TY - JOUR
T1 - Sex differences in the intergenerational link between maternal and neonatal whole blood DNA methylation
T2 - a genome-wide analysis in 2 birth cohorts
AU - Hu, Jie
AU - Xu, Xin
AU - Li, Jun
AU - Jiang, Yu
AU - Hong, Xiumei
AU - Rexrode, Kathryn M.
AU - Wang, Guoying
AU - Hu, Frank B.
AU - Zhang, Hongmei
AU - Karmaus, Wilfried J.
AU - Wang, Xiaobin
AU - Liang, Liming
N1 - Funding Information:
The authors wish to thank the study participants in the BBC, the nursing staff at labor and delivery of the Boston Medical Center, as well as the field team for their contributions to the Boston Birth Cohort. The authors are thankful to all the IOWBC participants and greatly appreciate the support of High-Performance Computing facility at the University of Memphis. The authors are thankful to the nurses and staff at the David Hide Asthma & Allergy Research Centre, Isle of Wight, UK, for their help in recruitment and sample collections, and are thankful to all the cohort participants.
Funding Information:
The Boston Birth Cohort (the parent study) was supported in part by the National Institutes of Health (NIH) grants (R21ES011666, 2R01HD041702, R21HD066471, R01HD086013, R01HD098232, R21AI154233, R01ES031272, R03HD096136, R01ES031521, and U01ES034983) and by the Health Resources and Services Administration (HRSA) of the U.S. Department of Health and Human Services (HHS) grant (UT7MC45949). The Isle of Wight birth cohort was supported by the NIH grants (R01AI121226 and R01AI091905). This information or content and conclusions are those of the author and should not be construed as the official position or policy of, nor should any endorsements be inferred by the funding agencies.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - Background: The mother–child inheritance of DNA methylation (DNAm) variations could contribute to the inheritance of disease susceptibility across generations. However, no study has investigated patterns of mother–child associations in DNAm at the genome-wide scale. It remains unknown whether there are sex differences in mother–child DNAm associations. Results: Using genome-wide DNAm profiling data (721,331 DNAm sites, including 704,552 on autosomes and 16,779 on the X chromosome) of 396 mother–newborn pairs (54.5% male) from the Boston Birth Cohort, we found significant sex differences in mother–newborn correlations in genome-wide DNAm patterns (Spearman’s rho = 0.91–0.98; p = 4.0 × 10–8), with female newborns having stronger correlations. Sex differences in correlations were attenuated but remained significant after excluding X-chromosomal DNAm sites (Spearman’s rho = 0.91–0.98; p = 0.035). Moreover, 89,267 DNAm sites (12.4% of all analyzed, including 88,051 [12.5% of analyzed] autosomal and 1,216 [7.2% of analyzed] X-chromosomal sites) showed significant mother–newborn associations in methylation levels, and the top autosomal DNAm sites had high heritability than the genome-wide background (e.g., the top 100 autosomal DNAm sites had a medium h2 of 0.92). Additionally, significant interactions between newborn sex and methylation levels were observed for 11 X-chromosomal and 4 autosomal DNAm sites that were mapped to genes that have been associated with sex-specific disease/traits or early development (e.g., EFHC2, NXY, ADCYAP1R1, and BMP4). Finally, 18,769 DNAm sites (14,482 [77.2%] on the X chromosome) showed mother–newborn differences in methylation levels that were significantly associated with newborn sex, and the top autosomal DNAm sites had relatively small heritability (e.g., the top 100 autosomal DNAm sites had a medium h2 of 0.23). These DNAm sites were mapped to 2,532 autosomal genes and 978 X-chromosomal genes with significant enrichment in pathways involved in neurodegenerative and psychological diseases, development, neurophysiological process, immune response, and sex-specific cancers. Replication analysis in the Isle of Wight birth cohort yielded consistent results. Conclusion: In two independent birth cohorts, we demonstrated strong mother–newborn correlations in whole blood DNAm on both autosomes and ChrX, and such correlations vary substantially by sex. Future studies are needed to examine to what extent our findings contribute to developmental origins of pediatric and adult diseases with well-observed sex differences.
AB - Background: The mother–child inheritance of DNA methylation (DNAm) variations could contribute to the inheritance of disease susceptibility across generations. However, no study has investigated patterns of mother–child associations in DNAm at the genome-wide scale. It remains unknown whether there are sex differences in mother–child DNAm associations. Results: Using genome-wide DNAm profiling data (721,331 DNAm sites, including 704,552 on autosomes and 16,779 on the X chromosome) of 396 mother–newborn pairs (54.5% male) from the Boston Birth Cohort, we found significant sex differences in mother–newborn correlations in genome-wide DNAm patterns (Spearman’s rho = 0.91–0.98; p = 4.0 × 10–8), with female newborns having stronger correlations. Sex differences in correlations were attenuated but remained significant after excluding X-chromosomal DNAm sites (Spearman’s rho = 0.91–0.98; p = 0.035). Moreover, 89,267 DNAm sites (12.4% of all analyzed, including 88,051 [12.5% of analyzed] autosomal and 1,216 [7.2% of analyzed] X-chromosomal sites) showed significant mother–newborn associations in methylation levels, and the top autosomal DNAm sites had high heritability than the genome-wide background (e.g., the top 100 autosomal DNAm sites had a medium h2 of 0.92). Additionally, significant interactions between newborn sex and methylation levels were observed for 11 X-chromosomal and 4 autosomal DNAm sites that were mapped to genes that have been associated with sex-specific disease/traits or early development (e.g., EFHC2, NXY, ADCYAP1R1, and BMP4). Finally, 18,769 DNAm sites (14,482 [77.2%] on the X chromosome) showed mother–newborn differences in methylation levels that were significantly associated with newborn sex, and the top autosomal DNAm sites had relatively small heritability (e.g., the top 100 autosomal DNAm sites had a medium h2 of 0.23). These DNAm sites were mapped to 2,532 autosomal genes and 978 X-chromosomal genes with significant enrichment in pathways involved in neurodegenerative and psychological diseases, development, neurophysiological process, immune response, and sex-specific cancers. Replication analysis in the Isle of Wight birth cohort yielded consistent results. Conclusion: In two independent birth cohorts, we demonstrated strong mother–newborn correlations in whole blood DNAm on both autosomes and ChrX, and such correlations vary substantially by sex. Future studies are needed to examine to what extent our findings contribute to developmental origins of pediatric and adult diseases with well-observed sex differences.
KW - Birth cohort
KW - DNA methylation
KW - Developmental origin of disease
KW - Intergenerational transmission
KW - Sex difference
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U2 - 10.1186/s13148-023-01442-8
DO - 10.1186/s13148-023-01442-8
M3 - Article
C2 - 36966332
AN - SCOPUS:85150999091
SN - 1868-7075
VL - 15
JO - Clinical Epigenetics
JF - Clinical Epigenetics
IS - 1
M1 - 51
ER -