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Meta-analysis of human methylation data for evidence of sex-specific autosomal patterns.

McCarthy NS, Melton PE, Cadby G, Yazar S, Franchina M, Moses EK, Mackey DA, Hewitt AW - BMC Genomics (2014)

Bottom Line: After excluding non-specific probes, we found 184 autosomal CpG sites differentially methylated by sex after correction for multiple testing.Many of the most significantly associated CpG probes were new.This study represents a comprehensive analysis of sex-specific methylation patterns.

View Article: PubMed Central - PubMed

Affiliation: Centre for the Genetic Origins of Health and Disease (GOHaD), University of Western Australia, Perth, Australia. nina.mccarthy@uwa.edu.au.

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.

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Related in: MedlinePlus

Principal Components plots using the 1sttwo principal components calculated using individual beta values at all autosomal CpG sites adjusted for study, coloured by study (A) and sex (B).
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Fig5: Principal Components plots using the 1sttwo principal components calculated using individual beta values at all autosomal CpG sites adjusted for study, coloured by study (A) and sex (B).

Mentions: PCA of individual beta values at autosomal CpG sites by sex was also highly confounded by batch effect, even after adjustment for study (Figure 5). Hence, to identify individual CpG sites differentially methylated between males and females, we conducted a random effects meta-analysis using the 39 studies (n = 4,172) in which both sexes were represented. Estimated overall effects (mean difference in beta values between females and males, weighted by study) and corresponding P values were calculated. Overall, 235 (0.9%) of the 26,225 CpG sites were associated with sex after Bonferroni correction (P <1.9e-06).Figure 5


Meta-analysis of human methylation data for evidence of sex-specific autosomal patterns.

McCarthy NS, Melton PE, Cadby G, Yazar S, Franchina M, Moses EK, Mackey DA, Hewitt AW - BMC Genomics (2014)

Principal Components plots using the 1sttwo principal components calculated using individual beta values at all autosomal CpG sites adjusted for study, coloured by study (A) and sex (B).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4255932&req=5

Fig5: Principal Components plots using the 1sttwo principal components calculated using individual beta values at all autosomal CpG sites adjusted for study, coloured by study (A) and sex (B).
Mentions: PCA of individual beta values at autosomal CpG sites by sex was also highly confounded by batch effect, even after adjustment for study (Figure 5). Hence, to identify individual CpG sites differentially methylated between males and females, we conducted a random effects meta-analysis using the 39 studies (n = 4,172) in which both sexes were represented. Estimated overall effects (mean difference in beta values between females and males, weighted by study) and corresponding P values were calculated. Overall, 235 (0.9%) of the 26,225 CpG sites were associated with sex after Bonferroni correction (P <1.9e-06).Figure 5

Bottom Line: After excluding non-specific probes, we found 184 autosomal CpG sites differentially methylated by sex after correction for multiple testing.Many of the most significantly associated CpG probes were new.This study represents a comprehensive analysis of sex-specific methylation patterns.

View Article: PubMed Central - PubMed

Affiliation: Centre for the Genetic Origins of Health and Disease (GOHaD), University of Western Australia, Perth, Australia. nina.mccarthy@uwa.edu.au.

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.

Show MeSH
Related in: MedlinePlus