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

Abstract

Sex differences are known to play a role in disease etiology, progression and outcome. Previous studies have revealed autosomal epigenetic differences between males and females in some tissues, including differences in DNA methylation patterns. Here, we report for the first time an analysis of autosomal sex differences in DNAme using the Illumina EPIC array in human whole blood (n=1171). We identified 554 sex-associated differentially methylated CpG sites (saDMPs) with the majority found to be hypermethylated in females (70%). These saDMP's are enriched in CpG islands and CpG shores and located preferentially at 5'UTRs, 3'UTRs and enhancers. Additionally, we identified 311 significant sex associated differentially methylated regions (saDMRs). Transcription factor binding site enrichment revealed enrichment of transcription factors related to critical developmental processes and sex determination such as SRY and SOX9. Our study reports a reliable catalogue of sex associated CpG sites and elucidates several characteristics of these sites.

recountmethylation enables flexible analysis of public blood DNA methylation array data

“…We replicated 40% of sex DMPs from [48] and 46% of sex DMPs from [47] using independent whole blood and PBMC compilations. These rates were similar to prior studies of sex DNAm differences, including a 38% validation rate of cord blood sex DMPs between two independent cohorts [46], and 44% validation rate of genes in nasal epithelium with DNAm differences by sex [45].…”

“…S7a). Further, (248/544 =) 46% of whole-blood sex DMPs independently reported in [47] overlapped DMPs in whole blood or PBMC. However, just 26 sex DMPs appeared in all of PBMC, whole blood, [48], and [47].…”

“…Further, (248/544 =) 46% of whole-blood sex DMPs independently reported in [47] overlapped DMPs in whole blood or PBMC. However, just 26 sex DMPs appeared in all of PBMC, whole blood, [48], and [47]. Mean (normalized) Beta-value was typically higher in females than males in whole blood (64-81% of DMPs) but not PBMC (35% of DMPs).…”

“…DNAm differences between sexes have been observed in mouse [43] and multiple human tissues including brain [43], pancreas [44], nasal epithelium [45], cord blood [46], and whole blood [47,48]. These DNAm differences can impact insulin secretion [44], risk of disease [45,46], and biological age [43].…”

“…Using cross-study and cross-platform compilations of whole blood and PBMC, we performed novel independent validation of previously published sets of probes with differential methylation between the sexes (a.k.a. "sex DMPs") from two previous studies in whole blood [47,48].…”