Preterm Birth Buccal Cell Epigenetic Biomarkers to Facilitate Preventative Medicine
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE194227 | GEO | 2022/03/09
REPOSITORIES: GEO
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Project description:Preterm birth is a significant clinical problem and an enormous burden on society, affecting one in eight pregnant women and their newborns. Despite decades of research, its pathogenesis remains unclear. Many studies have shown that preterm birth is associated with health risks across the later life course. The “fetal origins” hypothesis postulates that adverse intrauterine exposures are associated with later disease susceptibility. Our recent studies have focused on the placental epigenome at term. We extended these studies to genome-wide placental DNA methylation across a wide range of gestational ages. We applied methylation dependent immunoprecipitation/DNA sequencing (MeDIP-seq) to 9 placentas with gestational age from 25 weeks to term to identify differentially methylated regions (DMRs). Enrichment analysis revealed 427 DMRs with nominally significant differences in methylation between preterm and term placentas (p<0.01) and 21 statistically significant DMRs after multiple comparison correction (FDR p<0.05), of which 62% were hypo-methylated in preterm placentas vs term placentas. The majority of DMRs were in distal intergenic regions and introns. Significantly enriched pathways identified by Ingenuity Pathway Analysis (IPA) included Citrulline-Nitric Oxide Cycle and Fcy Receptor Mediated Phagocytosis in macrophages. The DMR gene set overlapped placental gene expression data, genes and pathways associated evolutionarily with preterm birth. These studies form the basis for future studies on the epigenetics of preterm birth, "fetal programming” and the impact of environment exposures on this important clinical challenge.
2018-09-26 | GSE120458 | GEO
Project description:We designed a microarray to test at exonic resolution for genomic imbalance for genes representative of all known chromosomal microdeletion/microduplication syndromes, all known causative genes for ID, all known genes encoding glutamate receptors and their known encoding proteins and all known genes encoding proteins with epigenetic regulatory function. We found 36 de novo copy number variants affecting 35 children in this study. 167 trios, each comprising an affected child and both its normal parents were analyzed by conducting two comparative hybridizations; child vs. mother and child vs. father, and only selecting a CNV if it appeared in both hybridizations, i.e., was de novo. De novo CNVs were independantly validated using quantitative PCR.
2012-07-23 | E-GEOD-39533 | biostudies-arrayexpress
Project description:Background Urothelial carcinoma of the bladder (UC) is a common malignancy. Although extensive transcriptome analysis has provided insights into the gene expression patterns of this tumor type, the mechanistic underpinnings of differential methylation remain poorly understood. Multi-level genomic data may be used to profile the regulatory potential and landscape of differential methylation in cancer and gain understanding of the processes underlying epigenetic and phenotypic characteristics of tumors. Methods We perform genome-wide DNA methylation profiling of 98 gene-expression subtyped tumors to identify between-tumor differentially methylated regions (DMRs). We integrate multi-level publically available genomic data generated by the ENCODE consortium to characterize the regulatory potential of UC DMRs. Results We identify 5,453 between-tumor DMRs and derive four DNA methylation subgroups of UC with distinct associations to clinicopathological features and gene expression subtypes. We characterize three distinct patterns of differential methylation and use ENCODE data to show that tumor subgroup-defining DMRs display differential chromatin state, and regulatory factor binding preferences. Finally, we characterize an epigenetic switch involving the HOXA-genes with associations to tumor differentiation states and patient prognosis. Conclusions Genome-wide DMR methylation patterns are reflected in the gene expression subtypes of UC. UC DMRs display three distinct methylation patterns, each associated with intrinsic features of the genome and differential regulatory factor binding preferences. Epigenetic inactivation of HOX-genes correlates with tumor differentiation states and may present an actionable epigenetic alteration in UC. MeDIP hybridizations on 98 human urothelial carcinoma samples and 4 normal urothelium samples on Nimblegen 3x720K RefSeq Promoter and CGI aCGH arrays.
2015-05-28 | E-GEOD-58256 | biostudies-arrayexpress
Project description:Environmental exposures such as chemical toxicants can alter gene expression and disease susceptibility through epigenetic processes. Epigenetic changes can be passed to future generations through germ cells through epigenetic transgenerational inheritance of increased disease susceptibility. The current study used an epigenome-wide association study (EWAS) to investigate whether specific transgenerational epigenetic signatures of differential DNA methylation regions (DMRs) exist that are associated with particular disease states in the F3 generation great-grand offspring of F0 generation rats exposed during gestation to the agricultural pesticide methoxychlor. The transgenerational epigenetic profile of sperm from F3 generation methoxychlor lineage rats that have only one disease state was compared to those that have no disease. Observations identify disease specific patterns of DMRs for these transgenerational rats that can potentially serve as epigenetic biomarkers for prostate disease, kidney disease, obesity, and the presence of multiple diseases. The chromosomal locations, genomic features, and gene associations of the DMRs are characterized. Disease specific DMR sets contained DMR associated genes that have previously been shown to be associated with that specific disease. Future epigenetic biomarkers could potentially be developed and validated for humans as a disease susceptibility diagnostic tool to facilitate preventative medicine and management of disease.
2020-12-16 | GSE158086 | GEO
Project description:Clinical laboratories are adopting array comparative genomic hybridization (AGH) as a standard clinical test. A number of whole genome AGH systems are available, but little is known about the comparative performance in a clinical context. We prospectively studied 30 children with idiopathic MR and both unaffected parents of each child using Affymetrix 500K GeneChip SNP arrays, Agilent Human Genome 244K oligonucleotide arrays and NimbleGen 385K Whole-Genome oligonucleotide arrays. We determined whether CNVs called on these platforms were detected by Illumina Hap550 beadchips or SMRT 32K BAC whole genome tiling arrays and tested 15 of the 30 trios on Affymetrix 6.0 SNP array. The Affymetrix 500K, Agilent and NimbleGen platforms identified 3061 autosomal and 117 X chromosome CNVs in 30 trios. 147 of these CNVs were de novo, but only 33 (22%) of the de novo CNVs were found on more than one platform. Performing genotype-phenotype correlations, we identified 7 pathogenic and 4 possibly pathogenic CNVs for MR. All 11 of these CNVs were detected by both the Agilent and NimbleGen arrays, 9 by the Affymetrix 500K and Illumina beadchips, and 5 by the SMRT BAC array. Two of the 4 pathogenic or possibly pathogenic CNVs present in the trios tested with the Affymetrix 6.0 array were identified. Our findings demonstrate that different results are obtained with different AGH platforms and illustrate the trade-off that exists between sensitivity and specificity. The large number of apparently false positive CNV calls supports the need for validating clinically important findings with a different methodology. 15 trios were analysed consisting of child (proband) and both normal parents. We performed separate hybridizations for the mother, father, and child and then performed pair-wise comparisons of the normalized hybridization intensities for the child to the mother and of the child to the father in silico.
2011-02-17 | E-GEOD-27145 | biostudies-arrayexpress
Project description:Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex heritability and higher prevalence in males. The neonatal epigenome has the potential to reflect past interactions between genetic and environmental factors during early development and influence future health outcomes. We performed whole-genome bisulfite sequencing of 152 umbilical cord blood samples from the MARBLES and EARLI high-familial risk prospective cohorts to identify an epigenomic signature of ASD at birth. Samples were split into discovery and replication sets and stratified by sex, and their DNA methylation profiles were tested for differentially methylated regions (DMRs) between ASD and typically developing control cord blood samples. DMRs were mapped to genes and assessed for enrichment in gene function, tissue expression, chromosome location, and overlap with prior ASD studies. DMR coordinates were tested for enrichment in chromatin states and transcription factor binding motifs. Results were compared between discovery and replication sets and between males and females. We identified DMRs stratified by sex that discriminated ASD from control cord blood samples in discovery and replication sets. At a region level, 7 DMRs in males and 31 DMRs in females replicated across two independent groups of subjects, while 537 DMR genes in males and 1762 DMR genes in females replicated by gene association. These DMR genes were significantly enriched for brain and embryonic expression, X chromosome location, and identification in prior epigenetic studies of ASD in post-mortem brain. In males and females, autosomal ASD DMRs were significantly enriched for promoter and bivalent chromatin states across most cell types, while sex differences were observed for X-linked ASD DMRs. Lastly, these DMRs identified in cord blood were significantly enriched for binding sites of methyl-sensitive transcription factors relevant to fetal brain development. At birth, prior to the diagnosis of ASD, a distinct DNA methylation signature was detected in cord blood over regulatory regions and genes relevant to early fetal neurodevelopment. Differential cord methylation in ASD supports the developmental and sex-biased etiology of ASD and provides novel insights for early diagnosis and therapy.
2020-03-24 | GSE140730 | GEO
Project description:We previously reported a child with transient neonatal diabetes mellitus (TNDM), who upon molecular diagnosis was homozygous for a one base-pair deletion in ZFP57, inheriting the mutations from both heterozygous parents. Methylation profiling at diagnosis revealed severe hypomethylation at PLAGL1 and mosaic loss-of-methylation (LOM) at GRB10, NAP1L5 and GNAS-XL DMRs. Some years after the first child, a second sibling was born with a comparable clinical presentation. Upon molecular investigation this child was shown to have the same homozygous deletion. Using Illumina Infinium BeadChip arrays, we confirmed similar hypomethylated signatures at ubiquitous imprinted DMRs. To further characterize the stability of the imprinting defects and understand the role of this mutation in tissue-specific mosaicism, we hybridised buccal-derived DNA and a second leukocyte sample from first child to the HumanMethylationEPIC arrays. When comparing the two blood-derived samples, we observed that the hypomethylation signature is stable over time with the PLAGL1 DMR being the most severely affected, consistent with this being the disease-causing locus. Furthermore, when comparing the leukocyte and buccal samples, the same imprinted DMRs were affected to a similar extent.
2020-11-27 | GSE149568 | GEO
Project description:Genome-wide association study of severe malaria in Gambian mother-father-child trios
| EGAS00000000087 | EGA
Project description:<p>Preterm labor resulting in the delivery of a premature child is a complex problem with an enormous impact on individuals, families and society. An estimated 500,000 children are born prematurely in the U.S. each year, and 5 million worldwide die annually of prematurity and its complications. Prematurity is also the single largest contributor to disability-adjusted life years, a measure of the lifetime impact of a disease. Despite the importance of the problem and its disproportionate occurrence in poor and minority populations, its underlying etiology (or etiologies) remains unknown; the single best predictor for preterm delivery is a previous preterm birth. The largest single cause of prematurity is spontaneous preterm labor, and suspected triggers for this include infection, stress, poor nutrition and genetic factors. Family and twin studies provide strong evidence that genetic factors underlie about 40% of the risk for prematurity. A major challenge in studying genetic factors in prematurity is maternal/uterine factors, fetal/placental factors, or both may influence risk. Thus, any approach to studying preterm birth should account for both infant and maternal risk, environmental covariates and interactions. The Danish National Birth Cohort (DNBC) is a well-established, prospective cohort that enrolled women early in pregnancy, prior to any adverse pregnancy outcomes, to minimize bias in data collection and sampling. See details at: <a href="http://www.ssi.dk/English" target="_blank">http://www.ssi.dk/English</a>.</p> <p>The DNBC followed over 100,000 pregnancies beginning in the first trimester and has extensive biological material and epidemiologic data on health outcomes in both mother and child. The current study posted on dbGaP contains data from a genome-wide case/control study using approximately 1,000 preterm mother-child pairs from the DNBC most with spontaneous onset of labor or preterm premature rupture of membranes (PPROM), along with 1,000 control pairs where the child was born at ~40 weeks' gestation. After data cleaning some small changes in case/control status and other variables resulted in minor changes in numbers of cases or controls in certain categories. Environmental variables are being used as covariates in the analysis.</p> <p>To replicate positive findings, we are using additional mother-child pairs from the DNBC and from the general Danish population, as well as 2200 samples coming primarily from an African-American population known to have high rates of preterm labor and delivery. This group includes over 1000 mostly very low birthweight infants, over 500 infant term controls, 326 term mother/baby pairs and 180 preterm mother/baby pairs. The data from these additional cohorts will be available in separate dbGaP postings. The study is expected to yield a better understanding of the biology of parturition, identify common genetic factors that play a role in preterm birth and its complications and suggest environmental modifications that can prolong gestation, with the goal of improving both neonatal and adult outcomes.</p> <p>This study is part of the Gene Environment Association Studies initiative (GENEVA, <a href="http://www.genevastudy.org" target="_blank">http://www.genevastudy.org</a>) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to prematurity and its complications through large-scale genome-wide association studies of a well-characterized cohort of Danish mothers and babies. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.</p>
| phs000103 | dbGaP
Project description:Fetal health is dependent upon the epigenetic-based regulation of gene expression in placenta. Genomic imprinting is an epigenetic phenomenon common to placenta and refers to the monoallelic expression of a gene in a parental-specific manner. We aimed to detect novel imprinted genes in human placenta by applying whole transcriptome RNA-sequencing and genotyping of coding variants. Ten family trios with healthy spontaneous single term pregnancy were recruited. Parental and child DNA genotypes were analysed using exome SNP genotyping microarrays, revealing the inheritance of parental alleles. Total RNA was extracted from placental tissue for whole transcriptome analysis. The imprinted genes showed consistent expression from either parental allele as demonstrated by the SNP content of sequenced transcripts. We found seven novel imprinted genes (ABP1, BCLAF1, IFI30, LGALS8, LGALS14, PAPPA2 and SPTLC3) and confirmed five known imprinted genes (AIM1, PEG10, RHOBTB3, ZFAT and ZFAT-AS1). The main functions of the proteins encoded by the imprinted genes can be grouped as being involved in: i) cellular apoptosis and tissue development; ii) regulating inflammation and modulating the immune system; iii) facilitating metabolic processes and iv) regulating the cell cycle. Ten family trios (mother, father, child) were analysed using SNP genotyping. Raw data contains additional two samples that were not used.
2014-09-01 | E-GEOD-56685 | biostudies-arrayexpress