Chromosome X-wide association study in multiple system atrophy identifies sex-differential risk loci

Year: 2026

Type: article

Abstract: The human X chromosome accounts for ∼5% of the genome. Despite its size, the role of X-chromosomal variants in human diseases is not well understood, mainly due to its distinct inheritance pattern and the frequent omission of sex chromosomes from genome-wide association studies. This study used whole-genome sequencing data from 888 multiple system atrophy (MSA) cases and 7128 controls to perform an X-chromosome-wide common variant association study. Our analyses revealed two sex-differential risk loci: one located at Xq28, associated with increased risk for MSA in females [index variant: rs4898389, odds ratio (OR) = 1.69, 95% confidence interval (CI) = 1.40-2.03, P-value = 2.43 × 10⁻⁸], and another at Xp22.2 within the TBL1X gene, identified in males (index variant: rs6638956, OR = 1.48, 95%CI = 1.26-1.73, P-value = 9.92 × 10⁻⁷). In the Xq28 locus, colocalization analyses pointed to FAM3A and PLXNA3 as genes of interest. These findings emphasize the vital role of sex-differential genetic factors in the pathogenesis of MSA.

Source: Brain

DOI: 10.1093/brain/awag062

Authors: Anindita Ray, Ruth Chia, Memoona Rasheed, Ece Bayram, Anindita Ray, Ruth Chia, Memoona Rasheed, Ece Bayram, Jinhui Ding, Ronald L Walton, Regina H Reynolds, Monica Diez-Fairen, Ignacio Alvarez, Alessandra Fanciulli, Nadia Stefanova, Klaus Seppi, Susanne Duerr, Fabian Leys, Florian Krismer, Victoria Sidoroff, Alexander Zimprich, Walter Pirker, Olivier Rascol, Alexandra Foubert-Samier, Wassilios G Meissner, François Tison, Anne Pavy-Le Traon, Maria Teresa Pellecchia, Paolo Barone, Maria Claudia Russillo, Juan Marín-Lahoz, Jaime Kulisevsky, Soraya Torres, Pablo Mir, Maria Teresa Periñán, Christos Proukakis, Viorica Chelban, Lesley Wu, Yee Y Goh, Laura Parkkinen, Michele T Hu, Christopher Kobylecki, Jennifer A Saxon, Sara Rollinson, Emily Garland, Italo Biaggioni, Irene Litvan, Ileana Rubio, Roy N Alcalay, Kimberly T Kwei, Steven J Lubbe, Qinwen Mao, Margaret E Flanagan, Rudolph J Castellani, Vikram Khurana, Alain Ndayisaba, Andrea Calvo, Gabriele Mora, Antonio Canosa, Gianluca Floris, Ryan C Bohannan, Anni Moore, Lucy Norcliffe-Kaufmann, Jose-Alberto Palma, Horacio Kaufmann, Ted M Dawson, Liana S Rosenthal, Alexander Pantelyat, Marilyn S Albert, Olga Pletnikova, Juan C Troncoso, Jon Infante, Carmen Lage, Pascual Sánchez-Juan, Geidy E Serrano, Thomas G Beach, Pau Pastor, Huw R Morris, Diego Albani, Jordi Clarimon, Zane Jaunmuktane, Karl Frontzek, Tamás Révész, Tom Warner, John A Hardy, Mina Ryten, Luigi Ferrucci, Eric Topol, Ali Torkamani, Alex R DeCasien, Adriano Chiò, Philip A Low, Wolfgang Singer, William P Cheshire, Zbigniew K Wszolek, Dennis W Dickson, Bryan J Traynor, J Raphael Gibbs, Clifton L Dalgard, Owen A Ross, Henry Houlden, Sonja W Scholz, Dennis W Dickson, Bryan J Traynor, J Raphael Gibbs, Clifton L Dalgard, Owen A Ross, Henry Houlden, Sonja W Scholz

Institutions: National Institute of Neurological Disorders and Stroke, National Institutes of Health, National Institute on Aging, University of Colorado Anschutz, Mayo Clinic, Mayo Clinic in Florida, Johns Hopkins University, Johns Hopkins Medicine, National Center for Advancing Translational Sciences, Johns Hopkins Hospital, Uniformed Services University of the Health Sciences, National Hospital for Neurology and Neurosurgery, UCL Queen Square Institute of Neurology, University College London

Language: English

Topic: Parkinson's Disease Mechanisms and Treatments

Subfield: Neurology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funders: U.S. Department of Health and Human Services, Louisiana Transportation Research Center, National Institutes of Health, National Institute on Aging, National Heart, Lung, and Blood Institute

OpenAlex ID: W7128806760