hallmark of Jewish and White populations, whereas p.L483P is the dominant pathogenic variant in Asian and Hispanic groups. Furthermore, novel variants continue to be discovered through targeted next-generation sequencing (NGS). For instance, a novel p.K505N variant was recently identified in Southern Italy, with structural in silico modeling confirming its potential to destabilize the protein structure, further expanding the known mutational spectrum of GBA1 (Gagliardi et al., 2025).

LRRK2 and the Role of Adaptive Immunity

While LRRK2 remains a primary focus for kinase inhibitor trials, recent research highlights the role of modifiers in disease risk. The P2RX7 gene, involved in the adaptive immune response, has been identified as a significant risk modifier. Specific variants like Arg276His are associated with an increased risk of PD specifically within LRRK2 carriers, while Glu496Ala is associated with an earlier age at onset in this group. This suggests that neuroinflammatory pathways may dictate the penetrance or timing of PD in individuals with a primary genetic predisposition (Shani et al., 2024).

Expert Commentary

The data presented by the ROPAD and PD GENEration studies represent a milestone in clinical neurogenetics. The high yield of variants in patients without family history (9.1% in North America) strongly supports the movement toward universal genetic testing for all PD patients. For the clinician, this information is no longer just prognostic; it is a gateway to precision medicine trials (e.g., GBA activators or LRRK2 inhibitors).

However, challenges remain. The identification of novel variants (like p.K505N) and “variants of uncertain significance” (VUS) requires sophisticated bioinformatics and structural modeling to determine clinical relevance. Furthermore, the MDSGene review highlights a concerning trend: cognitive decline often persists or worsens in GBA1 carriers even after successful motor interventions (like Deep Brain Stimulation), highlighting the need for early identification and tailored counseling regarding non-motor trajectories.

Conclusion

Genetic testing for Parkinson’s disease has matured into a standard-of-care component of patient evaluation. With approximately 15% of the global PD population harboring actionable variants—primarily in GBA1 and LRRK2—the focus must shift toward equitable access to testing and genetic counseling. Future research must continue to explore the interplay between primary genetic drivers and secondary immune modifiers like P2RX7 to unlock the full potential of precision therapeutics.

References

• Anis S, et al. Genetic testing for Parkinson’s disease in Israel: Insights from the Rostock Parkinson’s Disease (ROPAD) study. Parkinsonism Relat Disord. 2025;137:107940. PMID: 40617169.
• Westenberger A, et al. Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson’s disease study. Brain. 2024;147(8):2652-2667. PMID: 39087914.
• Gagliardi M, et al. Genetic analysis of GBA1 gene in a cohort of patients with Parkinson’s disease. Parkinsonism Relat Disord. 2025;139:108007. PMID: 40848607.
• Rossi M, et al. Classification and Genotype-Phenotype Relationships of GBA1 Variants: MDSGene Systematic Review. Mov Disord. 2025;40(4):605-618. PMID: 39927608.
• Shani S, et al. P2RX7, an adaptive immune response gene, is associated with Parkinson’s disease risk and age at onset. J Parkinsons Dis. 2024;14(8):1575-1583. PMID: 39957192.
• Cook L, et al. Parkinson’s disease variant detection and disclosure: PD GENEration, a North American study. Brain. 2024;147(8):2668-2679. PMID: 39074992.