Objective: To investigate chromosome X genetic risk factors for Parkinson’s disease (PD) across European and Ashkenazi Jewish ancestries and establish a robust framework for X-chromosome quality control (QC), imputation, and association testing.

Background: Although men are roughly 2 times more likely to develop PD than women, the X chromosome is often excluded from genome-wide association studies (GWAS) due to hemizygosity in males, X-inactivation in females, distinct recombination patterns, and specialized QC requirements [1–3]. Only one prior PD X-chromosome wide association study identified genome-wide significant loci, highlighting the need for standardized pipelines and larger datasets [4].

Method: We analyzed genotype array data from GP2 and the Fox Insight Genetics Study, along with whole-genome sequencing from UK Biobank. Sex- and region-specific preprocessing removed implausible male heterozygous genotypes, harmonized pseudoautosomal boundaries, and applied sex-stratified imputation. Association testing used PLINK2 logistic regression adjusted for demographic variables and genetic principal components [5]. Sex-stratified and sex-combined analyses were conducted per ancestry, followed by fixed-effect meta-analysis. Sex-heterogeneous effects were evaluated by combining sex-specific statistics into a chi-squared distribution. Genome-wide significance was set at p < 5×10⁻⁸.

Results: In GP2’s 46,504 European samples (26,388 individuals with PD; 20,116 controls), we replicated the previously reported sex-combined association at GPM6B and achieved genome-wide significance for the first time in sex-stratified analyses. In the combined analysis, we also identified an association at RTL9 at genome-wide significance for the first time, a gene previously highlighted through linkage analyses in multiplex PD families [4,6]. In addition, we detected a novel pseudoautosomal association at DHRSX in the combined analysis, which has been implicated in brain imaging-derived phenotypes and imaging genetics [7,8].

Conclusion: We establish a scalable framework for X-chromosome QC, imputation, and GWAS that addresses key analytical challenges. Our findings confirm known PD loci and expand the catalog of X-linked associations, including novel pseudoautosomal signals. These results demonstrate the importance of including the X chromosome in future genetic studies of PD.

References: 1. Cerri, S., Mus, L. & Blandini, F. Parkinson’s Disease in Women and Men: What’s the Difference? J Parkinsons Dis 9, 501–515 (2019).
2. Gorlov, I. P. & Amos, C. I. Why does the X chromosome lag behind autosomes in GWAS findings? PLoS Genet. 19, e1010472 (2023).
3. Step, K. et al. X chromosome-wide association studies in neurological disorders: uncovering the hidden influence of the X chromosome. Front. Genet. 16, 1650259 (2025).
4. Le Guen, Y. et al. Common X-chromosome variants are associated with Parkinson disease risk. Ann. Neurol. 90, 22–34 (2021).
5. Chang, C. C. et al. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience 4, (2015).
6. Pankratz, N. et al. Genome-wide linkage analysis and evidence of gene-by-gene interactions in a sample of 362 multiplex Parkinson disease families. Hum. Mol. Genet. 12, 2599–2608 (2003).
7. Jiang, Z. et al. The X chromosome’s influences on the human brain. Sci. Adv. 11, eadq5360 (2025).
8. Smith, S. M. et al. An expanded set of genome-wide association studies of brain imaging phenotypes in UK Biobank. Nat. Neurosci. 24, 737–745 (2021).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-analysis-of-the-x-chromosome-and-parkinsons-disease/