Insights into X-Linked Susceptibility to Parkinson’s Disease in the South African Population

X chromosome-wide association studies (XWAS) have successfully identified risk loci on the X chromosome associated with Parkinson's disease (PD) susceptibility. However, only three such studies have been completed to date. Here, we present the first XWAS using an African cohort, comprising 690 PD cases and 826 controls. We applied an established XWAS workflow to perform male- and female-stratified analyses, as well as a combined meta-analysis. The male-stratified analysis identified five significant variants, including one lead locus (rs200539602), while the female-stratified analysis revealed 29 significant variants and two lead loci (rs2499550 and rs58045540), where rs2499550 is an upstream variant of the protein-coding gene <i>FAAH2</i>. The remaining female-stratified significant variants are expression quantitative trait loci for <i>SPIN2A</i>, <i>SPIN2B</i>, and <i>SPIN3</i>, which are highly expressed in the brain and nerve tissues, making them strong candidates for further investigation. One previously reported PD XWAS locus (rs28602900) was also replicated at a significance threshold of 0.05. The meta-analysis identified five variants surpassing chromosome-wide significance, including two lead loci (rs140715059 and rs141026964), the latter has no significant expression quantitative trait locus information but lies closest to the protein-coding gene <i>MAGEC2</i>, which may warrant further follow-up. None of the meta-analysis signals replicated in prior neurodegenerative disease XWAS. Overall, this study provides novel insights into the contribution of the X chromosome to PD susceptibility and represents the first PD XWAS to include participants of African ancestry, highlighting the importance of extending genetic studies to diverse populations.