Cord blood epigenome-wide meta-analysis in six European-based child cohorts identifies signatures linked to rapid weight growth.
Cord blood epigenome-wide meta-analysis in six European-based child cohorts identifies signatures linked to rapid weight growth.
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DOI：
10.1186/s12916-022-02685-7
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发表时间：
2023-01-11
期刊：
影响因子：
9.3
通讯作者：
Plusquin, Michelle
中科院分区：
文献类型：
--
作者：
Alfano, Rossella;Zugna, Daniela;Barros, Henrique;Bustamante, Mariona;Chatzi, Leda;Ghantous, Akram;Herceg, Zdenko;Keski-Rahkonen, Pekka;de Kok, Theo M.;Nawrot, Tim S.;Relton, Caroline L.;Robinson, Oliver;Roumeliotaki, Theano;Scalbert, Augustin;Vrijheid, Martine;Vineis, Paolo;Richiardi, Lorenzo;Plusquin, Michelle
关键词：
出生后快速生长可能是由于在子宫内或生命早期暴露于不利条件下，并与以后的疾病有关，特别是与儿童肥胖症有关。DNA甲基化，连接早期生活暴露和随后的疾病，是早期生活编程的一种可能机制。在此，在6个基于欧洲的儿童队列（ALSPAC、ENVIRONAGE、Generation XXI、INMA、Piccolipiridine和RHEA，N = 2003）中进行了Illumina HumanMethylation 450 K/EPIC阵列分析，该分析将单个CpG位点和CpG基因组区域的脐带血DNA甲基化与1岁时体重快速增长（参照WHO生长图表定义）相关联。还通过荟萃分析探讨了胎龄加速（使用Bohlin表观遗传时钟计算）与体重快速增长的相关性。对已识别的DNA甲基化信号的后续分析包括预测快速体重增长，介导常规风险因素对快速体重增长的影响，与转录组学和代谢组学的整合，与儿童（4至8岁）超重的相关性，以及与先前发现的比较。47个CpG与体重快速增长相关，提示p值<1 e −05，其中3个CpG（cg 14459032，cg 25953130注释为ARID 5 B，cg 00049440注释为KLF 9）通过了全基因组显著性水平（p值<1.25e−07）。16个差异甲基化区域（DMR）被鉴定为与假发现率（FDR）调整/Siddak p值< 0.01的快速体重增长相关。生育年龄加速与体重快速增长的风险降低相关（p值= 9.75e-04）。除了传统的风险因素外，识别出的DNA甲基化信号略微增加了体重快速增长的预测。在鉴定的信号中，三个CpG部分介导了胎龄对体重快速增长的影响。CpG（N=3）和DMR（N=3）均与转录物（分别为N=10和7）的差异表达相关，包括长非编码RNA。AURKC DMR与儿童超重相关。我们观察到以前报道的与出生体重相关的CpG富集。我们的研究结果提供了脐带血DNA甲基化与体重快速增长之间相关性的证据，并表明与产前暴露的联系以及与儿童肥胖的联系，为早期预防提供了机会。在线版本包含补充材料，可通过10.1186/s12916-022-02685-7获得。
Rapid postnatal growth may result from exposure in utero or early life to adverse conditions and has been associated with diseases later in life and, in particular, with childhood obesity. DNA methylation, interfacing early-life exposures and subsequent diseases, is a possible mechanism underlying early-life programming. Here, a meta-analysis of Illumina HumanMethylation 450K/EPIC-array associations of cord blood DNA methylation at single CpG sites and CpG genomic regions with rapid weight growth at 1 year of age (defined with reference to WHO growth charts) was conducted in six European-based child cohorts (ALSPAC, ENVIRONAGE, Generation XXI, INMA, Piccolipiù, and RHEA, N = 2003). The association of gestational age acceleration (calculated using the Bohlin epigenetic clock) with rapid weight growth was also explored via meta-analysis. Follow-up analyses of identified DNA methylation signals included prediction of rapid weight growth, mediation of the effect of conventional risk factors on rapid weight growth, integration with transcriptomics and metabolomics, association with overweight in childhood (between 4 and 8 years), and comparison with previous findings. Forty-seven CpGs were associated with rapid weight growth at suggestive p-value <1e−05 and, among them, three CpGs (cg14459032, cg25953130 annotated to ARID5B, and cg00049440 annotated to KLF9) passed the genome-wide significance level (p-value <1.25e−07). Sixteen differentially methylated regions (DMRs) were identified as associated with rapid weight growth at false discovery rate (FDR)-adjusted/Siddak p-values < 0.01. Gestational age acceleration was associated with decreasing risk of rapid weight growth (p-value = 9.75e−04). Identified DNA methylation signals slightly increased the prediction of rapid weight growth in addition to conventional risk factors. Among the identified signals, three CpGs partially mediated the effect of gestational age on rapid weight growth. Both CpGs (N=3) and DMRs (N=3) were associated with differential expression of transcripts (N=10 and 7, respectively), including long non-coding RNAs. An AURKC DMR was associated with childhood overweight. We observed enrichment of CpGs previously reported associated with birthweight. Our findings provide evidence of the association between cord blood DNA methylation and rapid weight growth and suggest links with prenatal exposures and association with childhood obesity providing opportunities for early prevention. The online version contains supplementary material available at 10.1186/s12916-022-02685-7.
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