Objective: To prioritise causal variants within genetic loci associated with Parkinson’s disease (PD) risk and age at onset (AAO) using integrative fine-mapping approaches.

Background: The largest and most recent genome-wide association study (GWAS) of PD risk (GP2, 2025)(1) has identified 59 novel genetic loci, bringing the total number of known PD risk loci to 134. An upcoming GP2-led AAO GWAS is expected to identify additional loci associated with earlier disease onset. However, the true causal variants and genes underlying these loci have yet to be identified.

Method: We have implemented an integrated fine-mapping strategy to prioritise causal variants within PD risk and AAO loci. Using publicly available GWAS summary statistics from GP2 (2025)(1), we applied the SAFFARI pipeline(2), which combines SuSiE(3) and FINEMAP(4) to identify credible sets of likely causal variants. Functional annotations were incorporated using PolyFun(5). Following trait specific fine-mapping, PD risk and AAO loci will be compared to identify shared and distinct biological pathways.

Results: The results support previously established PD GWAS signals and also highlight alternative causal variants within several loci. For example, fine-mapping of the GBA1 region identified multiple credible sets containing previously reported PD risk variants, including rs2230288, rs76763715, and rs75548401, with posterior inclusion probabilities (PIP) approaching 1, indicating high probability that these variants are truly causal. Incorporating functional information using PolyFun supports these results. The AAK1 region, highlighted as a novel locus in the PD GWAS, showed variation in prioritised variants across methods. We will further follow up these fine-mapping results using OPERA(6) to assess whether PD GWAS signals and molecular QTL signals share causal variants.

Conclusion: By narrowing GWAS association signals to specific functional variants, this study highlights the importance of consensus across different methods, improves understanding of the biological mechanisms underlying PD and helps prioritise variants and pathways for future functional studies and therapeutic development. The results may also help validate previous evidence that variants driving PD risk are different to those influencing symptom progression.

References: 1. Leonard, H.L. (2025). Novel Parkinson’s Disease Genetic Risk Factors Within and Across European Populations. [preprint] doi:https://doi.org/10.1101/2025.03.14.24319455.

2. Koromina, M., Ravi, A., Panagiotaropoulou, G., Schilder, B.M., Humphrey, J., Braun, A., Bidgeli, T., Chatzinakos, C., Coombes, B.J., Kim, J., Liu, X., Terao, C., O’Connell, K.S., Adams, M.J., Adolfsson, R., Alda, M., Lars Alfredsson, Till, Andreassen, O.A. and Antoniou, A. (2025). Fine-mapping genomic loci refines bipolar disorder risk genes. Nature Neuroscience. doi:https://doi.org/10.1038/s41593-025-01998-z.

3. Wang, G., Sarkar, A., Carbonetto, P. and Stephens, M. (2020). A simple new approach to variable selection in regression, with application to genetic fine mapping. Journal of the Royal Statistical Society: Series B (Statistical Methodology), 82(5), pp.1273–1300. doi:https://doi.org/10.1111/rssb.12388.

4. Benner, C., Spencer, C.C.A., Havulinna, A.S., Salomaa, V., Ripatti, S. and Pirinen, M. (2016). FINEMAP: efficient variable selection using summary data from genome-wide association studies. Bioinformatics, 32(10), pp.1493–1501. doi:https://doi.org/10.1093/bioinformatics/btw018.

5. Weissbrod, O., Hormozdiari, F., Benner, C., Cui, R., Ulirsch, J., Gazal, S., Schoech, A.P., van de Geijn, B., Reshef, Y., Márquez-Luna, C., O’Connor, L., Pirinen, M., Finucane, H.K. and Price, A.L. (2020). Functionally informed fine-mapping and polygenic localization of complex trait heritability. Nature Genetics, 52(12), pp.1355–1363. doi:https://doi.org/10.1038/s41588-020-00735-5.

6. Wu, Y., Qi, T., Wray, N.R., Visscher, P.M., Zeng, J. and Yang, J. (2023). Joint analysis of GWAS and multi-omics QTL summary statistics reveals a large fraction of GWAS signals shared with molecular phenotypes. Cell genomics, 3(8), p.100344. doi:https://doi.org/10.1016/j.xgen.2023.100344.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/fine-mapping-genetic-risk-and-age-at-onset-loci-in-parkinsons-disease/