Limits...
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.

Show MeSH

Related in: MedlinePlus

Boxplot of meta analysis –log10Pfor all 26,225 autosomal CpGs, compared to those located in the genes included in the top four enriched GO Biological Processes; RNA splicing (n = 112 genes), DNA repair (n = 116 genes), protein modification by small protein conjugation (n = 122 genes) and viral reproduction (n = 140 genes).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig6: Boxplot of meta analysis –log10Pfor all 26,225 autosomal CpGs, compared to those located in the genes included in the top four enriched GO Biological Processes; RNA splicing (n = 112 genes), DNA repair (n = 116 genes), protein modification by small protein conjugation (n = 122 genes) and viral reproduction (n = 140 genes).

Mentions: Pathway analysis revealed significant enrichment of genes with sex-associated changes in CpG methylation in 53 GO Biological Pathways at P < 0.05 (FDR adjusted). All biological processes enriched at P < 0.01 (FDR adjusted) are shown in Table 2 and largely comprise cellular ‘housekeeping’ functions. Gene overlap between pathways was relatively low, with 367 (73%) of the 500 genes in the top four processes (RNA splicing, DNA repair, protein modification by small protein conjugation and viral reproduction) unique to only one of these pathways (Additional file 1: Figure S9). These top four processes were relatively distinct from the individually most strongly sex-associated CpG sites, with only 10 genes from these processes represented in the CpG sites which passed Bonferroni correction. The median –log10 P values of the CpG sites of the genes in the top four biological processes compared to P values across all CpG sites are displayed in Figure 6.Table 2


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)

Boxplot of meta analysis –log10Pfor all 26,225 autosomal CpGs, compared to those located in the genes included in the top four enriched GO Biological Processes; RNA splicing (n = 112 genes), DNA repair (n = 116 genes), protein modification by small protein conjugation (n = 122 genes) and viral reproduction (n = 140 genes).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig6: Boxplot of meta analysis –log10Pfor all 26,225 autosomal CpGs, compared to those located in the genes included in the top four enriched GO Biological Processes; RNA splicing (n = 112 genes), DNA repair (n = 116 genes), protein modification by small protein conjugation (n = 122 genes) and viral reproduction (n = 140 genes).
Mentions: Pathway analysis revealed significant enrichment of genes with sex-associated changes in CpG methylation in 53 GO Biological Pathways at P < 0.05 (FDR adjusted). All biological processes enriched at P < 0.01 (FDR adjusted) are shown in Table 2 and largely comprise cellular ‘housekeeping’ functions. Gene overlap between pathways was relatively low, with 367 (73%) of the 500 genes in the top four processes (RNA splicing, DNA repair, protein modification by small protein conjugation and viral reproduction) unique to only one of these pathways (Additional file 1: Figure S9). These top four processes were relatively distinct from the individually most strongly sex-associated CpG sites, with only 10 genes from these processes represented in the CpG sites which passed Bonferroni correction. The median –log10 P values of the CpG sites of the genes in the top four biological processes compared to P values across all CpG sites are displayed in Figure 6.Table 2

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