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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

Flow chart of sample quality control (A) and CpG quality control (B) for the data downloaded from the European Bioinformatics Institute (EBI) database. PBL: Peripheral blood leukocyte.
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Fig3: Flow chart of sample quality control (A) and CpG quality control (B) for the data downloaded from the European Bioinformatics Institute (EBI) database. PBL: Peripheral blood leukocyte.

Mentions: Following quality control, 27,231 CpG sites on the HumanMethylation27K chip remained for analysis in 6,795 individuals who were successfully classified by sex (Figure 3(A) and (B)). Of these, 26,225 CpG sites were located on the autosomes (Figure 3(B)). A density plot of individual methylation beta values for each of the 26,225 autosomal CpG sites for all 6,795 individuals (Figure 4(A)) showed that across all studies and for both sexes, the majority (68%) of CpG sites had methylation values <0.3, whilst 17.4% of CpG sites had beta values >0.7, the range at which probes would be considered to be fully methylated [20, 21]. These percentages were not substantially different by sex (Additional file 2: Table S2).Figure 3


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)

Flow chart of sample quality control (A) and CpG quality control (B) for the data downloaded from the European Bioinformatics Institute (EBI) database. PBL: Peripheral blood leukocyte.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig3: Flow chart of sample quality control (A) and CpG quality control (B) for the data downloaded from the European Bioinformatics Institute (EBI) database. PBL: Peripheral blood leukocyte.
Mentions: Following quality control, 27,231 CpG sites on the HumanMethylation27K chip remained for analysis in 6,795 individuals who were successfully classified by sex (Figure 3(A) and (B)). Of these, 26,225 CpG sites were located on the autosomes (Figure 3(B)). A density plot of individual methylation beta values for each of the 26,225 autosomal CpG sites for all 6,795 individuals (Figure 4(A)) showed that across all studies and for both sexes, the majority (68%) of CpG sites had methylation values <0.3, whilst 17.4% of CpG sites had beta values >0.7, the range at which probes would be considered to be fully methylated [20, 21]. These percentages were not substantially different by sex (Additional file 2: Table S2).Figure 3

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