Luo Rui, Mukherjee Nandini, Chen Su, Jiang Yu, Arshad S Hasan, Holloway John W, Hedman Anna, Gruzieva Olena, Andolf Ellika, Pershagen Goran, Almqvist Catarina, Karmaus Wilfried Jj
Division of Epidemiology, Biostatistics and Environmental Health, School of Public Health, University of Memphis, Memphis, TN, USA.
Department of Mathematical Sciences, University of Memphis, Memphis, TN, USA.
Epigenet Insights. 2020 Sep 10;13:2516865720930701. doi: 10.1177/2516865720930701. eCollection 2020.
How epigenetic modifications of DNA are associated with gestational age at birth is not fully understood. We investigated potential effects of differential paternal DNA methylation (DNAm) on offspring gestational age at birth by conducting an epigenome-wide search for cytosine-phosphate-guanine (CpG) sites.
Study participants in this study consist of male cohort members or partners of the F1-generation of the Isle of Wight Birth Cohort (IoWBC). DNAm levels in peripheral blood from F1-fathers (n = 92) collected around pregnancy of their spouses were analyzed using the Illumina 450K array. A 5-step statistical analysis was performed. First, a training-testing screening approach was applied to select CpG sites that are potentially associated with gestational age at birth. Second, functional enrichment analysis was employed to identify biological processes. Third, by centralizing on biologically informative genes, Cox proportional hazards models were used to assess the hazard ratios of individual paternal CpGs on gestational age adjusting for confounders. Fourth, to assess the validity of our results, we compared our CpG-gestational age correlations within a Born into Life Study in Sweden (n = 15). Finally, we investigated the correlation between the detected CpGs and differential gene expression in F2 cord blood in the IoWBC.
Analysis of DNAm of fathers collected around their partner's pregnancy identified 216 CpG sites significantly associated with gestational age at birth. Functional enrichment pathways analyses of the annotated genes revealed 2 biological pathways significantly related to cell-cell membrane adhesion molecules. Differential methylation of 9 cell membrane adhesion pathway-related CpGs were significantly associated with gestational age at birth after adjustment for confounders. The replication sample showed correlation coefficients of 2 pathway-related CpGs with gestational age at birth within 95% confidence intervals of correlation coefficients in IoWBC. Finally, CpG sites of protocadherin () gene clusters were associated with gene expression of in F2 cord blood.
Our findings suggest that differential paternal DNAm may affect gestational age at birth through cell-cell membrane adhesion molecules. The results are novel but require future replication in a larger cohort.
DNA的表观遗传修饰如何与出生时的胎龄相关联，目前尚未完全明确。我们通过对胞嘧啶-磷酸-鸟嘌呤（CpG）位点进行全表观基因组搜索，研究了父亲DNA甲基化差异（DNAm）对后代出生时胎龄的潜在影响。
本研究的参与者包括怀特岛出生队列（IoWBC）F1代的男性队列成员或伴侣。使用Illumina 450K芯片分析了在其配偶怀孕期间采集的F1代父亲（n = 92）外周血中的DNAm水平。进行了五步统计分析。首先，采用训练-测试筛选方法选择可能与出生时胎龄相关的CpG位点。其次，运用功能富集分析来确定生物学过程。第三，聚焦于具有生物学信息的基因，使用Cox比例风险模型评估个体父亲CpG对胎龄的风险比，并对混杂因素进行校正。第四，为评估我们结果的有效性，我们在瑞典的“生命诞生研究”（n = 15）中比较了我们的CpG与胎龄的相关性。最后，我们研究了在IoWBC中检测到的CpG与F2代脐带血中基因表达差异之间的相关性。
对在其伴侣怀孕期间采集的父亲的DNAm分析发现，216个CpG位点与出生时的胎龄显著相关。对注释基因的功能富集通路分析揭示了2条与细胞-细胞膜粘附分子显著相关的生物学通路。在对混杂因素进行校正后，9个与细胞膜粘附通路相关的CpG的差异甲基化与出生时的胎龄显著相关。重复样本显示，2个与通路相关的CpG与出生时胎龄的相关系数在IoWBC相关系数的95%置信区间内。最后，原钙黏蛋白（）基因簇的CpG位点与F2代脐带血中的基因表达相关。
我们的研究结果表明，父亲DNAm差异可能通过细胞-细胞膜粘附分子影响出生时的胎龄。这些结果是新颖的，但需要在更大的队列中进行未来的重复验证。
