Genome-wide Epistasis Identifies Key Variant Interactions in Parkinson’s Disease

Overview

A genome-wide epistasis screening pipeline (VARI3) identified and replicated three significant variant–variant interactions associated with Parkinson’s disease (PD) risk near SNCA, MAPT, and WNT3 loci. These interactions were validated across multiple cohorts of diverse ancestries and linked to PD-relevant biological pathways.

Background

Parkinson’s disease is a complex neurodegenerative disorder influenced by genetic and environmental factors. While genome-wide association studies (GWAS) have identified numerous common variants associated with PD, these explain only about 30% of the disease heritability. Epistasis, or interactions between genetic variants, may account for some of the missing heritability but has been challenging to study at a genome-wide level. This study developed a novel pipeline, VARI3, to systematically assess epistatic interactions across the genome in large PD cohorts.

Data Highlights

Key Findings

• VARI3 pipeline enabled genome-wide, hypothesis-free detection of epistatic interactions involving high minor allele frequency SNPs.
• Fourteen candidate variant–variant interactions were identified in the discovery stage across 14 European ancestry cohorts.
• Three epistatic interactions were successfully replicated in independent cohorts including individuals of European and Latino ancestry.
• Replicated interactions localized near SNCA and within MAPT and WNT3 genes, loci previously implicated in PD.
• Functional analyses showed these interactions affect gene expression in brain tissues and blood, and are enriched in PD-relevant pathways and chromatin interactions.

Clinical Implications

These findings highlight the importance of considering genetic interactions in understanding PD susceptibility beyond single-variant effects. Incorporating epistasis into genetic risk models may improve prediction accuracy and provide novel targets for therapeutic intervention. The VARI3 pipeline offers a publicly available tool for researchers to explore epistatic effects in PD and other complex diseases.

Conclusion

This study demonstrates that genome-wide epistasis contributes to Parkinson’s disease risk and identifies novel variant interactions with functional relevance. These results advance our understanding of PD genetics and underscore the value of integrating epistatic analyses in future genetic studies.

References

1. International Parkinson’s Disease Genomics Consortium 2019 -- Meta-analysis of Parkinson’s disease GWAS
2. Shi et al. -- Epistatic interactions between GBA and LRRK2 in PD
3. Fernandez-Santiago et al. -- Epistasis affecting age at onset in PD
4. VARI3 R package -- https://github.com/alexcis95/VARI3