Category: Parkinson's Disease: Genetics
Objective: To investigate the genetic spectrum and prevalence of POLG variants in PD across diverse ancestries.
Background: Variants in the polymerase gamma (POLG) gene are associated with a wide range of mitochondrial disorders. Emerging evidence suggests a potential link between POLG variants and Parkinson’s disease (PD); yet, results remain inconclusive.
Method: We leveraged multi-ancestry genetic data from the Global Parkinson’s Genetics Program (GP2) and the Accelerating Medicines Partnership Parkinson’s Disease (AMP-PD), including genotyping data from 68,090 and short-read sequencing data from 22,382 individuals. We performed a POLG rare variant screen, case-control association, and gene-level burden analyses.
Results: Five individuals (four PD cases and one control) carried potentially biallelic rare pathogenic POLG variants. Additionally, 471 individuals (<1%, 283 cases and 188 controls) carried 29 distinct heterozygous pathogenic variants, with no significant frequency differences between cases and controls. The pathogenic co-inherited variants p.Thr251Ile and p.Pro587Leu were present in <1% of cases and controls, without significant group differences. Variant-level association showed no enrichment of POLG variants in PD. Burden analyses revealed a significant nominal association between rare POLG variant burden and PD in the European population.
Conclusion: POLG variants are overall rare in PD. The identification of rare pathogenic variants among PD cases suggests that POLG-related mitochondrial dysfunction may contribute to PD in isolated instances, particularly under recessive inheritance. Although heterozygous variants showed no variant-level association with PD, the nominal burden signals in European populations suggest that rare POLG variation may have some relevance to PD susceptibility. Our findings support a role for POLG alterations in select cases and underscore the need for larger-scale sequencing and functional studies.
To cite this abstract in AMA style:
YW. Tay, I. Elsayed, D. Yeow, M. James, S. Rowe, PJ. Kong, L. Screven, H. Chen, A. Dilliott, R. Alcalay, ZH. Fang, AH. Tan, C. Sue, L. Lange, T. Perinan. Multi-ancestry analysis of POLG variants in Parkinson’s disease [abstract]. Mov Disord. 2026; 41 (suppl 1). https://www.mdsabstracts.org/abstract/multi-ancestry-analysis-of-polg-variants-in-parkinsons-disease/. Accessed October 1, 2026.« Back to 2026 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/multi-ancestry-analysis-of-polg-variants-in-parkinsons-disease/