Evolutionary transcriptomics implicates new genes and pathways in human pregnancy and adverse pregnancy outcomes.
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ABSTRACT:
SUBMITTER: Mika K
PROVIDER: S-EPMC8660021 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:To identify pathways between stress indicators and adverse pregnancy outcomes, we applied a nonparametric graph-learning algorithm, PC-KCI, to data from an observational prospective cohort study. The Measurement of Maternal Stress study (MOMS) followed 744 women with a singleton intrauterine pregnancy recruited between June 2013 and May 2015. Infant adverse pregnancy outcomes were prematurity (<37 weeks' gestation), infant days spent in hospital after birth, and being small for gestational age (percentile gestational weight at birth). Maternal adverse pregnancy outcomes were pre-eclampsia, gestational diabetes, and gestational hypertension. PC-KCI replicated well-established pathways, such as the relationship between gestational weeks and preterm premature rupture of membranes. PC-KCI also identified previously unobserved pathways to adverse pregnancy outcomes, including 1) a link between hair cortisol levels (at 12-21 weeks of pregnancy) and pre-eclampsia; 2) two pathways to preterm birth depending on race, with one linking Hispanic race, pre-gestational diabetes and gestational weeks, and a second pathway linking black race, hair cortisol, preeclampsia, and gestational weeks; and 3) a relationship between maternal childhood trauma, perceived social stress in adulthood, and low weight for gestational age. Our approach confirmed previous findings and identified previously unobserved pathways to adverse pregnancy outcomes. It presents a method for a global assessment of a clinical problem for further study of possible causal pathways.
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Project description:Obsessive-compulsive disorder is a severe psychiatric disorder linked to abnormalities in glutamate signaling and the cortico-striatal circuit. We sequenced coding and regulatory elements for 608 genes potentially involved in obsessive-compulsive disorder in human, dog, and mouse. Using a new method that prioritizes likely functional variants, we compared 592 cases to 560 controls and found four strongly associated genes, validated in a larger cohort. NRXN1 and HTR2A are enriched for coding variants altering postsynaptic protein-binding domains. CTTNBP2 (synapse maintenance) and REEP3 (vesicle trafficking) are enriched for regulatory variants, of which at least six (35%) alter transcription factor-DNA binding in neuroblastoma cells. NRXN1 achieves genome-wide significance (p = 6.37 × 10-11) when we include 33,370 population-matched controls. Our findings suggest synaptic adhesion as a key component in compulsive behaviors, and show that targeted sequencing plus functional annotation can identify potentially causative variants, even when genomic data are limited.Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder with symptoms including intrusive thoughts and time-consuming repetitive behaviors. Here Noh and colleagues identify genes enriched for functional variants associated with increased risk of OCD.
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Project description:Research suggests the health consequences of economic hardship can be transmitted across generations. Some of these disparities are thought to be passed to offspring during gestation. But this hypothesis has not been tested in contemporary American samples, and the mechanisms of transmission have not been characterized. Accordingly, this study had two goals: first, to determine if women exposed to economic hardship during childhood showed higher rates of adverse birth outcomes; and second, to evaluate the contribution of inflammation, psychosocial, lifestyle, and obstetric characteristics to this phenomenon. This prospective study enrolled 744 women with singleton pregnancies (59.1% White; 16.3% Black; 18.7% Latina; 5.9% Other). Childhood economic hardship was measured by self-report. Birth outcomes included length of gestation and incidence of preterm birth; birth weight percentile and small for gestational age; length of hospital stay and admission to Special Care Nursery. Analyses revealed that mothers' childhood economic hardship was independently associated with multiple adverse birth outcomes, even following adjustment for demographics, maternal education, and obstetrical confounders. Women raised in economically disadvantaged conditions had shorter gestation length and higher preterm delivery rates. Their babies had lower birth weights, were more likely to be small for gestational age, stayed in the hospital longer, and had more Special Care Nursery admissions. Mediation analyses suggested these associations arose through multiple pathways, and highlighted roles for inflammation, education, adiposity, and obstetric complications. Collectively, these findings suggest that childhood economic hardship predisposes women to adverse birth outcomes, and highlights likely behavioral and biological mechanisms.
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Project description:The olive fly, Bactrocera oleae, is the most devastating pest of cultivated olives. Its control has been traditionally based on insecticides, mainly organophosphates and pyrethroids. In recent years, the naturalyte spinosad is used against the olive fly. As with other insecticides, spinosad is subject to selection pressures that have led to resistance development. Mutations in the ?6 subunit of the nicotinic acetylcholine receptor (nAChR) have been implicated in spinosad resistance in several species (e.g., Drosophila melanogaster) but excluded in others (e.g., Musca domestica). Yet, additional mechanisms involving enhanced metabolism of detoxification enzymes (such as P450 monooxygenases or mixed function oxidases) have also been reported. In order to clarify the spinosad resistance mechanisms in the olive fly, we searched for mutations in the ?6-subunit of the nAChR and for up-regulated genes in the entire transcriptome of spinosad resistant olive flies.The olive fly ?6-subunit of the nAChR was cloned from the laboratory sensitive strain and a spinosad selected resistant line. The differences reflected silent nucleotide substitutions or conserved amino acid changes. Additionally, whole transcriptome analysis was performed in the two strains in order to reveal any underlying resistance mechanisms. Comparison of over 13,000 genes showed that in spinosad resistant flies nine genes were significantly over-expressed, whereas ~40 were under-expressed. Further functional analyses of the nine over-expressed and eleven under-expressed loci were performed. Four of these loci (Yolk protein 2, ATP Synthase FO subunit 6, Low affinity cationic amino acid transporter 2 and Serine protease 6) showed consistently higher expression both in the spinosad resistant strain and in wild flies from a resistant California population. On the other side, two storage protein genes (HexL1 and Lsp1) and two heat-shock protein genes (Hsp70 and Hsp23) were unfailingly under-expressed in resistant flies.The observed nucleotide differences in the nAChR-?6 subunit between the sensitive and spinosad resistant olive fly strains did not advocate for the involvement of receptor mutations in spinosad resistance. Instead, the transcriptome comparison between the two strains indicated that several immune system loci as well as elevated energy requirements of the resistant flies might be necessary to lever the detoxification process.
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Project description:The developmental origins and evolutionary histories of cell types, tissues, and organs contribute to the ways in which their dysfunction produces disease. In mammals, the nature, development and evolution of maternal-fetal interactions likely influence diseases of pregnancy. Here we show genes that evolved expression at the maternal-fetal interface in Eutherian mammals play essential roles in the evolution of pregnancy and are associated with immunological disorders and preterm birth. Among these genes is HAND2, a transcription factor that suppresses estrogen signaling, a Eutherian innovation allowing blastocyst implantation. We found dynamic HAND2 expression in the decidua throughout the menstrual cycle and pregnancy, gradually decreasing to a low at term. HAND2 regulates a distinct set of genes in endometrial stromal fibroblasts including IL15, a cytokine also exhibiting dynamic expression throughout the menstrual cycle and gestation, promoting migration of natural killer cells and extravillous cytotrophoblasts. We demonstrate that HAND2 promoter loops to an enhancer containing SNPs implicated in birth weight and gestation length regulation. Collectively, these data connect HAND2 expression at the maternal-fetal interface with evolution of implantation and gestational regulation, and preterm birth.
| S-EPMC7943190 | biostudies-literature
Project description:Interindividual variation in DNA-methylation level is widespread in the human genome, despite its critical role in regulating gene expression. The nature of this variation, including its tissue-specific nature, and the role it may play in human phenotypic variation and disease is still poorly characterized. The placenta plays a critical role in regulating fetal growth and development in ways that have lifelong effects on health. To identify genes with a high degree of interindividual DNA methylation variation in the human placenta, we surveyed the human genome using the Illumina GoldenGate Methylation Cancer panel targeting 1505 CpG sites of 807 genes. While many sites show a continuous pattern of methylation levels, WNT2, TUSC3 and EPHB4 were identified to have a polymorphic "on-or-off" pattern of DNA methylation variation at their promoter region which was confirmed by pyrosequencing. Methylation of these genes can be found in 7%-25% of over 100 placentas tested. The methylation state at the promoter of these genes is concordant with mRNA allelic expression. In three informative cases TUSC3 was observed to be methylated on the maternal allele, and it is thus possible this represents a polymorphically imprinted gene. Furthermore, TUSC3 promoter methylation showed evidence for association with preeclampsia. A biological significance of these methylation allelic polymorphisms (MAPs) to human placental diversity is further implied by their placental specificity and absence in mouse. An extended study of blood suggests that MAPs may also be found in other tissues, implicating their utility for tissue-specific association with complex disorders. The identification of such "epipolymorphism" in other tissues and their use in association studies, should improve our understanding of interindividual phenotypic variability and complex disease susceptibility.
| S-EPMC2760756 | biostudies-literature
Project description:BackgroundRenal insufficiency is associated with pregnancy complications including fetal growth restriction, preterm birth (PTB), and pre-eclampsia.ObjectiveTo determine the effect of preconception kidney function within the normal range on pregnancy outcome.Method1043 (50% black, 50% white) women who participated in the CARDIA study who had kidney function and biochemical analyses measured before at least one pregnancy delivered during the 20 years post-baseline period were included in analysis. Kidney function estimated as glomerular filtration rate (eGFR) via modified CKD-EPI equations, serum creatinine, and urinary albumin/creatinine ratio were evaluated as predictors of infant birthweight, gestational age, birthweight-for-gestational-age, and hypertensive disorders of pregnancy via self-report, using multiple regression with adjustment for confounders (age, race, smoking, BMI, center, parity, systolic blood pressure at baseline). Serum uric acid was also examined at both baseline and year 10.ResultsUnadjusted pre-pregnancy eGFR (baseline) was associated with lower average birthweight-for-gestational-age, but this disappeared after adjustment for confounders. A decline in GFR from baseline to year 10 was associated with lower birthweight (adjusted estimate -195 g, p = 0.03 overall), especially among whites. After adjustment for confounders, no association was found with gestational age or hypertensive disorders.ConclusionsNo strong evidence for an association between preconception kidney function in the normal range and birthweight or gestational age was found. Possible racial differences in these relationships warrant further examination.
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Project description:ObjectiveAutoimmune conditions are associated with an increased risk of adverse pregnancy complications and outcomes, suggesting that pregnancy complications may mediate the excess risk. We performed a causal mediation analysis to quantify the mediated effects of autoimmune conditions on adverse pregnancy outcomes.MethodsWe queried a California birth cohort created from linked birth certificates and hospital discharge summaries. From 2,963,888 births, we identified women with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriasis, and inflammatory bowel disease (IBD). Pregnancy complications included preeclampsia/hypertension, gestational diabetes mellitus, and infection in pregnancy. Adverse pregnancy outcomes were preterm birth, cesarean delivery, and small for gestational age. We performed a mediation analysis to estimate the total effects of each autoimmune condition and adverse pregnancy outcome and the indirect effects through pregnancy complications.ResultsAll 4 autoimmune conditions were associated with preterm birth and cesarean delivery, and RA, SLE, and IBD were associated with offspring that were small for gestational age. The strongest mediator of RA, SLE, and psoriasis was preeclampsia/hypertension, accounting for 20-33% of the excess risk of preterm births and 10-19% of excess cesarean deliveries. Gestational diabetes mellitus and infections generally mediated <10% of excess adverse pregnancy outcomes. Of the 4 autoimmune conditions, selected pregnancy complications mediated the least number of adverse pregnancy outcomes among women with IBD.ConclusionWe found evidence that some excess risk of adverse pregnancy outcomes is mediated through pregnancy complications, particularly preeclampsia/hypertension. Quantifying excess risk and associated pathways provides insight into the underlying etiologies of adverse pregnancy outcomes and can inform intervention strategies.
| S-EPMC7351244 | biostudies-literature
Project description:The Autism Spectrum Disorders (ASD) represent a clinically heterogeneous set of conditions with strong hereditary components. Despite substantial efforts to uncover the genetic basis of ASD, the genomic etiology appears complex and a clear understanding of the molecular mechanisms underlying Autism remains elusive. We hypothesized that focusing gene interaction networks on ASD-implicated genes that are highly expressed in the developing brain may reveal core mechanisms that are otherwise obscured by the genomic heterogeneity of the disorder. Here we report an in silico study of the gene expression profile from ASD-implicated genes in the unaffected developing human brain. By implementing a biologically relevant approach, we identified a subset of highly expressed ASD-candidate genes from which interactome networks were derived. Strikingly, immune signaling through NFκB, Tnf, and Jnk was central to ASD networks at multiple levels of our analysis, and cell-type specific expression suggested glia--in addition to neurons--deserve consideration. This work provides integrated genomic evidence that ASD-implicated genes may converge on central cytokine signaling pathways.
| S-EPMC3174192 | biostudies-literature
Project description:BackgroundMotor vehicle crashes are a leading cause of serious trauma during pregnancy, but little is known about their relationships with pregnancy outcomes.PurposeTo estimate the association between motor vehicle crashes and adverse pregnancy outcomes.MethodsA retrospective cohort study of 878,546 pregnant women, aged 16-46 years, who delivered a singleton infant in North Carolina from 2001 to 2008. Pregnant drivers in crashes were identified by probabilistic linkage of vital records and crash reports. Poisson regression modeled the association among crashes, vehicle safety features, and adverse pregnancy outcomes. Analyses were conducted in 2012.ResultsIn 2001-2008, 2.9% of pregnant North Carolina women were drivers in one or more crashes. After a single crash, compared to not being in a crash, pregnant drivers had slightly elevated rates of preterm birth (adjusted rate ratio [aRR]=1.23, 95% CI=1.19, 1.28); placental abruption (aRR=1.34, 95% CI=1.15, 1.56); and premature rupture of the membranes (PROM; aRR=1.32, 95% CI=1.21, 1.43). Following a second or subsequent crash, pregnant drivers had more highly elevated rates of preterm birth (aRR=1.54, 95% CI=1.24, 1.90); stillbirth (aRR=4.82, 95% CI=2.85, 8.14); placental abruption (aRR=2.97, 95% CI=1.60, 5.53); and PROM (aRR=1.95, 95% CI=1.27, 2.99). Stillbirth rates were elevated following crashes involving unbelted pregnant drivers (aRR=2.77, 95% CI=1.22, 6.28) compared to belted pregnant drivers.ConclusionsCrashes while driving during pregnancy were associated with elevated rates of adverse pregnancy outcomes, and multiple crashes were associated with even higher rates of adverse pregnancy outcomes. Crashes were especially harmful if drivers were unbelted.
| S-EPMC3859429 | biostudies-literature