Objective: To investigate potential differences in autosomal risk factors between males and females with Parkinson’s Disease (PD). This analysis was performed within and across genetically determined European ancestries (European, Ashkenazi Jewish, and Finnish) using data from the Global Parkinson’s Genetic Program (GP2, http://gp2.org/), previously published PD GWAS (IPDGC), and the Fox Insight Genetics Study (FIGS).

Background: Within European ancestry, men are approximately 1.5 times more likely to develop PD than women1, but the underlying reasons for this observed difference in prevalence remain unclear. Significant progress has been made in understanding the genetic architecture and etiology of PD through case-control studies, but despite this, very little is known about the potential autosomal risk factors that may vary between sexes. The largest sex-stratified autosomal meta-analysis in Europeans did not identify any genome-wide significant risk factors that were different between males and females, warranting further studies at larger sample sizes to further investigate potential autosomal differences 2.

Method: We performed a series of sex-stratified GWAS using genotyped imputed data from GP2 release 9 (DOI: 10.5281/zenodo.14510099), IPDGC, and Fox Insight within and across three ancestry groups: European (EUR), Ashkenazi Jewish (AJ), and Finnish (FIN). Genetically-defined ancestry groups for GP2, IPDGC, and Fox Insight were defined by the GP2 ancestry and QC pipeline (https://pypi.org/project/the-real-genotools/1.2.1/). Meta-analyses were performed in stages, splitting by ancestry and biobank data sources. The last stage combined all European ancestry groups into two final meta-analyses for males and females separately.

Results: In our preliminary analysis, we identified several genome-wide significant regions and found a high correlation between male and female genetic risk for PD using common autosomal variants. We also investigated correlation between male and female genetic risk and the estimated effects from the most recent PD GWAS.

Conclusion: We present here the largest sex-stratified GWAS of PD to date. Conducting sex-stratified GWAS with larger sample sizes and improved genotyping will help uncover sex-specific risk factors and provide deeper insights into the genetic architecture of PD.

References: 1. Van Den Eeden, S. K. et al. Incidence of Parkinson’s disease: variation by age, gender, and race/ethnicity. Am. J. Epidemiol. 157, 1015–1022 (2003).
2. Blauwendraat, C. et al. Investigation of autosomal genetic sex differences in Parkinson’s disease. Ann. Neurol. 90, 35–42 (2021).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/sex-specific-genetic-architecture-of-autosomal-risk-for-parkinsons-disease-from-the-global-parkinsons-genetics-program/