Sex-dependent DNA methylation in amyotrophic lateral sclerosis
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.
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Authors: Young Jun Kim, Alfredo Iacoangeli, Ramona A.J. Zwamborn, Wouter van Rheenen, Ross Patrick Byrne, Kristel R. van Eijk, Sarah J. Marzi, David Watson, Patrick Vourc’h, Philippe Corcia, Mamede de Carvalho, Marc Gotkine, Mónica Povedano Panadés, Jesús S. Mora, Fleur Garton, Allan F. McRae, Pamela J. Shaw, John E. Landers, Jonathan D. Glass, Christopher E. Shaw, Nazli Basak, Orla M. Hardiman, Philip Van Damme, Russell Lewis McLaughlin, Leonard H. van den Berg, Jonathan S. Mill, Ammar Al‐Chalabi, Ahmad Al Khleifat
Institutions: The University of Queensland, University of Sheffield, University of Exeter, KU Leuven, Emory University, University of Massachusetts Chan Medical School, Bellvitge University Hospital, VIB-KU Leuven Center for Brain & Disease Research, Koç University, King's College London, King's College Hospital, University of Jordan, Utrecht University, University Medical Center Utrecht, Trinity College Dublin, Hadassah Medical Center, Beaumont Hospital, Centre Hospitalier Universitaire de Tours, Instituto de Medicina Tropical, Hospital São Rafael