Abstract

Many epidemiological studies have linked low birthweight to an increased risk of non-communicable diseases (NCDs) in later life, with epigenetic proceseses suggested as an underlying mechanism. Here, we sought to identify neonatal methylation changes associated with birthweight, at both the individual CpG and genomic regional level, and whether the birthweight-associated methylation signatures were associated with specific maternal factors. Using the Illumina Human MethylationEPIC array we assessed DNA methylation in the cord blood of 557 and 483 infants from the UK Pregnancies Better Eating and Activity Trial and Southampton Women’s Survey, respectively. Adjusting for gestational age and other covariates, an epigenome-wide association study identified 2911 (FDR≤0.05) and 236 (Bonferroni corrected p≤6.45x10⁻⁸) differentially methylated CpGs (dmCpGs), and 1230 differentially methylated regions (DMRs) (Stouffer ≤0.05) associated with birthweight. The top birthweight-associated dmCpG was located within the Homeobox Telomere-Binding Protein 1 (HMBOX1) gene with a 195g (95%CI: -241, -149g) decrease in birthweight per 10% increase in methylation, while the top DMR was located within the promoter of corticotropin releasing hormone binding protein (CRHBP).. Furthermore, the birthweight-related dmCpGs were enriched for dmCpGs previously associated with gestational hypertension/pre-eclampsia (14.51%, p=1.37x10⁻²⁵⁵), maternal smoking (7.71%, p=1.50x10⁻⁵⁷) and maternal plasma folate levels during pregnancy (0.33%, p=0.029). The identification of birthweight-associated methylation markers, particularly those connected to specific pregnancy complications and exposures, may provide insights into the developmental pathways that affect birthweight and/or suggest surrogate markers to identify adverse prenatal exposures for stratifying for individuals at risk of later NCDs.

摘要

许多流行病学研究已将低出生体重与晚年非传染性疾病 (NCD) 风险增加联系起来，表观遗传过程被认为是潜在机制。在这里，我们试图在个体 CpG 和基因组区域水平上确定与出生体重相关的新生儿甲基化变化，以及出生体重相关的甲基化特征是否与特定的母体因素相关。使用 Illumina Human MethylationEPIC 阵列，我们分别评估了来自英国妊娠更好饮食和活动试验和南安普敦妇女调查的 557 名和 483 名婴儿的脐带血中的 DNA 甲基化。调整胎龄和其他协变量后，一项表观基因组范围的关联研究确定了 2911（FDR≤0.05）和 236（Bonferroni 校正 p≤6.45x10 ^-8) 差异甲基化 CpGs (dmCpGs)，以及 1230 个与出生体重相关的差异甲基化区域 (DMRs) (Stouffer ≤0.05)。与出生体重相关的最高 dmCpG 位于同源框端粒结合蛋白 1 ( HMBOX1 ) 基因内，甲基化每增加 10%，出生体重下降 195g（95%CI：-241，-149g），而最高 DMR 位于在促肾上腺皮质激素释放激素结合蛋白 ( CRHBP ) 的启动子内。此外，出生体重相关的 dmCpGs 富含先前与妊娠高血压/先兆子痫 (14.51%, p=1.37x10 ^-255 )、母亲吸烟 (7.71) 相关的dmCpGs %, p=1.50x10 ^-57) 和孕期母体血浆叶酸水平 (0.33%, p=0.029)。鉴定与出生体重相关的甲基化标记物，特别是那些与特定妊娠并发症和暴露有关的标记物，可能会深入了解影响出生体重的发育途径和/或建议使用替代标记物来识别不良的产前暴露，以便对有后期非传染性疾病风险的个体进行分层。