Chromosome X-wide association study in multiple system atrophy identifies sex-differential risk loci
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 7,128 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.
Authors
- Fabian Leys (ORCID: https://orcid.org/0000-0003-1714-5305)
- Vikram Khurana
- Anindita Ray (ORCID: https://orcid.org/0000-0003-4824-8913)
- William P. Cheshire (ORCID: https://orcid.org/0000-0002-6364-5362)
- Ileana Gabriela Sanchez Rubio (ORCID: https://orcid.org/0000-0003-4779-4533)
- Lesley Wu (ORCID: https://orcid.org/0000-0001-5464-5603)
- Sara Rollinson (ORCID: https://orcid.org/0000-0002-0921-4318)
- Victoria Sidoroff (ORCID: https://orcid.org/0000-0002-7434-6229)
- Ignacio Morales Álvarez
- Kimberly Kwei
- Anni Moore (ORCID: https://orcid.org/0000-0003-1953-6449)
- Regina Hertfelder Reynolds (ORCID: https://orcid.org/0000-0001-6470-7919)
- Maria Claudia Russillo
- C. Proukakis
- Ding Jinhui
- Mag Klaus Seppi
- Florian Krismer (ORCID: https://orcid.org/0000-0001-6427-6311)
- Jennifer A. Saxon (ORCID: https://orcid.org/0000-0002-6599-7433)
- Ronald L. Walton
- Karl Frontzek (ORCID: https://orcid.org/0000-0002-0945-8857)
- Alain Ndayisaba (ORCID: https://orcid.org/0000-0001-7611-7115)
- Yee Yen Goh
- Emily M. Garland (ORCID: https://orcid.org/0000-0001-9525-2929)
- Wolfgang Singer (ORCID: https://orcid.org/0000-0003-1263-6850)
- Ryan C. Bohannan
- Diego Albani (ORCID: https://orcid.org/0000-0002-1793-9212)
- Bayram Ece
- Jordi Clarimon
- Qinwen Mao
- Gabriele Mora
- Philip Low
- Soraya Torres
- J Kulisevsky
- Henry Houlden
- Irene Litvan
- Ruth Chia
- Juan Marín-Lahoz
- Alexander Pantelyat
- Pablo Mir
- Sonja W. Scholz
- Paolo Barone
- Zane Jaunmuktane
- Steven Lubbe
- Monica Diez-Fairen
- Pau Pastor
- Zbigniew K Wszolek
- Memoona Rasheed
- Thomas G Beach
- Margaret E Flanagan
- Maria Teresa Pellecchia
- Tamás Révész
- Carmen Lage
- Antonio Canosa
- Alexandra Foubert-Samier
- Liana S Rosenthal
- Maria Teresa Periñán
- Alex R DeCasien
- J Raphael Gibbs
- Geidy E Serrano
- Olga Pletnikova
- Walter Pirker
- Wassilios G Meissner
- Huw R Morris
- Nadia Stefanova
- Eric Topol
- Adriano Chiò
- Jon Infante
- Tom Warner
- Owen A Ross
- Lucy Norcliffe-Kaufmann
- Alexander Zimprich
- Alessandra Fanciulli
- Susanne Duerr
- Michele T Hu
- John A Hardy
- Christopher Kobylecki
- Ted M Dawson
- Rudolph J Castellani
- Juan C Troncoso
- Pascual Sánchez-Juan
- Laura Parkkinen
- Andrea Calvo
- Horacio Kaufmann
- François Tison
- Olivier Rascol
- Roy N Alcalay
- Mina Ryten
- Dennis W. Dickson
- Marilyn S Albert
- Ali Torkamani
- Clifton L Dalgard
Institutions
- Johns Hopkins University (US)
- Uniformed Services University of the Health Sciences (US)
- Queen Mary University of London (GB)
- Johns Hopkins Medicine (US)
- Jacksonville College (US)
- Johns Hopkins Bayview Medical Center (US)
- National Institute of Neurological Disorders and Stroke (US)
- National Institute on Aging (US)
- Mayo Clinic in Florida (US)
- National Center for Advancing Translational Sciences (US)
- National Hospital for Neurology and Neurosurgery (GB)
- University College London (GB)
- University of Colorado Anschutz Medical Campus (US)
Publication Details
- Journal
- Brain
- Published
- 2026-02-12
- DOI
- https://doi.org/10.1093/brain/awag062
- Primary Topic
- Genetic Neurodegenerative Diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00