Marin Jacobwitz, Michael Xie, Jamie Catalano, Ingo Helbig, J William Gaynor, Nancy Burnham, Rebecca L Linn, Juliana Gebb, Mark W Russell, Hakon Hakonarson, Barbara H Chaiyachati, Ana G Cristancho
{"title":"DNA甲基化差异通过标准化胎儿/胎盘重量比分层提示先天性心脏病新生儿神经发育缺陷。","authors":"Marin Jacobwitz, Michael Xie, Jamie Catalano, Ingo Helbig, J William Gaynor, Nancy Burnham, Rebecca L Linn, Juliana Gebb, Mark W Russell, Hakon Hakonarson, Barbara H Chaiyachati, Ana G Cristancho","doi":"10.1371/journal.pone.0317944","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>We lack early biomarkers for predicting neurodevelopment (ND) outcomes in children with congenital heart disease (CHD). Placentas of fetuses with CHD have abnormalities, including unbalanced fetal/placental weight ratios (F/P). Although DNA methylation profiles have revealed insights into the maternal-fetal environment (MFE), it is unknown if DNA methylation correlates to normalized F/P weight ratio groups and how these differences relate to ND outcomes.</p><p><strong>Methods: </strong>We prospectively recruited a cohort of pregnant women carrying a fetus with CHD. A subset of the cohort had DNA methylation performed on either umbilical cord blood or postnatal blood (45 full-term neonates). We calculated normalized F/P weight ratios, focusing on three normalized F/P ratio groups for analysis. We calculated differential methylation signals in eight ND disabilities-associated gene sets. Normalized F/P ratios were compared to 18-month Bayley Scales of Infant Development-III scores (BSID-III).</p><p><strong>Results: </strong>Unbiased gene ontology enrichment analysis of differentially methylated regions revealed enrichment for brain development-related pathways. Although there were no significant differences between normalized F/P weight ratio groups and BSID-III, disease-associated gene set pathway analysis revealed significant methylation differences between the most severely unbalanced F/P weight ratio and normal F/P weight ratio groups.</p><p><strong>Conclusion: </strong>Gene ontology enrichment analysis of differential methylation regions revealed significant differences between normalized F/P weight ratio groups in neurogenesis genes. Furthermore, our data identified methylation differences between unbalanced and balanced normalized F/P weight ratio groups in gene pathways associated with ND dysfunction common in the aging CHD population suggesting converging pathways for ND disorders that should be investigated further.</p>","PeriodicalId":20189,"journal":{"name":"PLoS ONE","volume":"20 8","pages":"e0317944"},"PeriodicalIF":2.6000,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12327636/pdf/","citationCount":"0","resultStr":"{\"title\":\"DNA methylation differences stratified by normalized fetal/placental weight ratios suggest neurodevelopmental deficits in neonates with congenital heart disease.\",\"authors\":\"Marin Jacobwitz, Michael Xie, Jamie Catalano, Ingo Helbig, J William Gaynor, Nancy Burnham, Rebecca L Linn, Juliana Gebb, Mark W Russell, Hakon Hakonarson, Barbara H Chaiyachati, Ana G Cristancho\",\"doi\":\"10.1371/journal.pone.0317944\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>We lack early biomarkers for predicting neurodevelopment (ND) outcomes in children with congenital heart disease (CHD). Placentas of fetuses with CHD have abnormalities, including unbalanced fetal/placental weight ratios (F/P). Although DNA methylation profiles have revealed insights into the maternal-fetal environment (MFE), it is unknown if DNA methylation correlates to normalized F/P weight ratio groups and how these differences relate to ND outcomes.</p><p><strong>Methods: </strong>We prospectively recruited a cohort of pregnant women carrying a fetus with CHD. A subset of the cohort had DNA methylation performed on either umbilical cord blood or postnatal blood (45 full-term neonates). We calculated normalized F/P weight ratios, focusing on three normalized F/P ratio groups for analysis. We calculated differential methylation signals in eight ND disabilities-associated gene sets. Normalized F/P ratios were compared to 18-month Bayley Scales of Infant Development-III scores (BSID-III).</p><p><strong>Results: </strong>Unbiased gene ontology enrichment analysis of differentially methylated regions revealed enrichment for brain development-related pathways. Although there were no significant differences between normalized F/P weight ratio groups and BSID-III, disease-associated gene set pathway analysis revealed significant methylation differences between the most severely unbalanced F/P weight ratio and normal F/P weight ratio groups.</p><p><strong>Conclusion: </strong>Gene ontology enrichment analysis of differential methylation regions revealed significant differences between normalized F/P weight ratio groups in neurogenesis genes. Furthermore, our data identified methylation differences between unbalanced and balanced normalized F/P weight ratio groups in gene pathways associated with ND dysfunction common in the aging CHD population suggesting converging pathways for ND disorders that should be investigated further.</p>\",\"PeriodicalId\":20189,\"journal\":{\"name\":\"PLoS ONE\",\"volume\":\"20 8\",\"pages\":\"e0317944\"},\"PeriodicalIF\":2.6000,\"publicationDate\":\"2025-08-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12327636/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"PLoS ONE\",\"FirstCategoryId\":\"103\",\"ListUrlMain\":\"https://doi.org/10.1371/journal.pone.0317944\",\"RegionNum\":3,\"RegionCategory\":\"综合性期刊\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"MULTIDISCIPLINARY SCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"PLoS ONE","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1371/journal.pone.0317944","RegionNum":3,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
DNA methylation differences stratified by normalized fetal/placental weight ratios suggest neurodevelopmental deficits in neonates with congenital heart disease.
Background: We lack early biomarkers for predicting neurodevelopment (ND) outcomes in children with congenital heart disease (CHD). Placentas of fetuses with CHD have abnormalities, including unbalanced fetal/placental weight ratios (F/P). Although DNA methylation profiles have revealed insights into the maternal-fetal environment (MFE), it is unknown if DNA methylation correlates to normalized F/P weight ratio groups and how these differences relate to ND outcomes.
Methods: We prospectively recruited a cohort of pregnant women carrying a fetus with CHD. A subset of the cohort had DNA methylation performed on either umbilical cord blood or postnatal blood (45 full-term neonates). We calculated normalized F/P weight ratios, focusing on three normalized F/P ratio groups for analysis. We calculated differential methylation signals in eight ND disabilities-associated gene sets. Normalized F/P ratios were compared to 18-month Bayley Scales of Infant Development-III scores (BSID-III).
Results: Unbiased gene ontology enrichment analysis of differentially methylated regions revealed enrichment for brain development-related pathways. Although there were no significant differences between normalized F/P weight ratio groups and BSID-III, disease-associated gene set pathway analysis revealed significant methylation differences between the most severely unbalanced F/P weight ratio and normal F/P weight ratio groups.
Conclusion: Gene ontology enrichment analysis of differential methylation regions revealed significant differences between normalized F/P weight ratio groups in neurogenesis genes. Furthermore, our data identified methylation differences between unbalanced and balanced normalized F/P weight ratio groups in gene pathways associated with ND dysfunction common in the aging CHD population suggesting converging pathways for ND disorders that should be investigated further.
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