Sex-specific DNA methylation differences in Amyotrophic lateral sclerosis.
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Grant Olivia A, Iacoangeli Alfredo, Zwamborn Ramona A J, van Rheenen Wouter, Byrne Ross, Van Eijk Kristel R, Kenna Kevin, van Vugt Joke J F A, Cooper-Knock Johnathan, Kenna Brendan, Vural Atay, Topp Simon, Campos Yolanda, Weber Markus, Smith Bradley, Dobson Richard, van Es Michael A, Vourc'h Patrick, Corcia Philippe, de Carvalho Mamede, Gotkine Marc, Panades Monica P, Mora Jesus S, Mill Jonathan, Garton Fleur, McRae Allan, Wray Naomi R, Shaw Pamela J, Landers John E, Glass Jonathan D, Shaw Christopher E, Basak Nazli, Hardiman Orla, Van Damme Philip, McLaughlin Russell L, van den Berg Leonard H, Veldink Jan H, Al-Chalabi Ammar, Al Khleifat Ahmad
Аннотация
Sex is an important covariate in all genetic and epigenetic research due to its role in the incidence, progression and outcome of many phenotypic characteristics and human diseases. Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with a sex bias towards higher incidence in males. Here, we report for the first time a blood-based epigenome-wide association study meta-analysis in 9274 individuals after stringent quality control (5529 males and 3975 females). We identified a total of 226 ALS saDMPs (sex-associated DMPs) annotated to a total of 159 unique genes. These ALS saDMPs were depleted at transposable elements yet significantly enriched at enhancers and slightly enriched at 3'UTRs. These ALS saDMPs were enriched for transcription factor motifs such as ESR1 and REST. Moreover, we identified an additional 10 genes associated with ALS saDMPs through chromatin loop interactions, suggesting a potential regulatory role for these saDMPs on distant genes. Furthermore, we investigated the relationship between DNA methylation at specific CpG sites and overall survival in ALS using Cox proportional hazards models. We identified two ALS saDMPs, cg14380013 and cg06729676, that showed significant associations with survival. Overall, our study reports a reliable catalogue of sex-associated ALS saDMPs in ALS and elucidates several characteristics of these sites using a large-scale dataset. This resource will benefit future studies aiming to investigate the role of sex in the incidence, progression and risk for ALS.