Sex differences in the intergenerational link between maternal and neonatal whole blood DNA methylation: An analysis in the Boston Birth Cohort

Principal Investigator: Liming Liang

Authors: Jie Hu, Xin Xu, Jun Li, Xiumei Hong, Kathryn M. Rexrode, Frank B. Hu, Xiaobin Wang, Liming Liang
Lay Abstract

DNA methylation (DNAm) is a process that regulates gene expression and downstream traits or health outcomes but does not alter that gene sequences. No study has investigated the patterns of transmission of DNAm between mother and newborn. Whether the mother-newborn transmission of DNAm patterns differ by newborn sex remains unknown. Based on genome-wide DNAm data of 396 mother-newborn pairs (54.5% male) from the Boston Birth Cohort, we found significant differences in mother-newborn correlations for overall DNAm patterns by newborn sex, with mother-female pairs having stronger correlations. We also observed significant mother-newborn associations in methylation levels for many DNAm sites, and these associations differed by newborn sex for 15 DNAm sites (11 on the X chromosome) that were mapped to genes whose functions involved in development, stem cells, and neurophysiological process. Additionally, we also found many DNAm sites (mostly on the X chromosome) whose mother-newborn differences in methylation levels were significantly associated with newborn sex, and these DNAm sites were mapped to genes whose functions involved in neurodegenerative and psychological diseases, neurophysiological process, development, and sex-specific cancers. The mother-newborn transmission of DNAm patterns significantly differs by newborn sex, particularly for the X chromosome, with more similarity between mothers and female newborns.

Scientific Abstract

Intergenerational inheritance of DNA methylation (DNAm) variation could contribute to the inheritance of disease susceptibility across generations. But little is known about the patterns of intergenerational transmission of genome-wide DNAm status and whether DNAm transmission patterns differ by newborn sex. Using genome-wide DNAm profiling data of 396 mother-newborn pairs (54.5% male) from the Boston Birth Cohort, we found significant sex differences in mother-newborn correlations in overall DNAm patterns, with mother-female pairs having stronger correlations (p=4.0×10-8). Moreover, 89,267 (12.4% of 721,331 analyzed) DNAm sites had significant mother-newborn associations in methylation levels. Significant interactions between newborn sex and methylation levels were observed for 15 DNAm sites (11 [73.3%] on ChrX) that were mapped to 12 genes with significant enrichment of pathways involved in development, stem cells, and neurophysiological process. Finally, 18,769 DNAm sites (14,482 [77.2%] on ChrX) showed mother-newborn differences in methylation levels that were significantly associated with newborn sex; these DNAm sites were mapped to 3,510 genes with significant enrichment of pathways involved in neurodegenerative and psychological diseases, neurophysiological process, development, and sex-specific cancers. In conclusion, mother-newborn transmission of DNAm patterns significantly differ by newborn sex, particularly for ChrX, and there is more similarity of DNAm between mothers and female newborns.

Clinical Implications
Elucidating sex differences in patterns of mother-newborn transmission of DNA methylation might offer new insight into developmental origins of many pediatric and adult diseases with remarkable sex differences in risk, such as autism, attention-deficit/hyperactivity disorder, cardiovascular diseases, and cancer.

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