Sex differences in DNA methylation assessed by 450 K BeadChip in newborns
Open accessAbstract
BACKGROUND: DNA methylation is an important epigenetic mark that can potentially link early life exposures to adverse health outcomes later in life. Host factors like sex and age strongly influence biological variation of DNA methylation, but characterization of these relationships is still limited, particularly in young children. METHODS: In a sample of 111 Mexican-American subjects (58 girls , 53 boys), we interrogated DNA methylation differences by sex at birth using the 450 K BeadChip in umbilical cord blood specimens, adjusting for cell composition. RESULTS: We observed that ~3% of CpG sites were differentially methylated between girls and boys at birth (FDR P < 0.05). Of those CpGs, 3031 were located on autosomes, and 82.8% of those were hypermethylated in girls compared to boys. Beyond individual CpGs, we found 3604 sex-associated differentially methylated regions (DMRs) where the majority (75.8%) had higher methylation in girls. Using pathway analysis, we found that sex-associated autosomal CpGs were significantly enriched for gene ontology terms related to nervous system development and behavior. Among hits in our study, 35.9% had been previously reported as sex-associated CpG sites in other published human studies. Further, for replicated hits, the direction of the association with methylation was highly concordant (98.5-100%) with previous studies. CONCLUSIONS: To our knowledge, this is the first reported epigenome-wide analysis by sex at birth that examined DMRs and adjusted for confounding by cell composition. We confirmed previously reported trends that methylation profiles are sex-specific even in autosomal genes, and also identified novel sex-associated CpGs in our methylome-wide analysis immediately after birth, a critical yet relatively unstudied developmental window.
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Biological confounders known to affect epigenetic patterns such as age, sex, ethnicity, body mass index, smoking behavior or nutritional aspects may introduce critical biases limiting the interpretation of epigenetic data.
“Biological confounders known to affect epigenetic patterns such as age (Xiao, Wang, & Kong, 2019), sex (Yousefi et al., 2015), ethnicity (Fraser, Lam, Neumann, & Kobor, 2012), body mass index (Sayols-Baixeras et al., 2017), smoking behavior (Li et al., 2018) or nutritional aspects (Gadecka & Bielak-Zmijewska, 2019) may introduce critical biases limiting the interpretation of epigenetic data.”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as Yousefi et al., 2015
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- Authors
- Yousefi, P., Huen, K., Davé, V., Barcellos, L., Eskenazi, B., & Holland, N.
- Affiliations
- University of California, Berkeley (US)
- Corresponding author
- Holland, Nina
- Venue
- BMC Genomics
- Published
- 2015-11-09
- Volume
- 16
- Issue
- 1
- Pages
- 911-911
- ISSN
- 1471-2164 (ISSN-L)
- PMC
- PMC4640166
- OpenAlex
- W2112500414
- Cited by
- 205
- References
- 50
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 17 · 2023: 25 · 2022: 32 · 2021: 36 · 2020: 19 · 2019: 14 · 2018: 15 · 2017: 15 · 2016: 9
- FWCI
- 5.65
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- BMC Genomics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- U.S. Environmental Protection Agency (RD83451301)
- National Institute of Environmental Health Sciences (ES009605, R01ES021369)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Keywords
- DNA methylation, sex differences, neonates, umbilical cord blood, differentially methylated regions, hypermethylation, brain development, epigenome-wide association study, Mexican-American population
- MeSH terms
- Female, Humans, Infant, Newborn, Male, CpG Islands, DNA Methylation, Epigenesis, Genetic, Genome-Wide Association Study, Epigenomics
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