scholarly journals Cortical morphology at birth reflects spatiotemporal patterns of gene expression in the fetal human brain

PLoS Biology ◽  
2020 ◽  
Vol 18 (11) ◽  
pp. e3000976
Author(s):  
Gareth Ball ◽  
Jakob Seidlitz ◽  
Jonathan O’Muircheartaigh ◽  
Ralica Dimitrova ◽  
Daphna Fenchel ◽  
...  
Keyword(s):  
Gene Expression ◽  
Preterm Birth ◽  
Cortical Development ◽  
Stem Cell Differentiation ◽  
Cell Populations ◽  
Regional Patterns ◽  
Cortical Structure ◽  
Increased Risk ◽  
Cortical Morphology ◽  
Age At Birth

Interruption to gestation through preterm birth can significantly impact cortical development and have long-lasting adverse effects on neurodevelopmental outcome. We compared cortical morphology captured by high-resolution, multimodal magnetic resonance imaging (MRI) in n = 292 healthy newborn infants (mean age at birth = 39.9 weeks) with regional patterns of gene expression in the fetal cortex across gestation (n = 156 samples from 16 brains, aged 12 to 37 postconceptional weeks [pcw]). We tested the hypothesis that noninvasive measures of cortical structure at birth mirror areal differences in cortical gene expression across gestation, and in a cohort of n = 64 preterm infants (mean age at birth = 32.0 weeks), we tested whether cortical alterations observed after preterm birth were associated with altered gene expression in specific developmental cell populations. Neonatal cortical structure was aligned to differential patterns of cell-specific gene expression in the fetal cortex. Principal component analysis (PCA) of 6 measures of cortical morphology and microstructure showed that cortical regions were ordered along a principal axis, with primary cortex clearly separated from heteromodal cortex. This axis was correlated with estimated tissue maturity, indexed by differential expression of genes expressed by progenitor cells and neurons, and engaged in stem cell differentiation, neuron migration, and forebrain development. Preterm birth was associated with altered regional MRI metrics and patterns of differential gene expression in glial cell populations. The spatial patterning of gene expression in the developing cortex was thus mirrored by regional variation in cortical morphology and microstructure at term, and this was disrupted by preterm birth. This work provides a framework to link molecular mechanisms to noninvasive measures of cortical development in early life and highlights novel pathways to injury in neonatal populations at increased risk of neurodevelopmental disorder.

scholarly journals Cortical morphology at birth reflects spatio-temporal patterns of gene expression in the fetal human brain

2020 ◽  
Author(s):  
G. Ball ◽  
J. Seidlitz ◽  
J. O’Muircheartaigh ◽  
R. Dimitrova ◽  
D. Fenchel ◽  
...  
Keyword(s):  
Gene Expression ◽  
Preterm Birth ◽  
Cortical Development ◽  
Stem Cell Differentiation ◽  
Cell Populations ◽  
Regional Patterns ◽  
Cortical Structure ◽  
Increased Risk ◽  
Cortical Morphology ◽  
Age At Birth

AbstractInterruption to gestation through preterm birth can significantly impact cortical development and have long-lasting adverse effects on neurodevelopmental outcome. We compared cortical morphology captured by high-resolution, multimodal MRI in n=292 healthy newborn infants (mean age at birth=39.9 weeks) with regional patterns of gene expression in the fetal cortex across gestation (n=156 samples from 16 brains, aged 12 to 37 post-conceptional weeks). We tested the hypothesis that noninvasive measures of cortical structure at birth mirror areal differences in cortical gene expression across gestation, and in a cohort of n=64 preterm infants (mean age at birth = 32.0 weeks), we tested whether cortical alterations observed after preterm birth were associated with altered gene expression in specific developmental cell populations.Neonatal cortical structure was aligned to differential patterns of cell-specific gene expression in the fetal cortex. Principal component analysis of six measures of cortical morphology and microstructure showed that cortical regions were ordered along a principal axis, with primary cortex clearly separated from heteromodal cortex. This axis was correlated to estimated tissue maturity, indexed by differential expression of genes expressed by progenitor cells and neurons; and engaged in stem cell differentiation, neuron migration and forebrain development. Preterm birth was associated with altered regional MRI metrics and patterns of differential gene expression in glial cell populations.The spatial patterning of gene expression in the developing cortex was thus mirrored by regional variation in cortical morphology and microstructure at term, and this was disrupted by preterm birth. This work provides a framework to link molecular mechanisms to noninvasive measures of cortical development in early life and highlights novel pathways to injury in neonatal populations at increased risk of neurodevelopmental disorder.

scholarly journals Risk of hypertension into adulthood in persons born prematurely: a national cohort study

2019 ◽  
Vol 41 (16) ◽  
pp. 1542-1550 ◽  
Author(s):  
Casey Crump ◽  
Jan Sundquist ◽  
Kristina Sundquist
Keyword(s):  
Cohort Study ◽  
Preterm Birth ◽  
Environmental Factors ◽  
Gestational Age ◽  
Large Population ◽  
Increased Risk ◽  
Extremely Preterm ◽  
National Cohort ◽  
Gestational Age At Birth ◽  
Age At Birth

Abstract Aims Preterm birth has been associated with elevated blood pressure early in life; however, hypertension risks from childhood into adulthood remain unclear. We conducted a large population-based study to examine gestational age at birth in relation to hypertension risks from childhood into adulthood. Methods and results A national cohort study was conducted of all 4 193 069 singleton live births in Sweden during 1973–2014, who were followed up for hypertension identified from nationwide inpatient and outpatient (specialty and primary care) diagnoses from any health care encounters through 2015 (maximum age 43 years; median 22.5). Cox regression was used to examine gestational age at birth in relation to hypertension risk while adjusting for other perinatal and maternal factors, and co-sibling analyses assessed the potential influence of unmeasured shared familial (genetic and/or environmental) factors. In 86.8 million person-years of follow-up, 62 424 (1.5%) persons were identified with hypertension (median age 29.8 years at diagnosis). Adjusted hazard ratios for new-onset hypertension at ages 18–29 years associated with preterm (<37 weeks) and extremely preterm (22–27 weeks) birth were 1.28 [95% confidence interval (CI), 1.21–1.36] and 2.45 (1.82–3.31), respectively, and at ages 30–43 years were 1.25 (1.18–1.31) and 1.68 (1.12–2.53), respectively, compared with full-term birth (39–41 weeks). These associations affected males and females similarly and appeared substantially related to shared genetic or environmental factors in families. Conclusions In this large national cohort, preterm birth was associated with increased risk of hypertension into early adulthood. Persons born prematurely may need early preventive evaluation and long-term monitoring for the development of hypertension.

scholarly journals Effect of aspirin response signature gene expression on preterm birth and preeclampsia among women with lupus: a pilot study

Lupus ◽  
2019 ◽  
Vol 28 (14) ◽  
pp. 1640-1647
Author(s):  
A M Eudy ◽  
D Voora ◽  
R A Myers ◽  
M E B Clowse
Keyword(s):  
Gene Expression ◽  
Preterm Birth ◽  
Pilot Study ◽  
Pregnancy Outcome ◽  
Quantitative Polymerase Chain Reaction ◽  
Linear Regression Models ◽  
Global Test ◽  
Increased Risk ◽  
Poor Pregnancy Outcome

Background Women with lupus have an increased risk of preeclampsia and preterm birth, and aspirin 81 mg/day is recommended as a preventative measure for preeclampsia. This pilot study quantified the association between a 60-gene aspirin response signature (ARS) gene expression with preterm birth and preeclampsia risk among women with lupus taking aspirin. Methods The analysis included 48 RNA samples from 23 pregnancies in the Duke Autoimmunity Pregnancy Registry. RNA was isolated from peripheral blood, and quantitative polymerase chain reaction was performed for ARS genes. The primary outcome was poor pregnancy outcome (preeclampsia or preterm birth). Gene expression was modeled as a response to presence or absence of a poor pregnancy outcome using linear regression models, stratified by trimester. Results Of the 23 pregnancies, nine delivered preterm and four had preeclampsia. Expression of PBX1 and MMD was higher in the second trimester among patients who experienced a poor pregnancy outcome compared to those who did not. However, in a global test of all ARS genes, we identified no association between expression of ARS genes and poor pregnancy outcomes. Conclusion Our pilot study identified two candidate genes that are reflective of the platelet function response to aspirin. Further work is needed to determine the role of these genes in identifying women with lupus at high risk for preeclampsia and preterm delivery despite aspirin therapy.

Preterm birth, low fetal growth and risk of suicide in adulthood: a national cohort and co-sibling study

2021 ◽  
Author(s):  
Casey Crump ◽  
Jan Sundquist ◽  
Kenneth S Kendler ◽  
Alexis C Edwards ◽  
Kristina Sundquist
Keyword(s):  
Preterm Birth ◽  
Environmental Factors ◽  
Fetal Growth ◽  
Gestational Age ◽  
Cox Regression ◽  
Suicide Death ◽  
Increased Risk ◽  
National Cohort ◽  
Gestational Age At Birth ◽  
Age At Birth

Abstract Background Adverse perinatal exposures have been associated with psychiatric disorders and suicidal behaviours later in life. However, the independent associations of gestational age at birth or fetal growth with suicide death, potential sex-specific differences, and causality of these associations are unclear. Methods A national cohort study was conducted of all 2 440 518 singletons born in Sweden during 1973–98 who survived to age 18 years, who were followed up through 2016. Cox regression was used to compute hazard ratios (HRs) for suicide death associated with gestational age at birth or fetal growth while mutually adjusting for these factors, sociodemographic characteristics and family history of suicide. Co-sibling analyses assessed the influence of unmeasured shared familial (genetic and/or environmental) factors. Results In 31.2 million person-years of follow-up, 4470 (0.2%) deaths by suicide were identified. Early preterm birth (22–33 weeks) was associated with an increased risk of suicide among females [adjusted hazard ratio (HR), 1.97; 95% confidence interval CI), 1.29, 3.01; P = 0.002) but not males (0.90; 0.64, 1.28; P = 0.56), compared with full-term birth (39–41 weeks). Small for gestational age was associated with a modestly increased risk of suicide among females (adjusted HR, 1.27; 95% CI, 1.08, 1.51; P = 0.005) and males (1.14; 1.03, 1.27; P = 0.02). However, these associations were attenuated and non-significant after controlling for shared familial factors. Conclusions In this large national cohort, preterm birth in females and low fetal growth in males and females were associated with increased risks of suicide death in adulthood. However, these associations appeared to be non-causal and related to shared genetic or prenatal environmental factors within families.

scholarly journals Greater genetic risk for adult psychiatric diseases increases vulnerability to adverse outcome after preterm birth

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Harriet Cullen ◽  
Saskia Selzam ◽  
Konstantina Dimitrakopoulou ◽  
Robert Plomin ◽  
A. David Edwards
Keyword(s):  
Bipolar Disorder ◽  
Preterm Birth ◽  
Gestational Age ◽  
Interaction Effect ◽  
Genetic Risk ◽  
Autism Spectrum ◽  
Cognitive Outcome ◽  
Increased Risk ◽  
Gestational Age At Birth ◽  
Age At Birth

AbstractPreterm birth is an extreme environmental stress associated with an increased risk of later cognitive dysfunction and mental health problems. However, the extent to which preterm birth is modulated by genetic variation remains largely unclear. Here, we test for an interaction effect between psychiatric polygenic risk and gestational age at birth on cognition at age four. Our sample comprises 4934 unrelated individuals (2066 individuals born < 37 weeks, 918 born <  = 34 weeks). Genome-wide polygenic scores (GPS’s) were calculated for each individual for five different psychiatric pathologies: Schizophrenia, Bipolar Disorder, Major Depressive Disorder, Attention Deficit Hyperactivity Disorder and Autism Spectrum Disorder. Linear regression modelling was used to estimate the interaction effect between psychiatric GPS and gestational age at birth (GA) on cognitive outcome for the five psychiatric disorders. We found a significant interaction effect between Schizophrenia GPS and GA (β = 0.038 ± 0.013, p = 6.85 × 10–3) and Bipolar Disorder GPS and GA (β = 0.038 ± 0.014, p = 6.61 × 10–3) on cognitive outcome. Individuals with greater genetic risk for Schizophrenia or Bipolar Disorder are more vulnerable to the adverse effects of birth at early gestational age on brain development, as assessed by cognition at age four. Better understanding of gene-environment interactions will inform more effective risk-reducing interventions for this vulnerable population.

37 Monitoring the evolution of inflammatory bowel disease (IBD) in pediatric and adult cohorts of patients to identify biomarkers to predict cancer risk

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A38-A38
Author(s):  
Shilpa Ravindran ◽  
Heba Sidahmed ◽  
Harshitha Manjunath ◽  
Rebecca Mathew ◽  
Tanwir Habib ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Colorectal Cancer ◽  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Mesenchymal Transition ◽  
Increased Risk ◽  
Hamad Medical Corporation ◽  
Inflammatory Bowel ◽  
Left And Right

BackgroundPatients with inflammatory bowel disease (IBD) have increased risk of developing colorectal cancer (CRC), depending on the duration and severity of the disease. The evolutionary process in IBD is driven by chronic inflammation leading to epithelial-to-mesenchymal transition (EMT) events in colonic fibrotic areas. EMT plays a determinant role in tumor formation and progression, through the acquisition of ‘stemness’ properties and the generation of neoplastic cells. The aim of this study is to monitor EMT/cancer initiating tracts in IBD in association with the deep characterization of inflammation in order to assess the mechanisms of IBD severity and progression towards malignancy.Methods10 pediatric and 20 adult IBD patients, admitted at Sidra Medicine (SM) and Hamad Medical Corporation (HMC) respectively, have been enrolled in this study, from whom gut tissue biopsies (from both left and right side) were collected. Retrospectively collected tissues (N=10) from patients with malignancy and history of IBD were included in the study. DNA and RNA were extracted from fresh small size (2–4 mm in diameter) gut tissues using the BioMasher II (Kimble) and All Prep DNA/RNA kits (Qiagen). MicroRNA (miRNA; N=700) and gene expression (N=800) profiling have been performed (cCounter platform; Nanostring) as well as the methylation profiling microarray (Infinium Methylation Epic Bead Chip kit, Illumina) to interrogate up to 850,000 methylation sites across the genome.ResultsDifferential miRNA profile (N=27 miRNA; p<0.05) was found by the comparison of tissues from pediatric and adult patients. These miRNAs regulate: i. oxidative stress damage (e.g., miR 99b), ii. hypoxia induced autophagy; iii. genes associated with the susceptibility to IBD (ATG16L1, NOD2, IRGM), iv. immune responses, such as TH17 T cell subset (miR 29). N=6 miRNAs (miR135b, 10a196b, 125b, let7c, 375) linked with the regulation of Wnt/b-catenin, EM-transaction, autophagy, oxidative stress and play role also in cell proliferation and mobilization and colorectal cancer development were differentially expressed (p<0.05) in tissues from left and right sides of gut. Gene expression signature, including genes associated with inflammation, stemness and fibrosis, has also been performed for the IBD tissues mentioned above. Methylation sites at single nucleotide resolution have been analyzed.ConclusionsAlthough the results warrant further investigation, differential genomic profiling suggestive of altered pathways involved in oxidative stress, EMT, and of the possible stemness signature was found. The integration of data from multiple platforms will provide insights of the overall molecular determinants in IBD patients along with the evolution of the disease.Ethics ApprovalThis study was approved by Sidra Medicine and Hamad Medical Corporation Ethics Boards; approval number 180402817 and MRC-02-18-096, respectively.

Maternal perceived stress and the increased risk of preterm birth in a majority non-Hispanic Black pregnancy cohort

2021 ◽  
Author(s):  
Sara L. Kornfield ◽  
Valerie M. Riis ◽  
Clare McCarthy ◽  
Michal A. Elovitz ◽  
Heather H. Burris
Keyword(s):  
Preterm Birth ◽  
Perceived Stress ◽  
Pregnancy Cohort ◽  
Increased Risk

scholarly journals Endometriosis and Risk of Adverse Pregnancy Outcome: A Systematic Review and Meta-Analysis

2021 ◽  
Vol 10 (4) ◽  
pp. 667
Author(s):  
Kjerstine Breintoft ◽  
Regitze Pinnerup ◽  
Tine Brink Henriksen ◽  
Dorte Rytter ◽  
Niels Uldbjerg ◽  
...  
Keyword(s):  
Preterm Birth ◽  
Cesarean Section ◽  
Placental Abruption ◽  
Gestational Hypertension ◽  
Adverse Pregnancy Outcome ◽  
Placenta Previa ◽  
Meta Analysis ◽  
Increased Risk ◽  
Spontaneous Hemoperitoneum ◽  
In Pregnancy

Background: This systematic review and meta-analysis summarizes the evidence for the association between endometriosis and adverse pregnancy outcome, including gestational hypertension, pre-eclampsia, low birth weight, and small for gestational age, preterm birth, placenta previa, placental abruption, cesarean section, stillbirth, postpartum hemorrhage, spontaneous hemoperitoneum in pregnancy, and spontaneous bowel perforation in pregnancy. Methods: We performed the literature review in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), by searches in PubMed and EMBASE, until 1 November 2020 (PROSPERO ID CRD42020213999). We included peer-reviewed observational cohort studies and case-control studies and scored them according to the Newcastle–Ottawa Scale, to assess the risk of bias and confounding. Results: 39 studies were included. Women with endometriosis had an increased risk of gestational hypertension, pre-eclampsia, preterm birth, placenta previa, placental abruption, cesarean section, and stillbirth, compared to women without endometriosis. These results remained unchanged in sub-analyses, including studies on spontaneous pregnancies only. Spontaneous hemoperitoneum in pregnancy and bowel perforation seemed to be associated with endometriosis; however, the studies were few and did not meet the inclusion criteria. Conclusions: The literature shows that endometriosis is associated with an increased risk of gestational hypertension, pre-eclampsia, preterm birth, placenta previa, placental abruption, cesarean section, and stillbirth.

scholarly journals Epigenome-wide association study of whole blood gene expression in Framingham Heart Study participants provides molecular insight into the potential role of CHRNA5 in cigarette smoking-related lung diseases

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Chen Yao ◽  
Roby Joehanes ◽  
Rory Wilson ◽  
Toshiko Tanaka ◽  
Luigi Ferrucci ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Dna Methylation ◽  
Cigarette Smoking ◽  
Association Study ◽  
Whole Blood ◽  
Lung Diseases ◽  
Epigenetic Modification ◽  
Blood Gene Expression ◽  
Increased Risk

Abstract Background DNA methylation is a key epigenetic modification that can directly affect gene regulation. DNA methylation is highly influenced by environmental factors such as cigarette smoking, which is causally related to chronic obstructive pulmonary disease (COPD) and lung cancer. To date, there have been few large-scale, combined analyses of DNA methylation and gene expression and their interrelations with lung diseases. Results We performed an epigenome-wide association study of whole blood gene expression in ~ 6000 individuals from four cohorts. We discovered and replicated numerous CpGs associated with the expression of cis genes within 500 kb of each CpG, with 148 to 1,741 cis CpG-transcript pairs identified across cohorts. We found that the closer a CpG resided to a transcription start site, the larger its effect size, and that 36% of cis CpG-transcript pairs share the same causal genetic variant. Mendelian randomization analyses revealed that hypomethylation and lower expression of CHRNA5, which encodes a smoking-related nicotinic receptor, are causally linked to increased risk of COPD and lung cancer. This putatively causal relationship was further validated in lung tissue data. Conclusions Our results provide a large and comprehensive association study of whole blood DNA methylation with gene expression. Expression platform differences rather than population differences are critical to the replication of cis CpG-transcript pairs. The low reproducibility of trans CpG-transcript pairs suggests that DNA methylation regulates nearby rather than remote gene expression. The putatively causal roles of methylation and expression of CHRNA5 in relation to COPD and lung cancer provide evidence for a mechanistic link between patterns of smoking-related epigenetic variation and lung diseases, and highlight potential therapeutic targets for lung diseases and smoking cessation.

scholarly journals First trimester employment, working conditions and preterm birth: a prospective population-based cohort study

2021 ◽  
pp. oemed-2020-107072
Author(s):  
Tanja Vrijkotte ◽  
Teus Brand ◽  
Gouke Bonsel
Keyword(s):  
Preterm Birth ◽  
Working Conditions ◽  
Work Load ◽  
First Trimester ◽  
Physical Work ◽  
Pregnancy Induced Hypertension ◽  
Prolonged Standing ◽  
Physical Work Load ◽  
Increased Risk ◽  
Induced Hypertension

ObjectivesTo explore the association between working conditions during first trimester and total preterm birth (PTB), and subtypes: spontaneous PTB and iatrogenic PTB, additionally to explore the role of hypertension.MethodsPregnant women from the Amsterdam Born Children and their Development study, filled out a questionnaire between January 2003 and March 2004, two weeks after first prenatal screening (singleton liveborn, n=7561). Working conditions were working hours/week, standing/walking hours/week, physical work load and job strain.ResultsProlonged standing/walking during first trimester was associated with an increased risk for total PTB (OR=1.5; 95% CI 1.0–2.3, after adjustments). Other working conditions were not related to total PTB. The separation into spontaneous and iatrogenic PTB revealed that standing/walking was associated with iatrogenic PTB only (OR=2.09; 95% CI 1.00–4.97). The highest risk was found for the combination of a long workweek with high physical work load (OR=3.42; 95% CI 1.04–8.21). Hypertension did not mediate these associations; however, stratified analysis revealed that high physical work load was only related to iatrogenic PTB when pregnancy-induced hypertension was present (OR=6.44; 95% CI 1.21–29.76).ConclusionThis study provides evidence that high physically demanding work is associated with an increased risk for iatrogenic PTB and not with spontaneous PTB. Pregnancy-induced hypertension may play a role: when present, high physical work load leads to a more severe outcome.

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