Objective: To investigate chromosome X genetic risk factors for Parkinson’s disease (PD) across European ancestries (European, Ashkenazi Jewish, Finnish) using data from the Global Parkinson’s Genetic Program (GP2; http://gp2.org/), IPDGC, Fox Insight Genetics Study, and UK Biobank.

Background: Men are roughly 2 times more likely to develop PD than women1, yet X chromosome variants remain understudied. The X chromosome is often excluded from typical GWAS due to unique inheritance patterns and specialized quality control requirements2. The largest X chromosome-wide association study (XWAS) identified two novel genome-wide significant risk factors in the GPM6B and RPL10 regions3. Both improved quality control pipelines and larger case-control studies are needed to identify additional X chromosome risk factors for PD.

Method: We used genotyped data from GP2 release 9, IPDGC, and Fox Insight across European, Ashkenazi Jewish, and Finnish ancestry groups. Our methods included: (1) Quality control with separate clustering of male/female genotypes, followed by autosomal and chrX-specific QC; (2) Association analysis using PLINK2 with logistic regression on case/control phenotypes, adjusting for age and 10 principal components; (3) Meta-analysis of XWAS summary statistics using a fixed-effect approach and testing for sex-heterogeneous effects by combining male/female effects into a chi-squared distribution. Genome-wide significance threshold was set at p < 5E-8.

Results: Our ongoing analysis has initiated pipelines to investigate X chromosome loci potentially associated with PD risk. Preliminary findings indicate suggestive associations at various loci, including regions near genes previously implicated in PD. These associations vary across ancestry groups, highlighting the importance of further investigations with larger, diverse cohorts.

Conclusion: The X chromosome is typically omitted from genome-wide analyses due to transcriptional silencing of one allele in females, hemizygosity in males, and distinct recombination patterns requiring specialized QC. We address these challenges by implementing tailored X chromosome analysis pipelines. The diverse genetic backgrounds across different ancestries indicate the X chromosome could uniquely influence PD risk in each population.

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. Le Guen, Y. et al. Common X-chromosome variants are associated with Parkinson disease risk. Ann. Neurol. 90, 22–34 (2021).

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