Objective: Estimating the distribution of GBA1 variants and estimating GBA1 odds ratios for Parkinson’s disease in the UK-based population.

Background: Mutations in GBA1 are an important risk factor for Parkinson’s disease [1]. An international study of around 10,000 participants calculated the odds ratio of GBA1+ PD patients to be 5.43 versus controls [2]. Sequencing of GBA1 has many pitfalls, which has left certain GBA1 mutations underexplored [3].

PD Frontline is the largest UK-based PD registry that provides genetic sequencing for GBA1 and LRRK2 [4]. The sequencing model utilises targeted Oxford MinION sequencing with subsequent Sanger confirmation, allowing the full resolution of the GBA1 gene [5].

The UK Biobank is a cohort study with a vast range of physical, health, and genetic data across ~500,000 individuals [6]. Gauchian, an algorithm that can effectively identify SVs and GBAP1-like variants on WGS [7], would improve the current sequencing of GBA1 in the UK Biobank. It would also highlight the shortfall of current gold-standard variant calling on available data.

Method: Data were retrieved from the PD Frontline sequencing database and from the publicly available UK Biobank database.

Results: Prevalence of GBA1 carriers among the PD Frontline cohort (n = 4114) was found to be 12.52%. Sex analysis of PD cases presented a frequency distribution significantly different across GBA1-wildtype (WT) and the categorised variant groups mild, risk, and severe. Total GBA1 variant carriers (n = 512) had a 41.41% female split, but severe variants exhibited a female heavy distribution (Female-Severe = 55.06% | p-value = 0.007476). Mean age at diagnosis was significantly lower in GBA1 variant carriers compared to WT (Mean Difference = 3.03 | p-value = 2.75e-06). After an ANOVA (p-value = 2.463-06), Post-hoc Tukey multiple comparison of means found significant difference in WT-Risk, WT-Mild, WT-Severe, and Risk-Severe ages (WT = 62.1, Risk = 60.5, Mild = 58.0, Severe = 55.7).

Conclusion: The analysis highlighted a younger mean age at diagnosis of PD in GBA1 variant carriers, and a sex-driven difference in the distribution of GBA1 variants. Further analysis of the UK Biobank data will be used to corroborate these findings.

References: 1. Malek, N., Weil, R.S., Bresner, C., Lawton, M.A., Grosset, K.A., Tan, M., Bajaj, N., Barker, R.A., Burn, D.J., Foltynie, T., Hardy, J., Wood, N.W., Ben-Shlomo, Y., Williams, N.W., Grosset, D.G. and Morris, H.R. (2018). Features of GBA-associated Parkinson’s disease at presentation in the UK Tracking Parkinson’s study. Journal of Neurology, Neurosurgery & Psychiatry, [online] 89(7), pp.702–709. doi: https://doi.org/10.1136/jnnp-2017-317348.
2. Sidransky, E., Nalls, M.A., Aasly, J.O., Aharon-Peretz, J., Annesi, G., Barbosa, E.R., Bar-Shira, A., Berg, D., Bras, J., Brice, A., Chen, C.-M. ., Clark, L.N., Condroyer, C., De Marco, E.V., Dürr, A., Eblan, M.J., Fahn, S., Farrer, M.J., Fung, H.-C. . and Gan-Or, Z. (2009). Multicenter Analysis of Glucocerebrosidase Mutations in Parkinson’s Disease. New England Journal of Medicine, [online] 361(17), pp.1651–1661. doi: https://doi.org/10.1056/nejmoa0901281.
3. Zampieri, S., Cattarossi, S., Bembi, B. and Dardis, A. (2017). GBA Analysis in Next-Generation Era. The Journal of Molecular Diagnostics, 19(5), pp.733–741. doi: https://doi.org/10.1016/j.jmoldx.2017.05.005.
4. Pdfrontline.com. (2026). PD Frontline – Home. [online] Available at: https://pdfrontline.com [Accessed 14 Mar. 2026].
5. Leija-Salazar, M., Sedlazeck, F.J., Toffoli, M., Mullin, S., Mokretar, K., Athanasopoulou, M., Donald, A., Sharma, R., Hughes, D., Schapira, A.H.V. and Proukakis, C. (2019). Evaluation of the detection of GBA missense mutations and other variants using the Oxford Nanopore MinION. Molecular Genetics & Genomic Medicine, [online] 7(3), p.e564. doi: https://doi.org/10.1002/mgg3.564.
6. Taylor, H., Lewins, M., Foody, M.G.B., Gray, O., Bešević, J., Conroy, M.C., Collins, R., Lacey, B., Allen, N. and Burkitt-Gray, L. (2025). UK Biobank—A Unique Resource for Discovery and Translation Research on Genetics and Neurologic Disease. Neurology Genetics, [online] 11(1). doi: https://doi.org/10.1212/nxg.0000000000200226.
7. Toffoli, M., Menozzi, E., Cullen, M., Chowdhury, K., Ahmed, S., Freemantle, N., Duffen, J., Wyse, R.K., Stott, S.R.W., Matthews, H., Dexter, D., Ikeji, F., Moss, J., Watts, P., Foltynie, T., Kieburtz, K., Rascol, O., Poewe, W. and Schapira, A.H.V. (2026). Protocol of ASPro-PD: a phase 3 trial of ambroxol to slow progression in genetically stratified Parkinson’s disease. Journal of Neurology, 273(2). doi: https://doi.org/10.1007/s00415-026-13683-7.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/elucidating-the-demographic-distributions-and-implications-of-gba1-gene-variants-in-parkinsons-disease/