Objective: To characterize the association between Human Leukocyte Antigen (HLA) alleles and dystonia.

Background: Dystonia is widely recognized to have great etiologic heterogeneity. A complex interaction of genetic and environmental factors is believed to mediate dystonia pathogenesis, particularly in adult-onset, focal dystonias. The role of the highly variable immune system, located at the interface of genetic predisposition and environment, has yet to be empirically explored. Human leukocyte antigen (HLA) genes encode cell-surface proteins responsible for regulating the immune system, particularly concerning immune cell function.

Method:

We analyzed genotype data from the global screening array (GSA) in the ProtectMove cohort (https://protect-move.de/). We included individuals of European ancestry only. The data were run through a specific HLA imputation pipeline to examine HLA allele information at 11 loci, including HLA-A, HLA-B, HLA-C, HLA-DPA, HLA-DPB, HLA-DQA, HLA-DQB, HLA-DRB1, HLA-DRB3, HLA-DRB4, and HLA-DRB5 (1). The resulting genotypes were tested for association in dystonia, Parkinson´s disease (PD) patients, and controls as well as in subgroups of patients with different types of focal dystonia using the Python PyHLA script (2). Ongoing work is investigating associated changes in frequencies of immune cell populations via flow cytometry panels.

Results: We included 3,165 patients with dystonia, 4,802 healthy controls, and a disease-control group of 2,040 patients with PD. When comparing all dystonia patients vs. healthy controls, we identified significant differences for loci B, C, DPA1, DPB1, DQB1, and DRB4 (Figure). The largest subgroup of focal dystonia patients comprised cervical dystonia (n=549) with significant associations in B and DPA1. In the group of cranial dystonia (n=266), an association was found to DRB5 and DPB1. When comparing dystonia vs. PD patients, alleles in DPB1, DQA1, DQB1, DRB1, DRB3, and DRB4 showed significant differences, while only variants in DRB3 and DRB4 revealed an association between PD patients and controls.

Conclusion: Large-scale genotyping identifies genetic variability in HLA genes associated with dystonia that were different from PD. We will further explore the associated loci and their role in dystonia by RNA sequencing and evaluate its impact on the composition and function of immune cells in patients’ blood.

Figure: Tested HLA alleles (X-axis) and p-value.

References: 1. Degenhardt F, Wendorff M, Wittig M, Ellinghaus E, Datta LW, Schembri J, Ng SC, Rosati E, Hübenthal M, Ellinghaus D, Jung ES, Lieb W, Abedian S, Malekzadeh R, Cheon JH, Ellul P, Sood A, Midha V, Thelma BK, Wong SH, Schreiber S, Yamazaki K, Kubo M, Boucher G, Rioux JD, Lenz TL, Brant SR, Franke A. Construction and benchmarking of a multi-ethnic reference panel for the imputation of HLA class I and II alleles. Hum Mol Genet 2019;28:2078-2092.
2. Fan Y, Song YQ. PyHLA: tests for the association between HLA alleles and diseases. BMC Bioinformatics 2017;18:90.

« Back to 2025 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/the-role-of-the-immune-system-in-dystonia-insights-from-hla-genotyping/