Browse
Submit Data
Databases
API
Help

Dataset Information

10 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Common genetic variants with fetal effects on birth weight are enriched for proximity to genes implicated in rare developmental disorders.

ABSTRACT: Birth weight is an important factor in newborn survival; both low and high birth weights are associated with adverse later-life health outcomes. Genome-wide association studies (GWAS) have identified 190 loci associated with maternal or fetal effects on birth weight. Knowledge of the underlying causal genes is crucial to understand how these loci influence birth weight and the links between infant and adult morbidity. Numerous monogenic developmental syndromes are associated with birth weights at the extreme ends of the distribution. Genes implicated in those syndromes may provide valuable information to prioritize candidate genes at the GWAS loci. We examined the proximity of genes implicated in developmental disorders (DDs) to birth weight GWAS loci using simulations to test whether they fall disproportionately close to the GWAS loci. We found birth weight GWAS single nucleotide polymorphisms (SNPs) fall closer to such genes than expected both when the DD gene is the nearest gene to the birth weight SNP and also when examining all genes within 258 kb of the SNP. This enrichment was driven by genes causing monogenic DDs with dominant modes of inheritance. We found examples of SNPs in the intron of one gene marking plausible effects via different nearby genes, highlighting the closest gene to the SNP not necessarily being the functionally relevant gene. This is the first application of this approach to birth weight, which has helped identify GWAS loci likely to have direct fetal effects on birth weight, which could not previously be classified as fetal or maternal owing to insufficient statistical power.

SUBMITTER: Beaumont RN

PROVIDER: S-EPMC8355446 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Mechanistic Insights into Lethal Lung Developmental Disorders. The Rare Informs the Common.

Project description: Not available

| S-EPMC6888662 | biostudies-literature

Cyclin-dependent kinases and rare developmental disorders.

Project description:Extensive studies in the past 30 years have established that cyclin-dependent kinases (CDKs) exert many diverse, important functions in a number of molecular and cellular processes that are at play during development. Not surprisingly, mutations affecting CDKs or their activating cyclin subunits have been involved in a variety of rare human developmental disorders. These recent findings are reviewed herein, giving a particular attention to the discovered mutations and their demonstrated or hypothesized functional consequences, which can account for pathological human phenotypes. The review highlights novel, important CDK or cyclin functions that were unveiled by their association with human disorders, and it discusses the shortcomings of mouse models to reveal some of these functions. It explains how human genetics can be used in combination with proteome-scale interaction databases to loom regulatory networks around CDKs and cyclins. Finally, it advocates the use of these networks to profile pathogenic CDK or cyclin variants, in order to gain knowledge on protein function and on pathogenic mechanisms.

| S-EPMC7410148 | biostudies-literature

Maternal residential proximity to major roadways, birth weight, and placental DNA methylation.

Project description:BACKGROUND:Exposure to traffic pollution during fetal development has been associated with reduced fetal growth, and there is evidence to suggest that epigenetic mechanisms in the placenta in the form of variant DNA methylation may be a potential mechanism underlying this effect. OBJECTIVES:To examine the association between residential proximity to nearest major roadway, as a marker of traffic-related pollution, fetal growth and placental DNA methylation. METHODS:We obtained residential addresses, placenta samples, and demographic data from 471 women following delivery of term infants. Using generalized linear models we evaluated the association between living close to a major roadway (defined as living ?150m from a primary highway or primary road or ?50m from a secondary road) and fetal growth and DNA methylation of repetitive elements (LINE-1 and AluYb8). We evaluated epigenome-wide methylation in a subset of 215 women to further investigate specific variation in DNA methylation associated with proximity to major roadways. RESULTS:Living close to a major roadway was associated with a 175.9g (95% CI: -319.4, -32.5; p=0.016) lower birth weight, 1.8 (95% CI: 0.9, 3.8; p=0.09) times the odds of being small for gestational age, and 0.82 percentage points (95% CI: -1.57, -0.07; p=0.03) lower mean placental LINE-1 methylation levels in fully adjusted models. In epigenome-wide analyses, 7 CpG sites were significantly associated with residential proximity to major roadways. Additional adjustment for placental methylation did not attenuate the association between roadway proximity and birth weight. CONCLUSIONS:Living close to major roadways was associated with both lower fetal growth and significant placental epigenetic changes. However, the observed epigenetic changes appear insufficient to explain the observed association between roadway proximity and fetal growth.

| S-EPMC4913202 | biostudies-literature

Future perspectives on rare pulmonary diseases and rare presentations of common disorders.

Project description: Not available

| S-EPMC9487357 | biostudies-literature

Developmental expression mapping of a gene implicated in multiple neurodevelopmental disorders, A2bp1 (Fox1).

Project description:The neuronal transcription splicing factor, A2BP1, has been implicated in a variety of neurodevelopmental disorders; however, the role of A2BP1 in brain development and gene regulatory function remains to be explicated. Here, we map A2bp1 gene expression, focusing on the developing forebrain of the C57BL6J mouse. Early in forebrain development, A2bp1 expression is highly reminiscent of the expression of genes marking postmitotic GABAergic cells emanating from the ventral telencephalon during migration to the dorsal pallium. Ventral pallial expression remains low after the migratory period. Broader dorsal pallial expression becomes more evident late prenatally and early postnatally. This is paralleled by dense, restricted expression in the ventrobasal dorsal thalamic complex and mid-hypothalamic region. Outside of the forebrain, there is significant expression in motor pathways. These data indicate that A2BP1 mutations may clinically affect very selective forebrain neuron types from early periods of development.

| S-EPMC3080782 | biostudies-literature

Enriched Environments as a Potential Treatment for Developmental Disorders: A Critical Assessment.

Project description:The beneficial effects of enriched environments have been established through a long history of research. Enrichment of the living conditions of captive animals in the form of larger cages, sensory stimulating objects, and opportunities for social interaction and physical exercise, has been shown to reduce emotional reactivity, ameliorate abnormal behaviors, and enhance cognitive functioning. Recently, environmental enrichment research has been extended to humans, in part due to growing interest in its potential therapeutic benefits for children with neurodevelopmental disorders (NDDs). This paper reviews the history of enriched environment research and the use of enriched environments as a developmental intervention in studies of both NDD animal models and children. We argue that while environmental enrichment may sometimes benefit children with NDDs, several methodological factors need to be more closely considered before the efficacy of this approach can be adequately evaluated, including: (i) operationally defining and standardizing enriched environment treatments across studies; (ii) use of control groups and better control over potentially confounding variables; and (iii) a comprehensive theoretical framework capable of predicting when and how environmental enrichment will alter the trajectory of NDDs.

| S-EPMC6414413 | biostudies-literature

Fetal Genotype and Maternal Glucose Have Independent and Additive Effects on Birth Weight.

Project description:Maternal glycemia is a key determinant of birth weight, but recent large-scale genome-wide association studies demonstrated an important contribution of fetal genetics. It is not known whether fetal genotype modifies the impact of maternal glycemia or whether it acts through insulin-mediated growth. We tested the effects of maternal fasting plasma glucose (FPG) and a fetal genetic score for birth weight on birth weight and fetal insulin in 2,051 European mother-child pairs from the Exeter Family Study of Childhood Health (EFSOCH) and the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study. The fetal genetic score influenced birth weight independently of maternal FPG and impacted growth at all levels of maternal glycemia. For mothers with FPG in the top tertile, the frequency of large for gestational age (birth weight ?90th centile) was 31.1% for offspring with the highest tertile genetic score and only 14.0% for those with the lowest tertile genetic score. Unlike maternal glucose, the fetal genetic score was not associated with cord insulin or C-peptide. Similar results were seen for HAPO participants of non-European ancestry (n = 2,842 pairs). This work demonstrates that for any level of maternal FPG, fetal genetics has a major impact on fetal growth and acts predominantly through independent mechanisms.

| S-EPMC5910006 | biostudies-literature

Genetic effects on the timing of parturition and links to fetal birth weight.

Project description:The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of gestational duration (n = 195,555), identifying 22 associated loci (24 independent variants) and an enrichment in genes differentially expressed during labor. A meta-analysis of preterm delivery (18,797 cases, 260,246 controls) revealed six associated loci and large genetic similarities with gestational duration. Analysis of the parental transmitted and nontransmitted alleles (n = 136,833) shows that 15 of the gestational duration genetic variants act through the maternal genome, whereas 7 act both through the maternal and fetal genomes and 2 act only via the fetal genome. Finally, the maternal effects on gestational duration show signs of antagonistic pleiotropy with the fetal effects on birth weight: maternal alleles that increase gestational duration have negative fetal effects on birth weight. The present study provides insights into the genetic effects on the timing of parturition and the complex maternal-fetal relationship between gestational duration and birth weight.

| S-EPMC10101852 | biostudies-literature

Fetal alleles predisposing to metabolically favorable adiposity are associated with higher birth weight.

Project description:BackgroundHigher birthweight is associated with higher adult body mass index (BMI). Alleles that predispose to greater adult adiposity might act in fetal life to increase fetal growth and birthweight. Whether there are fetal effects of recently identified adult metabolically favorable adiposity alleles on birthweight is unknown.AimWe aimed to test the effect on birthweight of fetal genetic predisposition to higher metabolically favorable adult adiposity and compare that with the effect of fetal genetic predisposition to higher adult BMI.MethodsWe used published genome wide association study data (n = upto 406 063) to estimate fetal effects on birthweight (adjusting for maternal genotype) of alleles known to raise metabolically favorable adult adiposity or BMI. We combined summary data across single nucleotide polymorphisms (SNPs) with random effects meta-analyses. We performed weighted linear regression of SNP-birthweight effects against SNP-adult adiposity effects to test for a dose-dependent association.ResultsFetal genetic predisposition to higher metabolically favorable adult adiposity and higher adult BMI were both associated with higher birthweight (3 g per effect allele (95% CI: 1-5) averaged over 14 SNPs; P = 0.002; 0.5 g per effect allele (95% CI: 0-1) averaged over 76 SNPs; P = 0.042, respectively). SNPs with greater effects on metabolically favorable adiposity tended to have greater effects on birthweight (R2 = 0.2912, P = 0.027). There was no dose-dependent association for BMI (R2 = -0.0019, P = 0.602).ConclusionsFetal genetic predisposition to both higher adult metabolically favorable adiposity and BMI is associated with birthweight. Fetal effects of metabolically favorable adiposity-raising alleles on birthweight are modestly proportional to their effects on future adiposity, but those of BMI-raising alleles are not.

| S-EPMC9169452 | biostudies-literature

Fetal Thyroid Function, Birth Weight, and in Utero Exposure to Fine Particle Air Pollution: A Birth Cohort Study.

Project description:BACKGROUND:Thyroid hormones are critical for fetal development and growth. Whether prenatal exposure to fine particle air pollution (? 2.5 ?m; PM2.5) affects fetal thyroid function and what the impact is on birth weight in normal healthy pregnancies have not been studied yet. OBJECTIVES:We studied the impact of third-trimester PM2.5 exposure on fetal and maternal thyroid hormones and their mediating role on birth weight. METHODS:We measured the levels of free thyroid hormones (FT3, FT4) and thyroid-stimulating hormone (TSH) in cord blood (n = 499) and maternal blood (n = 431) collected after delivery from mother-child pairs enrolled between February 2010 and June 2014 in the ENVIRONAGE birth cohort with catchment area in the province of Limburg, Belgium. RESULTS:An interquartile range (IQR) increment (8.2 ?g/m3) in third-trimester PM2.5 exposure was inversely associated with cord blood TSH levels (-11.6%; 95% CI: -21.8, -0.1) and the FT4/FT3 ratio (-62.7%; 95% CI: -91.6, -33.8). A 10th-90th percentile decrease in cord blood FT4 levels was associated with a 56 g decrease in mean birth weight (95% CI: -90, -23). Assuming causality, we estimated that cord blood FT4 mediated 21% (-19 g; 95% CI: -37, -1) of the estimated effect of an IQR increment in third-trimester PM2.5 exposure on birth weight. Third-trimester PM2.5 exposure was inversely but not significantly associated with maternal blood FT4 levels collected 1 day after delivery (-4.0%, 95% CI: -8.0, 0.2 for an IQR increment in third-trimester PM2.5). CONCLUSIONS:In our study population of normal healthy pregnancies, third-trimester exposure to PM2.5 air pollution was associated with differences in fetal thyroid hormone levels that may contribute to reduced birth weight. Additional research is needed to confirm our findings in other populations and to evaluate potential consequences later in life.

| S-EPMC5382000 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data