Landmark study confirms five key Parkinson's Disease variants in largest meta-analysis

By Dr. Priyom Bose, Ph.D.Reviewed by Lily Ramsey, LLMJan 10 2024

A recent Npj Parkinson's Disease study analyzed rare Parkinson’s disease (PD) variants in a large-scale cohort.

Study: Analysis of rare Parkinson’s disease variants in millions of people. Image Credit: Chinnapong/Shutterstock.com

Background

PD is a neurodegenerative disorder that affects dopaminergic neurons in the substantia nigra. The manifestation of this disease has been associated with a combination of factors, i.e., aging, environmental components, and genetics. Several studies have identified common and rare PD variants.

Since genetics contribute to the risks of PD development, analysis of an individual's genetic makeup indicates the likelihood of developing the disease. A large-scale cohort-based genetic analysis could help understand the prevalence of genetic factors linked to PD in the population.

The percentage of variant carriers with the disease or the penetrance of a specific genetic variant could be estimated.

A high penetrance indicates a strong association between a variant and disease status, increasing odds ratio. In contrast, low penetrance indicates that other factors are more related to disease manifestations.

PD genetics are studied via two approaches, i.e., genome-wide association studies (GWAS) and monogenic PD. Monogenic PD is a rare condition involving a single gene's mutation.

Only a small percentage of PD patients have developed this PD type. Genes, such as SNCA, and LRRK2, exhibited autosomal dominant inheritance, where one copy of either of these genes from one parent can express the disease. 

PINK1 and DJ-1 are linked to autosomal recessive inheritance, where both copies of genes, one from each parent are required for disease expression.

GWAS helps identify single nucleotide polymorphisms (SNPs) that enhance PD risk. These studies provide a broader outlook into the genetic landscape of PD in a population.

GWAS identifies the common variants with a minor allele frequency (MAF) of more than 5%. A previous large-scale case–control GWAS has determined ninety PD risk variants. GBA1 and LRRK2 variants have been determined to be the most common high-risk genetic factor for PD incidence. 

Since rare variants are associated with a slightly different PD phenotype, it is important to conduct more research on the same for a better understanding.

About the study

The current study evaluated PD mutations from the ClinVar database that comprises three large case-control cohorts linked with PD, namely, 23andMe, Inc., UK Biobank, and AMP-PD.

A total of 3 million individuals including 27,590 PD cases, 6,701 proxies, and 3,106,080 controls, were considered in this study. This cohort presents a greater opportunity to identify rare variants in PD.

The present study aimed to create a list of high and low-confidence PD variants, which will assist clinicians in recommending genetic testing in patients with suspected PD.

Study findings

669 genetic variants were selected for further studies to assess their association with PD manifestation. Around 70% of the annotated variants neither exhibited clinical significance nor had unclear interpretations in ClinVar.

However, 16.3% of the remaining 198 variants were classified as pathogenic and/or likely pathogenic, and 12.3% were classified as benign or probably benign variants. Five variants were identified as PD risk factors.

A total of 32 genes were found to account for 669 variants. Five high-risk and causal genes were identified, namely, PRKN p.R275W, LRRK2 p.G2019S, p.E365K, p.T408M, and GBA1 p.N409S.

Furthermore, five variants strongly associated with PD incidence were found, which are GBA1 p.R502C, p.R296Q, LRRK2 p.R1441H, p.L1795F, and p.D179H.

A large number of variants that were previously thought to be associated with PD were unlikely to be highly penetrant causes of PD. In contrast, these variants could be weakly penetrant or have a recessive mode of inheritance.

The current study indicates the significant role of PD variants, particularly LRRK2 and GBA1, in driving PD risk.

Compared to p.R1441H and p.G2019S variants, LRRK2 p.L1795F is less studied. However, all these variants play a significant damaging role in patients with PD. LRRK2 p.L1795F is located in the C-terminal of the ROC B region, whose expression can lead to PD development.

A recent study has indicated the functional effect of this variant linked to its pathogenicity. Notably, a statistically significant association between GBA1 p.D179H and PD was observed with higher odd ratios (ORs).  

The current findings failed to validate the results of a previous study that indicated six variants to be pathogenic or likely pathogenic.

Although the present study did not find any evidence that corroborated the aforementioned findings, these variants should be treated with caution and must be interpreted carefully in the future.

Conclusions

In sum, the current study provided a list of five variants that are strongly associated with PD. These variants could be accurately used to determine PD risks in an individual.

This study should enable genetic counselors to determine complications due to the presence of rare variants of PD.