Abstract
The majority of congenital heart defects (CHDs) are thought to result from the interaction between multiple genetic, epigenetic, environmental, and lifestyle factors. Epigenetic mechanisms are attractive targets in the study of complex diseases because they may be altered by environmental factors and dietary interventions. We conducted a population based, case-control study of genome-wide maternal DNA methylation to determine if alterations in gene-specific methylation were associated with CHDs. Using the Illumina Infinium Human Methylation27 BeadChip, we assessed maternal gene-specific methylation in over 27,000 CpG sites from DNA isolated from peripheral blood lymphocytes. Our study sample included 180 mothers with non-syndromic CHD-affected pregnancies (cases) and 187 mothers with unaffected pregnancies (controls). Using a multi-factorial statistical model, we observed differential methylation between cases and controls at multiple CpG sites, although no CpG site reached the most stringent level of genome-wide statistical significance. The majority of differentially methylated CpG sites were hypermethylated in cases and located within CpG islands. Gene Set Enrichment Analysis (GSEA) revealed that the genes of interest were enriched in multiple biological processes involved in fetal development. Associations with canonical pathways previously shown to be involved in fetal organogenesis were also observed. We present preliminary evidence that alterations in maternal DNA methylation may be associated with CHDs. Our results suggest that further studies involving maternal epigenetic patterns and CHDs are warranted. Multiple candidate processes and pathways for future study have been identified.
Highlights
Birth defects are the leading cause of infant mortality, and congenital heart defects (CHDs) are among the most fatal of all birth defects [1]
Identification of risk factors for CHDs are further complicated by the fact that both the maternal and fetal genetic susceptibilities may affect the intrauterine environment during gestation, and both may contribute to the development of CHDs [5,6]
We identified 425 CpG sites that were differentially methylated between cases and controls with P,0.005, an false discovery rate (FDR) threshold of 0.05 was not reached for any single CpG site (Table S1)
Summary
Birth defects are the leading cause of infant mortality, and congenital heart defects (CHDs) are among the most fatal of all birth defects [1]. Identification of risk factors for CHDs are further complicated by the fact that both the maternal and fetal genetic susceptibilities may affect the intrauterine environment during gestation, and both may contribute to the development of CHDs [5,6]. Multiple factors that have been shown to affect DNA methylation patterns including diet, genotype, and environmental exposures [10,12,13] have been recognized as maternal factors implicated in the modification of fetal phenotypes [14,15,16]. Alterations in maternal one-carbon plasma metabolites indicative of a cellular hypomethylation status have been associated with an increased risk of CHDs [19,20], a comprehensive study assessing maternal genomic methylation patterns has not yet been conducted
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