{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T16:19:19Z","timestamp":1767111559934,"version":"3.48.0"},"posted":{"date-parts":[[2025,12,27]]},"group-title":"Genetic and Genomic Medicine","reference-count":50,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,27]],"date-time":"2025-12-27T00:00:00Z","timestamp":1766793600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  X chromosome-wide association studies (XWAS) have successfully identified risk loci on the X chromosome associated with Parkinson\u2019s 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\n                  <jats:italic>FAAH2<\/jats:italic>\n                  . The remaining female-stratified significant variants are expression quantitative trait loci for\n                  <jats:italic>SPIN2A, SPIN2B<\/jats:italic>\n                  , and\n                  <jats:italic>SPIN3<\/jats:italic>\n                  , 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\n                  <jats:italic>MAGEC2<\/jats:italic>\n                  , 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.\n                <\/jats:p>","DOI":"10.64898\/2025.12.23.25342891","type":"posted-content","created":{"date-parts":[[2025,12,27]],"date-time":"2025-12-27T12:20:12Z","timestamp":1766838012000},"source":"Crossref","is-referenced-by-count":0,"title":["Insights into X-Linked Susceptibility to Parkinson\u2019s Disease in the South African Population"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4054-7030","authenticated-orcid":false,"given":"Kathryn","family":"Step","sequence":"first","affiliation":[{"name":"Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa"},{"name":"South African Medical Research Council Centre for Tuberculosis Research, Stellenbosch University, Cape Town, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1485-3710","authenticated-orcid":false,"given":"Emily","family":"Waldo","sequence":"additional","affiliation":[{"name":"Genome Sciences and Systems Biology, Cleveland Clinic Research, Cleveland Clinic Foundation, Cleveland, OH, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5829-6452","authenticated-orcid":false,"given":"Thiago Peixoto","family":"Leal","sequence":"additional","affiliation":[{"name":"Genome Sciences and Systems Biology, Cleveland Clinic Research, Cleveland Clinic Foundation, Cleveland, OH, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6114-7482","authenticated-orcid":false,"given":"Marla","family":"Mendes","sequence":"additional","affiliation":[{"name":"The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada"},{"name":"Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3508-3438","authenticated-orcid":false,"given":"Soraya","family":"Bardien","sequence":"additional","affiliation":[{"name":"Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa"},{"name":"South African Medical Research Council Centre for Tuberculosis Research, Stellenbosch University, Cape Town, South Africa"},{"name":"South African Medical Research Council\/Stellenbosch University Genomics of Brain Disorders Research Unit, Stellenbosch University, Cape Town, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1198-0633","authenticated-orcid":false,"given":"Ignacio F","family":"Mata","sequence":"additional","affiliation":[{"name":"Genome Sciences and Systems Biology, Cleveland Clinic Research, Cleveland Clinic Foundation, Cleveland, OH, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025123008154943000_2025.12.23.25342891v1.1","first-page":"1498756","article-title":"Global, regional, national epidemiology and trends of Parkinson\u2019s disease from 1990 to 2021: findings from the Global Burden of Disease Study 2021","volume":"16","year":"2024","journal-title":"Front. Aging Neurosci"},{"key":"2025123008154943000_2025.12.23.25342891v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(19)30287-X"},{"key":"2025123008154943000_2025.12.23.25342891v1.3","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1002\/mdc3.13584","article-title":"Gender differences in the prevalence of Parkinson\u2019s disease","volume":"10","year":"2023","journal-title":"Mov. Disord. Clin. Pract"},{"key":"2025123008154943000_2025.12.23.25342891v1.4","doi-asserted-by":"crossref","first-page":"501","DOI":"10.3233\/JPD-191683","article-title":"Parkinson\u2019s disease in women and men: What\u2019s the difference?","volume":"9","year":"2019","journal-title":"J. Parkinsons. Dis"},{"key":"2025123008154943000_2025.12.23.25342891v1.5","doi-asserted-by":"crossref","unstructured":"Terrin, F. , Tesoriere, A. , Plotegher, N. & Dalla Valle, L. Sex and brain: The role of sex chromosomes and hormones in brain development and Parkinson\u2019s disease. Cells 12, (2023).","DOI":"10.3390\/cells12111486"},{"key":"2025123008154943000_2025.12.23.25342891v1.6","doi-asserted-by":"publisher","DOI":"10.1002\/mds.23388"},{"key":"2025123008154943000_2025.12.23.25342891v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.genm.2011.05.002"},{"key":"2025123008154943000_2025.12.23.25342891v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.03.017"},{"key":"2025123008154943000_2025.12.23.25342891v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2023.04.009"},{"key":"2025123008154943000_2025.12.23.25342891v1.10","doi-asserted-by":"crossref","first-page":"1650259","DOI":"10.3389\/fgene.2025.1650259","article-title":"X chromosome-wide association studies in neurological disorders: uncovering the hidden influence of the X chromosome","volume":"16","year":"2025","journal-title":"Front. Genet"},{"key":"2025123008154943000_2025.12.23.25342891v1.11","doi-asserted-by":"publisher","DOI":"10.1038\/ng.877"},{"key":"2025123008154943000_2025.12.23.25342891v1.12","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26051"},{"key":"2025123008154943000_2025.12.23.25342891v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-10598-y"},{"key":"2025123008154943000_2025.12.23.25342891v1.14","doi-asserted-by":"publisher","DOI":"10.1038\/nature24265"},{"key":"2025123008154943000_2025.12.23.25342891v1.15","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.2006.103788"},{"key":"2025123008154943000_2025.12.23.25342891v1.16","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddg270"},{"key":"2025123008154943000_2025.12.23.25342891v1.17","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1002\/mds.29508","article-title":"X-chromosome association study in Latin American cohorts identifies new loci in Parkinson\u2019s Disease","volume":"38","year":"2023","journal-title":"Mov. Disord"},{"key":"2025123008154943000_2025.12.23.25342891v1.18","doi-asserted-by":"publisher","DOI":"10.1002\/mds.30252"},{"key":"2025123008154943000_2025.12.23.25342891v1.19","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.55.3.181"},{"key":"2025123008154943000_2025.12.23.25342891v1.20","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1002\/mds.28828","article-title":"The South African Parkinson\u2019s Disease Study Collection","volume":"37","year":"2022","journal-title":"Mov. Disord"},{"key":"2025123008154943000_2025.12.23.25342891v1.21","doi-asserted-by":"publisher","DOI":"10.1002\/mds.28494"},{"key":"2025123008154943000_2025.12.23.25342891v1.22","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1002\/mds.30051","article-title":"Advancing Parkinson\u2019s disease research in Africa: A strategic training framework of the global Parkinson\u2019s genetics program","volume":"40","year":"2025","journal-title":"Mov. Disord"},{"key":"2025123008154943000_2025.12.23.25342891v1.23","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.1002\/mds.29902","article-title":"NeuroBooster array: A genome-wide genotyping platform to study neurological disorders across diverse populations","volume":"39","year":"2024","journal-title":"Mov. Disord"},{"key":"2025123008154943000_2025.12.23.25342891v1.24","doi-asserted-by":"publisher","DOI":"10.1101\/2025.07.18.25331793"},{"key":"2025123008154943000_2025.12.23.25342891v1.25","doi-asserted-by":"publisher","DOI":"10.1101\/2025.08.01.25331910"},{"key":"2025123008154943000_2025.12.23.25342891v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.csbj.2022.04.009"},{"key":"2025123008154943000_2025.12.23.25342891v1.27","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq559"},{"key":"2025123008154943000_2025.12.23.25342891v1.28","doi-asserted-by":"publisher","DOI":"10.1186\/s13742-015-0047-8"},{"key":"2025123008154943000_2025.12.23.25342891v1.29","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3656"},{"key":"2025123008154943000_2025.12.23.25342891v1.30","doi-asserted-by":"publisher","DOI":"10.1159\/000334084"},{"key":"2025123008154943000_2025.12.23.25342891v1.31","doi-asserted-by":"publisher","DOI":"10.1038\/nature15393"},{"key":"2025123008154943000_2025.12.23.25342891v1.32","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3679"},{"key":"2025123008154943000_2025.12.23.25342891v1.33","first-page":"100235","article-title":"Universal genome-wide association studies: Powerful joint ancestry and association testing","volume":"4","year":"2023","journal-title":"HGG Adv"},{"key":"2025123008154943000_2025.12.23.25342891v1.34","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-12-246"},{"key":"2025123008154943000_2025.12.23.25342891v1.35","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-11-288"},{"key":"2025123008154943000_2025.12.23.25342891v1.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2024.11.008"},{"key":"2025123008154943000_2025.12.23.25342891v1.37","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01261-5"},{"key":"2025123008154943000_2025.12.23.25342891v1.38","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-016-0974-4"},{"key":"2025123008154943000_2025.12.23.25342891v1.39","doi-asserted-by":"publisher","DOI":"10.1093\/NAR\/GKAA840"},{"key":"2025123008154943000_2025.12.23.25342891v1.40","doi-asserted-by":"publisher","DOI":"10.1038\/S41588-021-00945-5"},{"key":"2025123008154943000_2025.12.23.25342891v1.41","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2653"},{"key":"2025123008154943000_2025.12.23.25342891v1.42","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2015.269"},{"key":"2025123008154943000_2025.12.23.25342891v1.43","doi-asserted-by":"crossref","first-page":"1990","DOI":"10.1175\/1520-0442(1999)012<1990:TENOSD>2.0.CO;2","article-title":"The effective number of spatial degrees of freedom of a time-varying field","volume":"12","year":"1999","journal-title":"J. Clim"},{"key":"2025123008154943000_2025.12.23.25342891v1.44","doi-asserted-by":"crossref","first-page":"2335","DOI":"10.1038\/s41380-024-02838-5","article-title":"X-chromosome-wide association study for Alzheimer\u2019s disease","volume":"30","year":"2025","journal-title":"Mol. Psychiatry"},{"key":"2025123008154943000_2025.12.23.25342891v1.45","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1038\/s41398-024-03058-9","article-title":"Chromosome X-wide association study in case control studies of pathologically confirmed Alzheimer\u2019s disease in a European population","volume":"14","year":"2024","journal-title":"Transl. Psychiatry"},{"key":"2025123008154943000_2025.12.23.25342891v1.46","doi-asserted-by":"crossref","first-page":"149703","DOI":"10.1016\/j.gene.2025.149703","article-title":"Investigating the role of a novel hemizygous FAAH2 variant in neurological and metabolic disorders","volume":"966","year":"2025","journal-title":"Gene"},{"key":"2025123008154943000_2025.12.23.25342891v1.47","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s13023-015-0248-3","article-title":"Defects in fatty acid amide hydrolase 2 in a male with neurologic and psychiatric symptoms","volume":"10","year":"2015","journal-title":"Orphanet J. Rare Dis"},{"key":"2025123008154943000_2025.12.23.25342891v1.48","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.bbi.2016.06.010","article-title":"Fatty acid amide hydrolase inhibition for the symptomatic relief of Parkinson\u2019s disease","volume":"57","year":"2016","journal-title":"Brain Behav. Immun"},{"key":"2025123008154943000_2025.12.23.25342891v1.49","doi-asserted-by":"crossref","first-page":"782","DOI":"10.3390\/ph17060782","article-title":"Exploring the role of ubiquitin-proteasome system in the pathogenesis of Parkinson\u2019s disease","volume":"17","year":"2024","journal-title":"Pharmaceuticals (Basel)"},{"key":"2025123008154943000_2025.12.23.25342891v1.50","doi-asserted-by":"crossref","first-page":"922675","DOI":"10.3389\/fcell.2022.922675","article-title":"The dual roles of MAGE-C2 in p53 ubiquitination and cell proliferation through E3 ligases MDM2 and TRIM28","volume":"10","year":"2022","journal-title":"Front. Cell Dev. Biol"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2025.12.23.25342891","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T16:15:59Z","timestamp":1767111359000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2025.12.23.25342891"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,27]]},"references-count":50,"URL":"https:\/\/doi.org\/10.64898\/2025.12.23.25342891","relation":{},"subject":[],"published":{"date-parts":[[2025,12,27]]},"subtype":"preprint"}}