Evidence for the placenta-brain axis: multi-omic kernel aggregation predicts intellectual and social impairment in children born extremely preterm

Santos, Hudson P.; Bhattacharya, Arjun; Joseph, Robert M.; Smeester, Lisa; Kuban, Karl; Marsit, Carmen J.; Fry, Rebecca C.

doi:10.1186/s13229-020-00402-w

Cited by 31 publications

(29 citation statements)

References 117 publications

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“…Using genotypes from umbilical cord blood 34 and mRNA expression, CpG methylation, and miRNA expression data from fetal-side placenta 15 from the ELGAN Study 21 for 272 infants born pre-term, we built genetic models to predict RNA expression levels for genes in the fetal placenta (demographic summary in Supplemental Table S4 ). Out of a total of 12,020 genes expressed across all samples in ELGAN, we successfully built significant models for 2,994 genes, with positive SNP-based expression heritability (nominal P < 0.05) and five-fold McNemar’s adjusted cross-validation (CV) R 2 ≥ 0.01 ( Figure 3A [Step 1]; Methods ).…”

Section: Resultsmentioning

confidence: 99%

“…Lastly, the ComBat function was used from the sva package to adjust for batch effects from sample plate 98 . In addition, to account for cell-type heterogeneity, 5 surrogate values were estimated and removed from the data to account using the sva package, as previously described 15,90,98 . The data were visualized using density distributions at all processing steps.…”

Section: Methodsmentioning

confidence: 99%

“…We imputed expression into individual-level ELGAN genotypes ( = 729). Controlling for race, sex, gestational duration, inflammation of the chorion, and maternal age, as described in Methods and Materials, we tested for associations for 6 representative traits measured at birth or at 24 months: neonatal chronic lung disease, head circumference Z-score, fetal growth restriction, birth weight Z-score, necrotizing enterocolitis, and Bayley II Mental Development Index (MDI) at 24 months (Santos Jr et al, 2020). Shown in Figure 3B and Supplemental Table S10, at FDR-adjusted < 0.05, we detected negative associations between SEC11A GReX and birthweight Z-score (effect size: -0.248, 95% adjusted CI: [-0.434,-0.063]) and GReX of ATPAF2 and head circumference Z-score (-0.173, [-0.282,-0.064]).…”

Section: Genes With Multiple Gtas Have Phenome-wide Associations In Early-and Later-life Traitsmentioning

confidence: 99%

“…For binary traits, we used a logistic regression with the same predictors and covariates. These covariates have been previously used in placental genomic studies of neonatal traits (Santos et al, 2018(Santos et al, , 2019Santos Jr et al, 2020) because of their strong correlations with the outcomes and with placental transcriptomics and methylomics.…”

Section: Multi-trait Scans In Ukbb and Elganmentioning

confidence: 99%

“…Although combining genetics, transcriptomics, and epigenomics lends insight into the influence of placental genomics on complex traits (Santos Jr et al, 2020), genome-wide screens for GTAs that integrate different molecular profiles and generate functional hypotheses require more sophisticated computational methods.…”

Section: Introductionmentioning

confidence: 99%

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Genetic control of fetal placental genomics contributes to development of health and disease

Bhattacharya

Freedman

Avula

et al. 2021

Preprint

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As the master regulator of the intrauterine environment, the placenta is core to the Developmental Origins of Health and Disease (DOHaD) but is understudied in relation to tissue-specific gene and trait regulation. We performed distal mediator-enriched transcriptome-wide association studies (TWAS) for 40 health traits across 5 physiological categories, using gene expression models trained with multi-omic data from the Extremely Low Gestational Age Newborn Study (N = 272). At P < 2.5 × 10-6, we detected 248 gene-trait associations (GTAs) across 176 genes, mostly for metabolic and neonatal traits and enriched for cell growth and immunological pathways. Of these GTAs, 89 showed significant mediation through genetic variants distal to the gene, identifying potential targets for functional validation. Functional validation of a mediator gene (EPS15) in human placenta-derived JEG-3 trophoblasts resulted in increased expression of its predicted targets, SPATA13 and FAM214A, both associated with the trait of waist-hip ratio in TWAS. These results illustrate the profound health impacts of placental genetic and genomic regulation in developmental programming across the life course.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Genes With Multiple Gtas Have Phenome-wide Associations In Early-and Later-life Traitsmentioning

confidence: 99%

Section: Multi-trait Scans In Ukbb and Elganmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Genetic control of fetal placental genomics contributes to development of health and disease

Bhattacharya

Freedman

Avula

et al. 2021

Preprint

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A multi‐omic approach identifies an autism spectrum disorder (ASD) regulatory complex of functional epimutations in placentas from children born preterm

et al. 2023

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Children born preterm are at heightened risk of neurodevelopmental impairments, including Autism Spectrum Disorder (ASD). The placenta is a key regulator of neurodevelopmental processes, though the precise underlying molecular mechanisms remain unclear. Here, we employed a multi‐omic approach to identify placental transcriptomic and epigenetic modifications related to ASD diagnosis at age 10, among children born preterm. Working with the extremely low gestational age (ELGAN) cohort, we hypothesized that a pro‐inflammatory placental environment would be predictive of ASD diagnosis at age 10. Placental messenger RNA (mRNA) expression, CpG methylation, and microRNA (miRNA) expression were compared among 368 ELGANs (28 children diagnosed with ASD and 340 children without ASD). A total of 111 genes displayed expression levels in the placenta that were associated with ASD. Within these ASD‐associated genes is an ASD regulatory complex comprising key genes that predicted ASD case status. Genes with expression that predicted ASD case status included Ewing Sarcoma Breakpoint Region 1 (EWSR1) (OR: 6.57 (95% CI: 2.34, 23.58)) and Bromodomain Adjacent To Zinc Finger Domain 2A (BAZ2A) (OR: 0.12 (95% CI: 0.03, 0.35)). Moreover, of the 111 ASD‐associated genes, nine (8.1%) displayed associations with CpG methylation levels, while 14 (12.6%) displayed associations with miRNA expression levels. Among these, LRR Binding FLII Interacting Protein 1 (LRRFIP1) was identified as being under the control of both CpG methylation and miRNAs, displaying an OR of 0.42 (95% CI: 0.17, 0.95). This gene, as well as others identified as having functional epimutations, plays a critical role in immune system regulation and inflammatory response. In summary, a multi‐omic approach was used to identify functional epimutations in the placenta that are associated with the development of ASD in children born preterm, highlighting future avenues for intervention.

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Prenatal epigenetic factors are predisposing for neurodevelopmental disorders—Considering placenta as a model

Durbagula

Korlimarla

Ravikumar

et al. 2022

Birth Defects Research

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The heterogeneous characteristics of neurodevelopmental disorders (NDDs) have resulted in varied perspectives on their causation. The biology behind the phenotypic heterogeneity in NDDs is not yet well‐defined, but a strong genetic basis has become well accepted as causal for NDDs. Alongside this, there is growing focus on epigenetic mechanisms. The evidence mounting for in‐utero origins of NDDs has promoted research focused on epigenetic mechanisms that impact genes that program early brain development. Considering that placenta is a vital organ, this review emphasizes the prenatal factors and their effects on epigenetic changes influencing the normal functioning of the placenta, and factors mediating pathology in the developing fetus. Overall, it is an attempt to bring focus on the hypothesis that “Prenatal epigenetic factors in the placenta could be predisposing to NDDs (with special interest on autism spectrum disorders).” This review finds growing evidence for epigenetic modifications in the placenta that affect glucocorticoid, nutrient, and immune signaling pathways, eventually impacting fetal brain development. This evidence largely comes from animal models. Given the multicellular nature of placenta, we conclude that, there is a need for placental research focused on employing single‐cell approaches and genome‐wide methylation profiles to bring insights into specific molecular pathways in the placenta that regulate early brain development.

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Evidence for the placenta-brain axis: multi-omic kernel aggregation predicts intellectual and social impairment in children born extremely preterm

Cited by 31 publications

References 117 publications

Genetic control of fetal placental genomics contributes to development of health and disease

Genetic control of fetal placental genomics contributes to development of health and disease

A multi‐omic approach identifies an autism spectrum disorder (ASD) regulatory complex of functional epimutations in placentas from children born preterm

Prenatal epigenetic factors are predisposing for neurodevelopmental disorders—Considering placenta as a model

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