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Sex-associated autosomal DNA methylation differences are wide-spread and stable throughout childhood

View ORCID ProfileMatthew Suderman, View ORCID ProfileAndrew Simpkin, View ORCID ProfileGemma Sharp, View ORCID ProfileTom Gaunt, Oliver Lyttleton, View ORCID ProfileWendy McArdle, View ORCID ProfileSusan Ring, View ORCID ProfileGeorge Davey Smith, View ORCID ProfileCaroline Relton
doi: https://doi.org/10.1101/118265
Matthew Suderman
1School of Social and Community Medicine, University of Bristol, Bristol, UK
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  • For correspondence: matthew.suderman@bristol.ac.uk
Andrew Simpkin
1School of Social and Community Medicine, University of Bristol, Bristol, UK
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Gemma Sharp
1School of Social and Community Medicine, University of Bristol, Bristol, UK
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Tom Gaunt
1School of Social and Community Medicine, University of Bristol, Bristol, UK
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Oliver Lyttleton
1School of Social and Community Medicine, University of Bristol, Bristol, UK
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Wendy McArdle
1School of Social and Community Medicine, University of Bristol, Bristol, UK
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Susan Ring
1School of Social and Community Medicine, University of Bristol, Bristol, UK
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George Davey Smith
1School of Social and Community Medicine, University of Bristol, Bristol, UK
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Caroline Relton
1School of Social and Community Medicine, University of Bristol, Bristol, UK
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Abstract

Almost all species show sexual discordance in many traits and diseases. DNA methylation is known to contribute to these differences through well-established mechanisms including X-inactivation in females, imprinting and parent-of-origin effects. Here we investigate sex discordance in DNA methylation throughout childhood in a sample of 700 individuals from the Avon Longitudinal Study of Parents and Children. We show that autosomal sex-discordant methylation is widespread, affecting approximately 12,000 CpG sites at any given age, and stable; at least 8,500 sites are consistently different across all time points and a large proportion discordant in both the fetal and adult brain cortices. Just over 1,000 methylation differences change from birth to late adolescence, 90% of these between birth and around age seven. Sexually discordant CpG sites are enriched in genomic loci containing androgen but not estrogen targets and in genes involved in tissue development but not housekeeping functions. A methylation-derived sex score capturing the variance was calculated at each time point and found to be highly correlated between time points. This score is nominally associated with sex hormone levels in childhood as well as some phenotypes previously linked to sex hormone levels. These findings suggest that sex-discordant autosomal DNA methylation is widespread throughout the genome, likely due to the first androgen exposures in utero. It is then stably maintained from birth to late adolescence. Methylation variation at sex-discordant sites within the sexes, as summarized by the methylation sex score, likely reflects in utero androgen exposure which is relevant to human health.

Significance Statement Although we know that sex hormones are critical for establishing sexual discordance, less is known about how this discordance is achieved and maintained. Here we present evidence for widespread differences in DNA methylation between male and female children. We show that most of these differences are established prenatally, likely due to the first androgen exposures in utero, and then stably maintained throughout childhood, despite extreme fluctuations in the levels of these very same hormones. Our results support a role for DNA methylation as a means for recording and maintaining the effects of exposure to sex hormones and thus to better understand sexual variation and how it is driven by the prenatal environment.

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Posted March 19, 2017.
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Sex-associated autosomal DNA methylation differences are wide-spread and stable throughout childhood
Matthew Suderman, Andrew Simpkin, Gemma Sharp, Tom Gaunt, Oliver Lyttleton, Wendy McArdle, Susan Ring, George Davey Smith, Caroline Relton
bioRxiv 118265; doi: https://doi.org/10.1101/118265
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Sex-associated autosomal DNA methylation differences are wide-spread and stable throughout childhood
Matthew Suderman, Andrew Simpkin, Gemma Sharp, Tom Gaunt, Oliver Lyttleton, Wendy McArdle, Susan Ring, George Davey Smith, Caroline Relton
bioRxiv 118265; doi: https://doi.org/10.1101/118265

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