title: Meta-analysis of human methylation data for evidence of sex-specific autosomal patterns.
abstract: BACKGROUND
  Several individual studies have suggested that autosomal CpG methylation differs by sex both in terms of individual CpG sites and global autosomal CpG methylation. However, these findings have been inconsistent and plagued by spurious associations due to the cross reactivity of CpG probes on commercial microarrays. We collectively analysed 76 published studies (n = 6,795) for sex-associated differences in both autosomal and sex chromosome CpG sites.
  
  
  RESULTS
  Overall autosomal methylation profiles varied substantially by study, and we encountered substantial batch effects. We accounted for these by conducting random effects meta-analysis for individual autosomal CpG methylation associations. After excluding non-specific probes, we found 184 autosomal CpG sites differentially methylated by sex after correction for multiple testing. In line with previous studies, average beta differences were small. Many of the most significantly associated CpG probes were new. Of note was differential CpG methylation in the promoters of genes thought to be involved in spermatogenesis and male fertility, such as SLC9A2, SPESP1, CRISP2, and NUPL1. Pathway analysis revealed overrepresentation of genes differentially methylated by sex in several broad Gene Ontology biological processes, including RNA splicing and DNA repair.
  
  
  CONCLUSIONS
  This study represents a comprehensive analysis of sex-specific methylation patterns. We demonstrate the existence of sex-specific methylation profiles and report a large number of novel DNA methylation differences in autosomal CpG sites between sexes.
authors.affiliation: Centre for the Genetic Origins of Health and Disease (GOHaD), University of Western Australia, Perth, Australia. nina.mccarthy@uwa.edu.au.
authors.forename: Nina S
authors.initials: NS
authors.lastname: McCarthy
authors.forename: Phillip E
authors.initials: PE
authors.lastname: Melton
authors.forename: Gemma
authors.initials: G
authors.lastname: Cadby
authors.forename: Seyhan
authors.initials: S
authors.lastname: Yazar
authors.forename: Maria
authors.initials: M
authors.lastname: Franchina
authors.forename: Eric K
authors.initials: EK
authors.lastname: Moses
authors.forename: David A
authors.initials: DA
authors.lastname: Mackey
authors.forename: Alex W
authors.initials: AW
authors.lastname: Hewitt
mesh_terms: D002877:Chromosomes, Human; D041321:Chromosomes, Human, X; D019295:Computational Biology; D018899:CpG Islands; D019175:DNA Methylation; D066264:Datasets as Topic; D005260:Female; D006801:Humans; D008297:Male; D012372:ROC Curve; D012737:Sex Factors; D049951:X Chromosome Inactivation