A cross-cohort analysis of autosomal DNA methylation sex differences in the term placenta

Abstract

Background Human placental DNA methylation (DNAme) data is a valuable resource for studying sex differences during gestation, as DNAme profiles after delivery reflect the cumulative effects of gene expression patterns and exposures across gestation. Here, we present an analysis of sex differences in autosomal patterns of DNAme in the uncomplicated term placenta (n=343) using the Illumina 450K array. Results Using a false discovery rate < 0.05 and a mean sex difference in DNAme beta value of > 0.10, we identified 162 autosomal CpG sites that were differentially methylated by sex, and that replicated in an independent cohort of samples (n=293). Several of these differentially methylated CpG sites were part of larger correlated regions of differential DNAme, and many also exhibited sex-specific DNAme variability. Although global DNAme levels did not differ by sex, the majority of significantly differentially methylated CpGs were more highly methylated in male placentae, the opposite of what is seen in differential methylation analyses of somatic tissues. Interestingly, patterns of autosomal DNAme at these significantly differentially methylated CpGs organized placental samples along a continuum, rather than into discrete male and female clusters, and sample position along the continuum was significantly associated with maternal age and newborn birthweight standard deviation. Conclusions Our results provide a comprehensive analysis of sex differences in autosomal DNAme in the term human placenta. We report a list of high-confidence autosomal sex-associated differentially methylated CpGs, and identify several key features of these loci that suggest their relevance to sex differences observed in normative and complicated pregnancies.

Characterising sex differences of autosomal DNA methylation in whole blood using the Illumina EPIC array

“…Several genome wide association methylome studies (or Epigenome Wide Association Studies - EWAS) have highlighted differences in DNA methylation patterns linked to sex differences in genes on the autosomes (17–20). Previous studies have reported sites showing varying methylation due to sex differences in various tissues such as saliva, placenta, brain, pancreatic islets and whole blood (17, 19, 21–27). Early studies in this area did not account for cross hybridizing probes which map to both autosomal and sex chromosome loci (28, 29).…”