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MINI REVIEW article

Front. Genet.

Sec. Neurogenomics

Volume 16 - 2025 | doi: 10.3389/fgene.2025.1650259

This article is part of the Research TopicThink Rare: Current Advances on Understanding and Treatment of X-Linked Neurodevelopmental DisordersView all 7 articles

X chromosome-wide association studies in neurological disorders: Uncovering the hidden influence of the X chromosome

Provisionally accepted
Kathryn StepKathryn Step1,2Thiago Peixoto LealThiago Peixoto Leal3Walaa Ahmed KamelWalaa Ahmed Kamel4Emily WaldoEmily Waldo3Soraya BardienSoraya Bardien1,2,5Ignacio Fernandez MataIgnacio Fernandez Mata3*
  • 1South African Medical Research Council for Tuberculosis Research, Stellenbosch University, Cape Town, South Africa
  • 2Faculty of Medicine and Health Sciences, Division of Molecular Biology and Human Genetics, Stellenbosch University, Cape Town, South Africa
  • 3Cleveland Clinic Lerner Research Institute Genomic Medicine Institute, Cleveland, United States
  • 4Department of Neurology, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
  • 5Faculty of Medicine and Health Sciences and South African Medical Research Council/ Stellenbosch University Genomics of Brain Disorders Research Unit, Stellenbosch University, Cape Town, South Africa

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X chromosome-wide association studies (XWAS) have identified susceptibility variants for various neurodegenerative and neurodevelopmental diseases. The unique characteristics of the chromosome require more complex analytical approaches than standard genome-wide association studies. Over the past two decades, refined XWAS methods have better accounted for this biology. Given that many neurological diseases show sex-biased prevalence, XWAS offers a valuable framework for investigating sex-specific genetic contributions. This review summarizes published neurological XWAS (N=10), highlighting methodological approaches. Despite the challenges of genetic analyses for the X chromosome, XWAS remains a key approach for studying its role in disease mechanisms.

Keywords: Parkinson's disease, X-chromosome-wide association study, neurodegenerative disease, XWAS, association analysis, sex bias, susceptibility variants

Received: 20 Jun 2025; Accepted: 21 Jul 2025.

Copyright: © 2025 Step, Peixoto Leal, Kamel, Waldo, Bardien and Mata. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Ignacio Fernandez Mata, Cleveland Clinic Lerner Research Institute Genomic Medicine Institute, Cleveland, United States

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Supplementary Material