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Review
. 2023 Sep 8;13(1):14838.
doi: 10.1038/s41598-023-41360-6.

A permutation-based approach using a rank-based statistic to identify sex differences in epigenetics

Alice J Sommer  1   2 , Jude Okonkwo  3 , Jonathan Monteiro  4 , Marie-Abèle C Bind  5   6
Affiliations
Review

A permutation-based approach using a rank-based statistic to identify sex differences in epigenetics

Alice J Sommer et al. Sci Rep. .

Abstract

Epigenetic sex differences and their resulting implications for human health have been studied for about a decade. The objective of this paper is to use permutation-based inference and a new ranked-based test statistic to identify sex-based epigenetic differences in the human DNA methylome. In particular, we examine whether we could identify separations between the female and male distributions of DNA methylation across hundred of thousands CpG sites in two independent cohorts, the Swedish Adoption Twin study and the Lamarck study. Based on Fisherian p-values, we set a threshold for methylation differences "worth further scrutiny". At this threshold, we were able to confirm previously-found CpG sites that stratify with respect to sex. These CpG sites with sex differences in DNA methylation should be further investigated for their possible contribution to various physiological and pathological functions in the human body. We followed-up our statistical analyses with a literature review in order to inform the proposed disease implications for the loci we uncovered.

Trial registration: ClinicalTrials.gov NCT01492517.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Visualization of the separation scenari in the primary analysis. Upper panel: CpG sites for which the average DNA methylation is higher in male (scenario M>F). Lower panel: CpG sites for which the average DNA methylation is higher in female (scenario F>M). Individual graph top label: Chromosome. X-axis: DNA methylation as a percentage. Number: value of the separation statistic.
Figure 2
Figure 2
Visualization of DNA methylation separation for opposite sex twins. Upper panel: CpG sites for which the average DNA methylation is higher in males than females. Lower panel: CpG sites for which the average DNA methylation is higher in females than males. X-axis: DNA methylation as a percentage. Number: value of the separation statistic.
Figure 3
Figure 3
Visualization of the separation scenarios in the EPA data. Upper panel: CpG sites for which the average DNA methylation is higher for males than females. Lower panel: CpG sites for which the average DNA methylation is higher for females than males. X-axis: DNA methylation as a percentage.
Figure 4
Figure 4
Age distribution comparison between sex.
Figure 5
Figure 5
Volcano plot. Left panel: CpG sites for which the average DNA methylation is higher in male. Right panel: CpG sites for which the average DNA methylation is higher in female.
See this image and copyright information in PMC

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