Abstract
BackgroundThe association of in vitro fertilisation (IVF) and DNA methylation has been studied predominantly at regulatory regions of imprinted genes and at just thousands of the ~28 million CpG sites in the human genome.MethodsWe investigated the links between IVF and DNA methylation patterns in whole cord blood cells (n = 98) and cord blood mononuclear cells (n = 82) from newborn twins using genome-wide methylated DNA immunoprecipitation coupled with deep sequencing.ResultsAt a false discovery rate (FDR) of 5%, we identified one significant whole blood DNA methylation change linked to conception via IVF, which was located ~3 kb upstream of TNP1, a gene previously linked to male infertility. The 46 most strongly associated signals (FDR of 25%) included a second region in a gene also previously linked to infertility, C9orf3, suggesting that our findings may in part capture the effect of parental subfertility. Using twin modelling, we observed that individual-specific environmental factors appear to be the main overall contributors of methylation variability at the FDR 25% IVF-associated differentially methylated regions, although evidence for methylation heritability was also obtained at several of these regions. We replicated previous findings of differential methylation associated with IVF at the H19/IGF2 region in cord blood mononuclear cells, and we validated the signal at C9orf3 in monozygotic twins. We also explored the impact of intracytoplasmic sperm injection on the FDR 25% signals for potential effects specific to male or female infertility factors.ConclusionsTo our knowledge, this is the most comprehensive study of DNA methylation profiles at birth and IVF conception to date, and our results show evidence for epigenetic modifications that may in part reflect parental subfertility.
Highlights
The association of in vitro fertilisation (IVF) and DNA methylation has been studied predominantly at regulatory regions of imprinted genes and at just thousands of the ~28 million CpG sites in the human genome
Principal component analysis was used to identify factors that were significantly associated with genome-wide variability in DNA methylation profiles
We were able to identify significant and suggestive Differentially methylated region (DMR) related to IVF conception (IVF-DMRs) in Whole blood cell (WBC), our results suggest that at least some of these changes may be linked to parental subfertility, which is confounded with IVF treatment
Summary
The association of in vitro fertilisation (IVF) and DNA methylation has been studied predominantly at regulatory regions of imprinted genes and at just thousands of the ~28 million CpG sites in the human genome. As the frequency of in vitro fertilisation (IVF) treatment increases worldwide, much research effort has focused on exploring both short- and long-term health outcomes associated with conception via IVF, with contradictory results. Further research is required to identify potential factors associated with conception via IVF, including health outcomes and biological consequences such as epigenetic modifications. Given that birth weight and imprinting disorders are controlled at least in part by epigenetic factors [7, 8], IVF may have an influence on epigenetic profiles, potentially resulting in changes that persist well after birth and over the life course. Establishment of DNA methylation profiles in the germ line and embryo takes place early in development [10] This epigenetic reprogramming could be influenced by IVFrelated interventions that occur very early, prior to blastocyst implantation. Induction of ovulation, embryo culturing, and cryopreservation, among others, have all been linked to specific alterations in DNA methylation in mice, results are somewhat inconsistent [11,12,13]
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