Pre-pregnancy BMI-associated miRNA and mRNA expression signatures in the placenta highlight a sexually-dimorphic response to maternal underweight status
Jeliyah Clark, Lauren A Eaves, Adriana R Gaona, Hudson P Santos Jr, Lisa Smeester, Jacqueline T Bangma, Julia E Rager, T Michael O'Shea, Rebecca C Fry
Sci Rep. 2021 Aug 3;11(1):15743. doi: 10.1038/s41598-021-95051-1. PMID: 34344912; PMCID: PMC8333418.
Genome-wide mRNA and miRNA expression levels were assessed in the placentas of infants born extremely preterm. Differences in expression were evaluated according to pre-pregnancy BMI status (1) overall and (2) in male and female placentas separately. Overall, 719 mRNAs were differentially expressed in relation to underweight status. Unexpectedly, no genes were differentially expressed in relation to overweight or obese status. In male placentas, 572 mRNAs were associated with underweight status, with 503 (70%) overlapping genes identified overall. Notably, 43/572 (8%) of the mRNAs associated with underweight status in male placentas were also gene targets of two miRNAs (miR-4057 and miR-128-1-5p) associated with underweight status in male placentas. Pathways regulating placental nutrient metabolism and angiogenesis were among those enriched in mRNAs associated with underweight status in males.
Development of the genomic inflammatory index (GII) to assess key maternal antecedents associated with placental inflammation.
Kirsi S Oldenburg, Lauren A Eaves, Lisa Smeester, Hudson P Santos, T Michael O'Shea, Rebecca C Fry
Placenta. 2021 Aug;111:82-90. doi: 10.1016/j.placenta.2021.06.010. Epub 2021 Jun 18. PMID: 34182215.
The Genomic Inflammatory Index demonstrated a nine-fold difference across subjects and displayed positive trends with other indicators of placental inflammation. Significant differences in the GII were observed for race where women who self-identified as Black displayed higher levels of placental inflammation than those who self-identified as White women (p < 0.001). Additionally, married Black women showed reduced placental inflammation compared to those who were unmarried (beta value: 0.828, p-value: 0.032). Placentas from women who were treated with steroids during the delivery of the infant displayed higher GII levels than those who were not (p = 0.023). Overall, the GII demonstrated an association between various perinatal factors and placental inflammation. It is anticipated that the GII will provide a novel genomics tool for quantifying placental inflammation, allowing for further investigation of causes, and ultimately the prevention, of inflammation in the placenta.
Changes in Neurodevelopmental Outcomes From Age 2 to 10 Years for Children Born Extremely Preterm
Genevieve L Taylor, Robert M Joseph, Karl C K Kuban, Laurie M Douglass, Jeff Laux, Bree Andrews, Rebecca C Fry, Wayne A Price, Thomas M O'Shea
Pediatrics. 2021 May;147(5):e2020001040. doi: 10.1542/peds.2020-001040. Epub 2021 Apr 6. PMID: 33824183; PMCID: PMC8086004.
Among children classified as having moderate to severe neurodevelopmental impairment (NDI) at 2 years, 63% had none to mild NDI at 10 years; among children classified as having profound NDI at 2 years, 36% had none to mild NDI at 10 years. We fond minimal to fair agreement between NDI at 2 and 10 years. NDI in infancy, as defined in this study, only weakly predicts NDI in middle childhood. For the parents at risk for delivery of an extremely preterm infant, a hopeful message can be taken from our findings that one-third of surviving children classified as having profound NDI and nearly two-thirds of those classified as having moderate to severe NDI at 2 years had none to mild NDI at 10 years.
Anxiety and Depression Correlates at Age 10 in Children Born Extremely Preterm
Phoebe S Moore, Irina Mokrova, Jean A Frazier, Robert M Joseph, Hudson P Santos, Yael Dvir, Stephen R Hooper, T Michael O'Shea, Laurie M Douglass, Karl C K Kuban
J Pediatr Psychol. 2021 Jan 4; jsaa118.
Anxiety and depression rates are elevated in prematurely-born children and adolescents. This prospective study examines demographic, academic, and physical health correlates of anxiety and depression symptoms in a sample of 10-y-o children born EP. Participants were 889 (51.2% male; 62.3% White). Level of prematurity was significantly related to both parent and teacher reports of anxiety. Public health insurance and IEP were associated with both parent and teacher reports of depression. Hispanic ethnicity, public insurance, IEP status, and asthma were significantly associated with both parent-reported anxiety and depression. Gross motor impairment was associated with parent-reported anxiety and teacher-reported depression. Child obesity was associated with teacher reports of anxiety, while male sex was significantly related to teacher reports of depression.
Evidence for the placenta-brain axis: multi-omic kernel aggregation predicts intellectual and social impairment in children born extremely preterm
Hudson P Santos Jr, Arjun Bhattacharya, Robert M Joseph, Lisa Smeester, Karl C K Kuban, Carmen J Marsit, T Michael O'Shea, Rebecca C Fry
Mol Autism. 2020 Dec 11;11(1):97.
We examined associations between placental transcriptomic & epigenomic profiles and assessed their ability to predict intellectual and social impairment at age 10 years in 379 children from the ELGAN cohort. Genes with important roles in neuro-development and placental tissue organization were associated with intellectual and social impairment. Kernel aggregations of placental multi-omics strongly predicted IQ and social function, explaining ~ 8% and 12% of variance in SRS and IQ scores via cross-validation, respectively. Predicted in-sample SRS and IQ showed sign positive and negative associations with ASD case-control status. Aggregating information from biomarkers within and among molecular data types improves prediction of complex traits like social and intellectual ability in children born EP, suggesting that traits within the placenta-brain axis may be omnigenic.
Placental programming, perinatal inflammation, and neurodevelopment impairment among those born extremely preterm
Jacqueline T. Bangma, Hadley Hartwell, Hudson P. Santos Jr., T. Michael O’Shea & Rebecca C. Fry
Pediatr Res. 2020 Nov 12;1-10.
Individuals born EP are at significant risk for impaired neurodevelopment. After discharge from the NICU, associations between child’s well-being and factors in the home and social environment become increasingly apparent. We review early life predictors of inter-individual differences in later life neurodevelopment among those born EP. Among biological mechanisms that mediate relationships between early life predictors and later neurodevelopmental outcomes, we highlight evidence for disrupted placental processes, regulated at least in part via epigenetic mechanisms, as well as perinatal inflammation. In relation to these mechanisms, we focus on four prenatal antecedents of impaired neurodevelopment, namely, (1) fetal growth restriction, (2) maternal obesity, (3) placental microorganisms, and (4) socioeconomic adversity. The findings highlighted here may inform efforts to detect and prevent adverse outcomes in infants born extremely preterm.
Histologic chorioamnionitis and risk of neurodevelopmental impairment at age 10 years among extremely preterm infants born before 28 weeks of gestation
Kartik K Venkatesh, Alan Leviton, Jonathan L Hecht, Robert M Joseph, Laurie M Douglass, Jean A Frazier, Julie L Daniels, Rebecca C Fry, T Michael O'Shea, Karl C K Kuban
Am J Obstet Gynecol. 2020 Nov;223(5):745.e1-745.e10.
We investigated ass’n between histo chorioamnionitis (CA) & neurodevelopmental (ND) impairment at 10 yrs among children born EP. CA defined by histo stage (early, mod, advanced) and grade (mild/mod, severe) of chorionic plate & umbilical cord inflammation. Children examined for CP, ASD, Cog I, & epilepsy at 10 yrs. Among 805 placentas, 43% (347/805) had histo CA by mod or adv mat stage, 36% (286/805) by severe mat grade, 18% (132/737) by mod or adv fetal stage, and 1% (10/737) by severe fetal grade. Impairment frequencies were 11% (88/767) for CP, 7% (56/773) for ASD, 15% (120/788) for CogI, and 7% (52/763) for epilepsy. Adj OR for association between histo CA & CP was increased with advanced mat stage (adj OR, 2.5; 95% CI, 1.6-3.9), severe mat grade (adj OR, 2.0; 95% CI, 1.2-3.4), mod fetal stage (adj OR, 2.20; 95% CI, 2.1-2.2), and mild or mod fetal grade (adj OR, 1.5; 95% CI, 1.0-2.2). Similarly, adj OR for association between histo CA and epilepsy was increased with advanced mat stage (adj OR, 1.5; 95% CI, 1.3-1.6) and severe fetal grade (adj OR, 5.9; 95% CI, 1.9-17.8). Adj OR for association between histo CA and ASD was increased with mild or mod fetal grade (adj OR, 1.7; 95% CI, 1.0-2.9). Histo CA not associated with CogI. Findings held after adj for delivery GA. In contrast to histo CA, a clinical dx of CA is not associated with ND impairment.
CUE: CpG impUtation ensemble for DNA methylation levels across the human methylation450 (HM450) and EPIC (HM850) BeadChip platforms
Gang Li, Laura Raffield, Mark Logue, Mark W Miller, Hudson P Santos Jr, T Michael O'Shea, Rebecca C Fry, Yun Li
Epigenetics. 2020 Oct 4;1-11.
Here, we present CpG impUtation Ensemble (CUE), which leverages multiple statistical and modern machine learning methods, to impute from Illumina Human-Methylation450 (HM450) BeadChip to the Illumina Human-Methylation-EPIC (HM850) BeadChip. Data were analyzed from 2 cohorts with methylation measured both by HM450 and HM850: the ELGAN study (n = 127, placenta) and the VA Boston PTSD genetics repository (n = 144, whole blood). Cross-validation results show CUE achieves lowest predicted root-mean-square error (RMSE) (0.026 in PTSD) and highest accuracy (99.97% in PTSD) compared with five methods tested, including k-nearest-neighbors, logistic regression, penalized functional regression, random forest, and XGBoost. Finally, among all 339,033 HM850-only CpG sites shared between ELGAN and PTSD, CUE successfully (RMSE < 0.05 and accuracy >95%in PTSD) imputed 289,604 (85.4%) sites. In summary, CUE is a valuable tool for imputing CpG methylation from the HM450 to HM850 platform.
A role for microRNAs in the epigenetic control of sexually dimorphic gene expression in the human placenta
Lauren Eaves, Preeyaphan Phookphan, Julia Rager, Jacqueline Bangma, Hudson P Santos Jr, Lisa Smeester, Thomas Michael O'Shea, Rebecca Fry
Epigenomics. 2020 Sep;12(17):1543-1558.
Aim: The contribution of miRNAs as epigenetic regulators of sexually dimorphic gene expression in the placenta is unknown. Materials & methods: 382 placentas from the extremely low gestational age newborns (ELGAN) cohort were evaluated for expression levels of 37,268 mRNAs and 2,102 miRNAs using genome-wide RNA-sequencing. Results: Sexually dimorphic expression was observed for 128 mRNAs and 59 miRNAs. A set of 25 miRNA master regulators was identified that likely contribute to sexual dimorphic mRNA expression. Conclusion: These data highlight sex-dependent miRNA and mRNA patterning in the placenta and provide insight into a potential mechanism for observed sex differences in outcomes.
Placental genomic and epigenomic signatures associated with infant birth weight highlight mechanisms involved in collagen and growth factor signaling
Alexis Payton, Jeliyah Clark, Lauren Eaves, Hudson P Santos Jr, Lisa Smeester, Jacqueline T Bangma, T Michael O'Shea, Rebecca C Fry, Julia E Rager
Reprod Toxicol. 2020 Jul 25;96:221-230.
Birth weight (BW) can be influenced by endogenous and exogenous factors and is known to be heavily impacted in utero by the health and function of the placenta. We set out to test hypothesis that genes involved in critical placental cell signaling are associated with infant BW, and are likely regulated, in part, through epigenetic mechanisms based on microRNA (miRNA) mediation. This study leveraged a robust dataset based on 390 infants born at low gestational age (ranged 23-27 weeks) to evaluate genome-wide expression profiles of both mRNAs and miRNAs in placenta tissues and relate these to infant BW. A total of 254 mRNAs and 268 miRNAs were identified as associated with BW, the majority of which showed consistent associations across placentas derived from both males and females. BW-associated mRNAs were found to be enriched for important biological pathways, including glycoprotein VI (the major receptor for collagen), human growth, and hepatocyte growth factor signaling, a portion of which were predicted to be regulated by BW-associated miRNAs. These miRNA-regulated pathways highlight key mechanisms potentially linking endogenous/exogenous factors to changes in birth outcomes that may be deleterious to infant and later-in-life health.