Biology subjects

Celedon, J. C.

Publications and source records attributed to Celedon, J. C..

8 recordsLinked to original sources

bioRxiv2026

eQTM (expression quantitative trait methylation) Atlas: a comprehensive resource of over 11 million DNA methylation-gene expression associations through across 11 tissues and 4 diseases

MotivationEpigenome-wide association studies (EWAS) have identified numerous DNA methylation (DNAm) CpG sites associated with complex traits and diseases, but interpretation of those CpG sites remains challenging because in EWAS, CpGs are mostly linked to nearby genes based only on genomic proximity. Expression quantitative trait methylation (eQTM) analyses connect DNAm CpGs with statistically associated gene expression levels. However, a comprehensive, searchable resource integrating eQTMs across diverse tissues and disease contexts has been lacking. ResultsWe developed the eQTM Atlas, a web-based resource that manually curates more than 11 million DNAm-gene expression associations from eight cohorts, covering 11 tissue types, four broad disease contexts, 173,886 unique CpG probes and 20,231 unique genes. The Atlas supports gene- or CpG-searches by tissue or disease type and finding associated CpG or genes, visualization of cis- and trans-eQTMs through genome browser, heatmap interfaces across various tissues, and cohort-level data downloads. By integrating eQTM results with EWAS resources, the eQTM Atlas enables users to connect disease- or trait-associated CpGs to statistically associated genes rather than relying solely on proximity-based gene annotation, supporting functional interpretation of EWAS findings and generation of disease-specific regulatory hypotheses. Availability and implementationThe eQTM Atlas is freely available at https://shiny.crc.pitt.edu/eqtm_browser/. The web interface is implemented in R Shiny and hosted through the University of Pittsburgh Center for Research Computing (CRC). Source code is available at https://github.com/ads303/eQTM-Atlas.

genetics↗

bioRxiv2025

DNA-methylation markers associated with lung function at birth and childhood reveal early life programming of inflammatory pathways

RationaleLung function deficits may be caused by early life epigenetic programming. Early childhood studies are necessary to understand life-course trends in lung diseases. ObjectivesWe aimed to examine whether DNA-methylation at birth and childhood is associated with lung function growth. MethodsWe measured DNA-methylation in leukocytes from participants in two childhood asthma cohorts (CAMP [n=703, mean-age 12.9 years] and GACRS [n=788, mean-age 9.3 years]) and cord blood from participants in the VDAART study (n=572) to identify CpGs and pathways associated with lung function. ResultsWe identified 1,049 consistent differentially methylated CpGs (608 relatively hypermethylated) across all three studies (FDR-P<0.05). Relatively hypomethylated CpGs were enriched for gluconeogenesis, cell adhesion and VEGF signaling. Relatively hypermethylated CpGs were enriched for Hippo, B-cell and growth hormone receptor signaling. Functional enrichment suggested potential regulatory roles for active enhancers and histone modifications. Additionally, enrichment in PI3K/AKT and Notch pathways in males and enrichment in hormonal pathways in females was identified. Gaussian graphical models identified sex-differential DNA-methylation nodes and hub scores at birth and childhood. Integrating with previously identified polygenic risk scores for asthma and drug-target enrichment identified seven robust genes including MPO, CHCHD3, CACNA1S, PI4KA, EP400, CREBBP and KCNA10 with known associations as biomarkers for asthma severity and drug targets for airway inflammation. ConclusionsEpigenetic variability from birth through puberty provides mechanistic insights into fetal programming of developmental and immune pathways associated with lung function. These early life observations reveal potential targets for mitigating risk for lung function decline and asthma progression in later life. Key messagesO_LIWe identified consistent DNA methylation signatures between birth and childhood in critical metabolic, lung development and immune pathways that were associated with lung function and may be influenced by sex and genetics. C_LIO_LIOur integrative findings provide a deeper understanding for accelerated lung function decline across the life-course and could pave the way for translational interventions for lung diseases based on epigenetic plasticity. C_LI

genomics↗

bioRxiv2023

Methyl-TWAS: A powerful method for in silico transcriptome-wide association studies (TWAS) using long-range DNA methylation

In silico transcriptome-wide association studies (TWAS) are commonly used to test whether expression of specific genes is linked to a complex trait. However, genotype-based in silico TWAS such as PrediXcan, exhibit low prediction accuracy for a majority of genes because genotypic data lack tissue- and disease-specificity and are not affected by the environment. Because methylation is tissue-specific and, like gene expression, can be modified by environment or disease status, methylation should predict gene expression with more accuracy than SNPs. Therefore, we propose Methyl-TWAS, the first approach that utilizes long-range methylation markers to impute gene expression for in silico TWAS through penalized regression. Methyl-TWAS 1) predicts epigenetically regulated/associated expression (eGReX), which incorporates tissue-specific expression and both genetically- (GReX) and environmentally-regulated expression to identify differentially expressed genes (DEGs) that could not be identified by genotype-based methods; and 2) incorporates both cis- and trans- CpGs, including various regulatory regions to identify DEGs that would be missed using cis-methylation only. Methyl-TWAS outperforms PrediXcan and two other methods in imputing gene expression in the nasal epithelium, particularly for immunity-related genes and DEGs in atopic asthma. Methyl-TWAS identified 3,681 (85.2%) of the 4,316 DEGs identified in a previous TWAS of atopic asthma using measured expression, while PrediXcan could not identify any gene. Methyl-TWAS also outperforms PrediXcan for expression imputation as well as in silico TWAS in white blood cells. Methyl-TWAS is a valuable tool for in silico TWAS, leveraging a growing body of publicly available genome-wide DNA methylation data for a variety of human tissues.

bioinformatics↗

bioRxiv2023

Validation of human telomere length trans-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as novel human telomere length regulation genes

Telomere length genome-wide association studies (GWAS) have become well-powered to detect novel genes in telomere length regulation. However, no prior work has validated these putative novel genes to confirm the contribution of GWAS loci to telomere length regulation. We conducted a trans-ancestry meta-analysis of 211,369 individuals. Through enrichment analyses of chromatin state and cell-type heritability we identified blood and immune cells as the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6, a component of an E3 ubiquitin ligase complex, and POP5, a component of the Ribonuclease P/MRP complex, and demonstrating that both lengthened telomeres as predicted by our statistical analyses. CRISPR/Cas9 deletion of the predicted causal regions of these association peaks in K562 immortalized blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5, respectively. Together our results demonstrate the utility of telomere length GWAS in the identification of novel telomere length regulation mechanisms and highlight the importance of the proteasome-ubiquitin pathway in telomere length regulation.

genetics↗

bioRxiv2020

Expression quantitative trait methylation analysis reveals methylomic associations with gene expression in childhood asthma

Nasal airway epithelial methylation profiles have been associated with asthma, but the effects of such profiles on expression of distant cis-genes are largely unknown. We identified 16,867 significant methylation-gene expression pairs in nasal epithelium from Puerto Rican children and adolescents (with and without asthma) in an expression quantitative trait methylation (eQTM) analysis of cis-genes located within 1 Mb of the methylation probes tested. Most eQTM methylation probes were distant from their target genes, and more likely located in enhancer regions of their target genes in lung tissue than control probes. The top 500 eQTM genes were enriched in pathways for immune processes and epithelial integrity, and also more likely to be differentially expressed in atopic asthma. Moreover, we identified 5,934 paths through which methylation probes could affect atopic asthma through gene expression. Our findings suggest that distant epigenetic regulation of gene expression in airway epithelium plays a role in atopic asthma.

genomics↗

bioRxiv2019

De novo mutations across 1,465 diverse genomes reveal novel mutational insights and reductions in the Amish founder population.

de novo Mutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) program, we directly estimate and analyze DNM counts, rates, and spectra from 1,465 trios across an array of diverse human populations. Using the resulting call set of 86,865 single nucleotide DNMs, we find a significant positive correlation between local recombination rate and local DNM rate, which together can explain up to 35.5% of the genome-wide variation in population level rare genetic variation from 41K unrelated TOPMed samples. While genome-wide heterozygosity does correlate weakly with DNM count, we do not find significant differences in DNM rate between individuals of European, African, and Latino ancestry, nor across ancestrally distinct segments within admixed individuals. However, interestingly, we do find significantly fewer DNMs in Amish individuals compared with other Europeans, even after accounting for parental age and sequencing center. Specifically, we find significant reductions in the number of T[->]C mutations in the Amish, which seems to underpin their overall reduction in DNMs. Finally, we calculate near-zero estimates of narrow sense heritability (h2), which suggest that variation in DNM rate is significantly shaped by non-additive genetic effects and/or the environment, and that a less mutagenic environment may be responsible for the reduced DNM rate in the Amish. SignificanceHere we provide one of the largest and most diverse human de novo mutation (DNM) call sets to date, and use it to quantify the genome-wide relationship between local mutation rate and population-level rare genetic variation. While we demonstrate that the human single nucleotide mutation rate is similar across numerous human ancestries and populations, we also discover a reduced mutation rate in the Amish founder population, which shows that mutation rates can shift rapidly. Finally, we find that variation in mutation rates is not heritable, which suggests that the environment may influence mutation rates more significantly than previously realized.

genetics↗

bioRxiv2017

Gene co-expression networks in whole blood implicate multiple interrelated molecular pathways in obese asthma

BackgroundAsthmatic children who develop obesity have poorer outcomes compared to those that do not, including poorer control, more severe symptoms, and greater resistance to standard treatment. Gene expression networks are powerful statistical tools for characterizing the underpinnings of human disease that leverage the putative co-regulatory relationships of genes to infer biological pathways altered in disease states.\n\nObjectiveThe aim of this study was to characterize the biology of childhood asthma complicated by adult obesity.\n\nMethodsWe performed weighted gene co-expression network analysis (WGCNA) of gene expression data in whole blood from 514 adult subjects from the Childhood Asthma Management Program (CAMP). We then performed module preservation and association replication analyses in 418 subjects from two independent asthma cohorts (one pediatric and one adult).\n\nResultsWe identified a multivariate model in which four gene co-expression network modules were associated with incident obesity in CAMP (each P < 0.05). The module memberships were enriched for genes in pathways related to platelets, integrins, extracellular matrix, smooth muscle, NF-{kappa}B signaling, and Hedgehog signaling. The network structures of each of the four obese asthma modules were significantly preserved in both replication cohorts (permutation P = 9.999E-05). The corresponding module gene sets were significantly enriched for differential expression in obese subjects in both replication cohorts (each P < 0.05).\n\nConclusionsOur gene co-expression network profiles thus implicate multiple interrelated pathways in the biology of an important endotype of obese asthma.\n\nKey MessagesO_LIWe hypothesized that individuals with asthma complicated by obesity had distinct blood gene expression signatures.\nC_LIO_LIGene co-expression network analysis implicated several inflammatory biological pathways in one form of obese asthma.\nC_LI\n\nCapsule SummaryThis work addresses a knowledge gap about the molecular relationship between asthma and obesity, suggesting that an endotype of obese asthma, known as asthma complicated by obesity, is underpinned by coherent biological mechanisms.\n\nAbbreviations

genomics↗

bioRxiv2017

Whole Genome Sequencing of Pharmacogenetic Drug Response in Racially and Ethnically Diverse Children with Asthma

Asthma is the most common chronic disease of children, with significant racial/ethnic differences in prevalence, morbidity, mortality and therapeutic response. Albuterol, a bronchodilator medication, is the first-line therapy for asthma treatment worldwide. We performed the largest whole genome sequencing (WGS) pharmacogenetics study to date using data from 1,441 minority children with asthma who had extremely high or low bronchodilator drug response (BDR). We identified population-specific and shared pharmacogenetic variants associated with BDR, including genome-wide significant (p < 3.53 x 10-7) and suggestive (p < 7.06 x 10-6) loci near genes previously associated with lung capacity (DNAH5), immunity (NFKB1 and PLCB1), and {beta}-adrenergic signaling pathways (ADAMTS3 and COX18). Functional analyses centered on NFKB1 revealed potential regulatory function of our BDR-associated SNPs in bronchial smooth muscle cells. Specifically, these variants are in linkage disequilibrium with SNPs in a functionally active enhancer, and are also expression quantitative trait loci (eQTL) for a neighboring gene, SLC39A8. Given the lack of other asthma study populations with WGS data on minority children, replication of our rare variant associations is infeasible. We attempted to replicate our common variant findings in five independent studies with GWAS data. The age-specific associations previously found in asthma and asthma-related traits suggest that the over-representation of adults in our replication populations may have contributed to our lack of statistical replication, despite the functional relevance of the NFKB1 variants demonstrated by our functional assays. Our study expands the understanding of pharmacogenetic analyses in racially/ethnically diverse populations and advances the foundation for precision medicine in at-risk and understudied minority populations.\n\nAUTHOR SUMMARYAsthma is the most common chronic disease among children. Albuterol, a bronchodilator medication, is the first-line therapy for asthma treatment worldwide. In the U.S., asthma prevalence is the highest among Puerto Ricans, intermediate among African Americans and lowest in Whites and Mexicans. Asthma disparities extend to mortality, which is four- to five-fold higher in Puerto Ricans and African Americans compared to Mexicans [1]. Puerto Ricans and African Americans, the populations with the highest asthma prevalence and death rate, also have the lowest albuterol bronchodilator drug response (BDR). We conducted the largest pharmacogenetic study using whole genome sequencing data from 1,441 minority children with asthma who had extremely high or low albuterol bronchodilator drug response. We identified population-specific and shared pharmacogenetic variants associated with BDR. Our findings help inform the direction of future development of asthma medications and our study advances the foundation of precision medicine for at-risk, yet understudied, racially/ethnically diverse populations.

genetics↗