Sex-dependent DNA methylation in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) shows well-established sex differences in incidence, age at onset and progression, but their biological basis is unclear. We hypothesised that the DNA methylation changes associated with ALS differ between the sexes, which would point to sex-specific disease processes. To test this, we performed a blood-based epigenome-wide association meta-analysis of ALS cases and controls from Project MinE, an international ALS genomics consortium, and an independent Australian cohort, comprising 8,946 individuals after quality control (5,129 males and 3,817 females; 8,942 with complete covariates in the primary models). We analysed 781,648 autosomal CpGs using complementary sex-stratified case–control models and an ALS-by-sex interaction model that directly tested whether ALS-associated methylation effects differed by sex. Sex-stratified analyses identified no genome-wide significant differences between male and female ALS effects. In contrast, interaction testing identified seven robust sex-dependent ALS-associated differentially methylated positions ( P < 9 × 10 −8 ), mapping to KCNQ1 , ADPRH , HLA-F , GHRLOS , IRF5 , RAD51B and one intergenic region. The strongest signal was at KCNQ1 ( P = 3.1 × 10 −9 ). Six of the seven remained genome-wide significant in a four-stratum sensitivity analysis, and none was detected in previous conventional ALS or population sex-associated methylation analyses. Together, these findings suggest a distinct sex-conditional component of the ALS blood methylome, implicating immune, metabolic and ion-channel loci and providing new candidates for investigating biological heterogeneity between males and females with ALS.

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Publication Details

Journal
bioRxiv (Cold Spring Harbor Laboratory)
Published
2026-10-08
DOI
https://doi.org/10.64898/2026.09.30.755680
Primary Topic
Epigenetics and DNA Methylation
Type
preprint

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preprint

Sex-dependent DNA methylation in amyotrophic lateral sclerosis

Philip Van Damme, John E. Landers, Ross Patrick Byrne, Philippe Corcia et al.
bioRxiv (Cold Spring Harbor Laboratory)
Epigenetics and DNA Methylation
preprint

Sex-dependent DNA methylation in amyotrophic lateral sclerosis

Philip Van Damme, John E. Landers, Ross Patrick Byrne, Philippe Corcia, Allan F. McRae, Orla M. Hardiman, Marc Gotkine, Ammar Al‐Chalabi, Russell Lewis McLaughlin, Sarah J. Marzi, Jonathan S. Mill, Ramona A.J. Zwamborn, Christopher E. Shaw, Leonard H. van den Berg, Patrick Vourc’h, Wouter van Rheenen, Pamela J. Shaw, Ahmad Al Khleifat, Kristel R. van Eijk, Mónica Povedano Panadés, Jesús S. Mora, Fleur Garton, Jonathan D. Glass, Nazli Basak, Young Jun Kim, Alfredo Iacoangeli, David Watson, Mamede de Carvalho
preprint en

Abstract

Amyotrophic lateral sclerosis (ALS) shows well-established sex differences in incidence, age at onset and progression, but their biological basis is unclear. We hypothesised that the DNA methylation changes associated with ALS differ between the sexes, which would point to sex-specific disease processes. To test this, we performed a blood-based epigenome-wide association meta-analysis of ALS cases and controls from Project MinE, an international ALS genomics consortium, and an independent Australian cohort, comprising 8,946 individuals after quality control (5,129 males and 3,817 females; 8,942 with complete covariates in the primary models). We analysed 781,648 autosomal CpGs using complementary sex-stratified case–control models and an ALS-by-sex interaction model that directly tested whether ALS-associated methylation effects differed by sex. Sex-stratified analyses identified no genome-wide significant differences between male and female ALS effects. In contrast, interaction testing identified seven robust sex-dependent ALS-associated differentially methylated positions ( P < 9 × 10 −8 ), mapping to KCNQ1 , ADPRH , HLA-F , GHRLOS , IRF5 , RAD51B and one intergenic region. The strongest signal was at KCNQ1 ( P = 3.1 × 10 −9 ). Six of the seven remained genome-wide significant in a four-stratum sensitivity analysis, and none was detected in previous conventional ALS or population sex-associated methylation analyses. Together, these findings suggest a distinct sex-conditional component of the ALS blood methylome, implicating immune, metabolic and ion-channel loci and providing new candidates for investigating biological heterogeneity between males and females with ALS.

bioRxiv (Cold Spring Harbor Laboratory)
University of Jordan (JO), Koç University (TR), Emory University (US), The University of Queensland (AU), University of Massachusetts Chan Medical School (US), King's College London (GB), Utrecht University (NL), Trinity College Dublin (IE), University of Exeter (GB), Hadassah Medical Center (IL), Beaumont Hospital (IE), Bellvitge University Hospital (ES), University Medical Center Utrecht (NL), Centre Hospitalier Universitaire de Tours (FR), Instituto de Medicina Tropical (PY), Hospital São Rafael (BR), King's College Hospital (GB), VIB-KU Leuven Center for Brain & Disease Research (BE), University of Sheffield (GB), KU Leuven (BE)
UK Research and Innovation, European Commission
Good health and well-being
Epigenetics and DNA Methylation
DOIOpen Access PDFOpenAlex
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