Division of Women's Health, Department of Medicine, Bigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Department of Epidemiology, Harvard T.H. Chan School of Public Health, 655 Huntington Avenue, Building 2, Room 207, Boston, MA, 02115, USA.
Clin Epigenetics. 2023 Mar 25;15(1):51. doi: 10.1186/s13148-023-01442-8.
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.
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), 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 h 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 h 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.
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.
DNA 甲基化（DNAm）变异的母子遗传可能有助于跨代遗传疾病易感性。然而，尚无研究在全基因组范围内调查 DNAm 的母子关联模式。母子 DNAm 关联是否存在性别差异仍不清楚。
使用来自波士顿出生队列的 396 对母婴（54.5%为男性）的全基因组 DNAm 分析数据（721,331 个 DNAm 位点，包括 704,552 个常染色体和 16,779 个 X 染色体），我们发现全基因组 DNAm 模式中存在显著的母子相关性性别差异（Spearman rho=0.91-0.98；p=4.0×10），女性新生儿相关性更强。在排除 X 染色体 DNAm 位点后，相关性的性别差异减弱，但仍具有统计学意义（Spearman rho=0.91-0.98；p=0.035）。此外，89,267 个 DNAm 位点（所有分析的 12.4%，包括 88,051 个[分析的 12.5%]常染色体和 1,216 个[分析的 7.2%]X 染色体）在甲基化水平上显示出与母子关联，并且常染色体上排名靠前的 DNAm 位点具有比全基因组背景更高的遗传力（例如，排名前 100 的常染色体 DNAm 位点的遗传力为 0.92）。此外，在 11 个 X 染色体和 4 个常染色体 DNAm 位点上观察到新生性别和甲基化水平之间存在显著的相互作用，这些位点映射到与性别特异性疾病/特征或早期发育相关的基因（例如，EFHC2、NXY、ADCYAP1R1 和 BMP4）。最后，18,769 个 DNAm 位点（X 染色体上的 14,482 个[77.2%]）在甲基化水平上显示出母子差异，与新生性别显著相关，并且常染色体上排名靠前的 DNAm 位点遗传力相对较小（例如，排名前 100 的常染色体 DNAm 位点的遗传力为 0.23）。这些 DNAm 位点映射到 2,532 个常染色体基因和 978 个 X 染色体基因，在涉及神经退行性和心理疾病、发育、神经生理过程、免疫反应和性别特异性癌症的途径中存在显著富集。在怀特岛出生队列中的复制分析产生了一致的结果。
在两个独立的出生队列中，我们在常染色体和 ChrX 上都证明了全血 DNAm 中存在强烈的母子相关性，并且这种相关性在性别上有很大差异。需要进一步的研究来研究我们的发现在多大程度上有助于具有明显性别差异的儿科和成人疾病的发育起源。
