Biology subjects

MacIsaac, J. L.

Publications and source records attributed to MacIsaac, J. L..

14 recordsLinked to original sources

bioRxiv2026

Prenatal diet buffers infant epigenetic changes linked to pollution and transient wheeze

Prenatal air pollution exposure is associated with childhood asthma, particularly among biological males. The mechanisms remain unclear, but may involve lasting epigenetic changes, such DNA methylation (DNAm), that occur during gestation in response to oxidative stress and inflammation. Higher maternal intake of "protective" micronutrients, like antioxidants, could buffer pollution-induced oxidative stress and inflammation to mitigate potentially adverse DNAm differences contributing to asthma. Using data from 515 CANDLE participants, we examined associations between prenatal NO2, PM2.5, and PM10 and cord blood DNAm, evaluated DNAm mediation of pollution associations with childhood wheeze phenotypes (transient, persistent, and late-onset), and assessed buffering of DNAm by maternal polyunsaturated fatty acid, vitamin C, or folate intake, and overall diet quality measured by the Alternative Healthy Eating Index-Pregnancy (AHEI-P). We identified 19, seven, and five regional DNAm differences associated NO2, PM2.5, and PM10. Mediation analyses suggested a role for HLA-DPA1/DPB1 DNAm in NO2 and PM2.5 associations with transient wheeze. To assess buffering, we fit pollutant-by-diet interaction models, defining buffering as an interaction opposite in sign to the main pollutant effect. One or more micronutrients or AHEI-P attenuated pollutant effects at 16 of 19 NO2-associated DMRs, including HLA-DPA1/DPB1, and all PM2.5- and PM10-associated DMRs. However, attenuation of HLA-DPA1/DPB1 DNAm did not significantly reduce the indirect effect of NO2 on transient wheeze. In sex-stratified analyses, biological males exhibited lower PM2.5-associated DNAm in SERPINB9, a gene linked to lung function. These findings suggest prenatal air pollution alters DNAm, which may contribute to transient wheeze, with some differences partially buffered by maternal diet. Significance StatementPrenatal air pollution exposure contributes to child wheeze and asthma, potentially through the oxidative stress response and subsequent changes to infant DNA methylomes. Here, we used data from the CANDLE cohort to identify cord blood DNAm differences associated with NO2, PM2.5, or PM10. We examined if any alterations mediated the relationship between prenatal air pollution exposures and transient, persistent, or late-onset wheeze at age 4 to 6 years. Some of these DNAm differences appeared to be at least partially buffered by maternal micronutrients and/or overall diet quality.

genomics↗

bioRxiv2025

RAMEN: Dissecting individual, additive and interactive gene-environment contributions to DNA methylome variability in cord blood

DNA methylation (DNAme) is the most commonly studied epigenetic mark in human populations. DNAme has gained attention in the Developmental Origins of Health and Disease field due to its gene expression regulation and potential long-term stability. Genetic variation and environmental exposures are amongst the main factors influencing inter-individual DNAme variability. However, the proportion and genomic distribution of their individual, additive and interactive effects on the DNA methylome remains unclear. Here, we introduce RAMEN, a Findable, Accessible, Interoperable, and Reusable (FAIR) framework tailored for DNAme microarrays. Using machine learning and statistical techniques, RAMEN models and dissects gene-environment contributions to genome-wide Variably Methylated Regions (VMRs), while controlling for spurious associations. To comprehensively test the power of RAMEN, we analyzed and characterized VMRs from cord blood samples from two independent cohorts (CHILD and PREDO; overall n=1,662). We identified genetics as a consistent key contributor to DNAme variability, usually in additive and interactive combinations with the environment, with genetic terms explaining the largest proportion of DNAme variance, compared to environmental and interaction terms. Operationalizing RAMEN as an R package to conduct scalable genome-exposome contribution analyses, our results highlighted the importance of genetic variation in sculpting DNAme patterns in early life.

bioinformatics↗

bioRxiv2024

Considerations for Cell Type Heterogeneity in Pediatric Salivary DNA Methylation Analyses: Comparison of Reference Panels & Stratification by Estimated Cell TypeProportion

Saliva is widely used in biomedical population research, including epigenetic analyses to investigate gene-environment interplay and identify biomarkers. Its minimally invasive collection procedure makes it ideal for studies in pediatric populations. Saliva is a heterogenous tissue composed of immune and buccal epithelial cells (BEC). Amongst the many epigenetic marks, DNA methylation (DNAm) is the most studied in human populations. Given DNAms integral role to cellular differentiation and maintenance, DNAm profiles are often highly cell type (CT)-specific and CT composition can drive salivary DNAm associations with environments or health as well as epigenetic age acceleration (EAA), discrepancy between chronological age and biological age derived from DNAm. To address this, reference-based CT deconvolution and statistically adjustment with estimated CT in DNAm analyses have become a common practice. However, it remains unclear how different CT reference panels--constructed from adult versus pediatric samples--affect DNAm results. Additionally, whether DNAm and EAA associations in saliva primarily originate from immune cells or BECs, or if they persist across saliva samples despite varying CT proportions, has yet to be examined. The current study used salivary DNAm samples obtained from 529 children (mean age=7.26 years, SD=0.26 years) in a community-based cohort, the Family Life Project. Our results highlighted the impact of estimated CT discrepancies across child and adult reference panels on DNAm associations. Upon stratifying the salivary DNAm samples into three subsamples--primarily BECs, primarily immune cells, and an approximately equal mix of both, we found significantly different EAAs across stratified samples when CT proportions were not accounted for. In both the context of DNAm and EAA associations, we detected stronger effects of cotinine concentrations, a tobacco smoke-exposure biomarker, in the subsample with primarily immune cells. We discussed the implications of our findings for the interpretation and replication of epigenetic research involving pediatric saliva samples.

bioinformatics↗

bioRxiv2024

Genetic Basis, Quantitative Nature, and Functional Relevance of Evolutionarily Conserved DNA Methylation

DNA methylation (DNAm) is a key epigenetic mark that modulates regulatory elements and gene expression, playing a crucial role in mammalian development and physiological function. Despite extensive characterization of DNAm profiles across species, little is known about its evolutionary conservation. Here, we conducted a comparative epigenome-wide analysis of great apes to identify and characterize sequence- and methylation-conserved CpGs (MCCs). Using 202 DNAm arrays, alongside 6 matched genotype and 13 matched transcriptomic datasets, we identified 11,500 MCCs for which methylation was evolutionarily related to sequences of CpGs and methylation quantitative trait loci. MCCs were the most stable across healthy human tissues and exhibited weaker genetic associations than other CpGs. Moreover, MCCs showed minimal associations with demographic, environmental factors, and noncancer diseases, yet demonstrated stronger associations with certain cancers than other CpGs, particularly gastrointestinal cancers. Functional enrichment analysis revealed that genes associated with MCC methylation in cancer were enriched for cancer driver genes and canonical cancer pathways, highlighting a significant regulatory role for MCCs in tumorigenesis. Collectively, our findings reveal the extent of DNAm conservation in great ape evolution, its association with genetic conservation, and its relevance to human diseases. These integrative analyses offer evolutionary insights into epigenetic variation and its functional implications in human populations.

genetics↗

bioRxiv2024

Complete Reference Genome and Pangenome Expand Biologically Relevant Information for Genome-Wide DNA Methylation Analysis Using Short-Read Sequencing and Array Data

BackgroundThe new complete telomere-to-telomere human genome assembly, T2T-CHM13, and the first draft of the human pangenome reference provide unique opportunities to update the reference genome for epigenetics investigations and clinical research. However, it is largely unclear how these reference genome updates may impact DNA methylation (DNAm) analysis. ResultsCompared to the previous GRCh38 assembly, we found an average increase of 7.4% (range 5.4%-9.9% across samples and sequencing methods) in the number of CpGs genome-wide using T2T-CHM13 with data from four commonly used short-read sequencing DNAm profiling methods. The increase in number of CpGs facilitated discovery of 88 new differentially methylated CpGs within cancer driver genes in an epigenome-wide association study (EWAS) of colon cancer. Further, by aligning probe sequences from the commonly used and recently released Illumina DNAm arrays to T2T-CHM13 and GRCh38, we showed the enhanced utility of T2T-CHM13 for evaluation of potential probe cross-reactivity (i.e., where probes match multiple regions) and mismatch (i.e., where probes do not perfectly match the target region), resulting in the identification of new and more reproducible sets of unambiguous probes (i.e., probes uniquely mapping to the target region) (HM450K, n = 430,719; EPIC, n = 777,491; EPICv2, n = 859,216). In EWASs of 24 cancer types, an average of 945 additional differentially methylated CpG sites were identified in the new unambiguous probe set rather than in the GRCh38-based unambiguous probe set, with enrichments in cancer driver genes and cancer signaling pathways. Moreover, the pangenome called 4.5% more CpGs on average in short-read sequencing data than T2T-CHM13 and identified cross-population and population-specific unambiguous probes in DNAm arrays, owing to its improved representation of genetic diversity. These additional CpGs were overlapped with the promoters and gene bodies of various biologically and medically relevant genes and pangenome-based unambiguous probes can potentially facilitate the discovery of DNAm alterations in more than 200 cancer driver genes in each cancer type. ConclusionsUse of T2T-CHM13 and pangenome references can benefit epigenome-wide association studies by including CpGs previously unobserved in short-read sequencing data and by improving the identification of unambiguous probes for DNAm arrays, thus expanding biologically relevant information. This study highlights the practical applications of T2T-CHM13 and pangenome for genome biology and provides a basis for expansion of epigenetics investigations.

genomics↗

bioRxiv2024

Comparison of Infinium MethylationEPIC v2.0 to v1.0 for human population epigenetics: considerations for addressing EPIC version differences in DNA methylation-based tools

The recently launched Illumina Infinium MethylationEPIC v2.0 (EPICv2), successor of MethylationEPIC v1.0 (EPICv1), retains a majority of probes in EPICv1, while expanding coverage of regulatory elements. The concordance between the two EPIC versions in DNA methylation-based tools has not yet been investigated. To address this, DNA methylation was profiled on both versions using matched blood samples across four cohorts spanning early to late adulthood. High concordance between versions at the array level but variable agreement at the individual probe level was noted. A significant contribution of EPIC version to DNA methylation variation was observed, though it was to a smaller extent compared to sample relatedness and cell type composition. Modest but significant differences in DNA methylation-based estimates between versions were observed, irrespective of the data preprocessing method used. Adjustments for EPIC version or calculation of estimates separately for each version largely mitigated these version-specific discordances. This work emphasizes the importance of accounting for EPIC version differences in research scenarios, especially in meta-analyses and longitudinal studies that require data harmonization across versions. Summary blurbOur work illustrates the importance of accounting for EPIC version in DNA methylation-based tools, specifically in research scenarios when samples profiled across different versions are harmonized.

genomics↗

bioRxiv2023

Cross-Tissue Specificity of Pediatric DNA Methylation Associated with Cumulative Family Adversity

BackgroundCumulative family adversity (cumulative FA), characterized by co-occurring stressors in a family context, may be biologically embedded through DNA methylation (DNAm) and contribute to later health outcomes. Materials & MethodsWe compared epigenome-wide DNAm associated with cumulative FA in buccal epithelial cells (BECs; n=218) and peripheral blood mononuclear cells (PBMCs; n=51) from 7-13-year-old children in Canada, accounting for sex, age, predicted cell-type proportion, and genetic ancestry. ResultsHigher levels of cumulative FA were associated with DNAm at seven sites, primarily in stress- and immune-related genes, only in PBMCs. Negative mother-child interaction contributed to this association. ConclusionsThe findings of this study suggested that PBMC DNAm can be used as a marker for biological embedding of cumulative FA.

genomics↗

bioRxiv2023

Persistent DNA methylation changes associated with prenatal NO2 exposure in a Canadian prospective birth study

BackgroundAccumulating evidence suggests prenatal air pollution exposure alters DNA methylation (DNAm), which could go on to affect long-term health. However, it remains unclear whether prenatal DNAm alterations persist through early life. Identifying DNAm changes that persist from birth into childhood would provide greater insight into the molecular mechanisms that most likely contribute to the association of prenatal air pollution exposure with health outcomes such as atopic disease. ObjectivesThis study investigated the persistence of DNAm changes associated with prenatal NO2 exposure (a surrogate measure of traffic-related air pollution) at age one to begin characterizing which DNAm changes most likely to contribute to atopic disease. MethodsWe used an atopy-enriched subset of CHILD study participants (N=145) to identify individual and regional cord blood DNAm differences associated with prenatal NO2, followed by an investigation of persistence in age one peripheral blood. As we had repeated DNAm measures, we also isolated postnatal-specific DNAm changes and examined their association with NO2 exposure in the first year of life. MANOVA tests were used to examine the association between DNAm changes associated with NO2 and child wheeze and atopy. ResultsWe identified 24 regions of altered cord blood DNAm, with several annotated to HOX genes. Two regions annotated to MPDU1 and C5orf63 were significantly associated with age one wheeze. Further, we found the effect of prenatal NO2 exposure across CpGs within all altered regions remained similar at age one. A single region of postnatal-specific DNAm annotated to HOXB6 was associated with year one NO2 and age one atopy. DiscussionRegional cord blood DNAm changes associated with prenatal NO2 exposure persist through at least the first year of life, and some of these changes are associated with age one wheeze. The early-postnatal period remains a sensitive window to DNAm perturbations that may also influence child health.

genetics↗

bioRxiv2019

Internalizing Symptoms Associate with the Pace of Epigenetic Aging in Childhood

Childhood psychiatric symptoms may be associated with advanced biological aging. This study examined whether epigenetic age acceleration (EAA) associates with internalizing and externalizing symptoms across childhood in a longitudinal cohort study. At age 6 buccal epithelial cells from 148 children (69 girls) were collected to survey genome-wide DNA methylation. EAA was estimated using the Horvath clock. Internalizing symptoms at ages 2.5 and 4 years significantly predicted higher EAA at age 6, which in turn was significantly associated with internalizing symptoms from ages 6 to 10 years. Similar trends for externalizing symptoms did not reach significance. These findings indicate advanced biological aging in relation to child mental health and may help better identify those at risk for lasting impairments associated with internalizing disorders.

genetics↗

bioRxiv2018

Maternal psychosocial risk factors and offspring gestational epigenetic age acceleration in a South African birth cohort study

Epigenetic age (EA) acceleration is associated with higher risk of chronic disease and mortality in adults. However, little is known about whether and how in utero exposures might shape gestational EA acceleration at birth. We aimed to explore associations between maternal psychosocial risk factors and offspring gestational EA acceleration at birth in a South African birth cohort study - the Drakenstein Child Health Study. Maternal psychosocial risk factors included trauma/stressor exposure; posttraumatic stress disorder (PTSD); depression, psychological distress; and alcohol/tobacco use. Offspring gestational EA acceleration at birth was calculated using an epigenetic clock previously devised for neonates. Bivariate linear regression was used to explore unadjusted associations between maternal risk factors and offspring gestational EA acceleration at birth. A stepwise regression method was then used to determine the best multivariable model for adjusted associations. Data from 272 maternal-offspring dyads were included in the current analysis. In the stepwise regression model, maternal trauma exposure ({beta}=7.92; p<0.01) or PTSD ({beta}=7.46; p<0.01) were significantly associated with offspring gestational EA acceleration at birth, controlling for ethnicity, offspring sex, head circumference at birth, maternal HIV status, and prenatal tobacco or alcohol use. In site-stratified models, these associations retained statistical significance and direction of effect. Maternal trauma exposure or PTSD may thus be associated with offspring gestational EA acceleration at birth. Given the novelty of this preliminary finding, and its potential translational relevance, further studies to delineate underlying biological pathways and to explore clinical implications of EA acceleration are warranted.

genomics↗

bioRxiv2018

Variably methylated regions in the newborn epigenome: environmental, genetic and combined influences

BackgroundEpigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. We examined the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs), defined as consecutive CpGs showing the highest variability of DNAm in 4 independent cohorts (PREDO, DCHS, UCI, MoBa, N=2,934).\n\nResultsWe used Akaikes information criterion to test which factors best explained variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E) including maternal demographic, psychosocial and metabolism related phenotypes, genotypes in cis (G), or their additive (G+E) or interaction (GxE) effects. G+E and GxE models consistently best explained variability in DNAm of VMRs across the cohorts, with G explaining the remaining sites best. VMRs best explained by G, GxE or G+E, as well as their associated functional genetic variants (predicted using deep learning algorithms), were located in distinct genomic regions, with different enrichments for transcription and enhancer marks. Genetic variants of not only G and G+E models, but also of variants in GxE models were significantly enriched in genome wide association studies (GWAS) for complex disorders.\n\nConclusionGenetic and environmental factors in combination best explain DNAm at VMRs. The CpGs best explained by G, G+E or GxE are functionally distinct. The enrichment of GxE variants in GWAS for complex disorders supports their importance for disease risk.

genetics↗

bioRxiv2018

Differences in DNA methylation of white blood cell types at birth and in adulthood reflect postnatal immune maturation and influence accuracy of cell type prediction

BackgroundDNA methylation profiling of peripheral blood leukocytes has many research applications, and characterizing the changes in DNA methylation of specific white blood cell types between newborn and adult could add insight into the maturation of the immune system. As a consequence of developmental changes, DNA methylation profiles derived from adult white blood cells are poor references for prediction of cord blood cell types from DNA methylation data. We thus examined cell-type specific differences in DNA methylation in leukocyte subsets between cord and adult blood, and assessed the impact of these differences on prediction of cell types in cord blood.\n\nResultsThough all cell types showed differences between cord and adult blood, some specific patterns stood out that reflected how the immune system changes after birth. In cord blood, lymphoid cells showed less variability than in adult, potentially demonstrating their naive status. In fact, cord CD4 and CD8 T cells were so similar that genetic effects on DNA methylation were greater than cell type effects in our analysis, and CD8 T cell frequencies remained difficult to predict, even after optimizing the library used for cord blood composition estimation. Myeloid cells showed fewer changes between cord and adult and also less variability, with monocytes showing the fewest sites of DNA methylation change between cord and adult. Finally, including nucleated red blood cells in the reference library was necessary for accurate cell type predictions in cord blood.\n\nConclusionChanges in DNA methylation with age were highly cell type specific, and those differences paralleled what is known about the maturation of the postnatal immune system.

genetics↗

bioRxiv2018

Exploring the Genetic Basis of Human Population Differences in DNA Methylation and their Causal Impact on Immune Gene Regulation

DNA methylation is influenced by both environmental and genetic factors and is increasingly thought to affect variation in complex traits and diseases. Yet, the extent of ancestry-related differences in DNA methylation, its genetic determinants, and their respective causal impact on immune gene regulation remain elusive. We report extensive population differences in DNA methylation between individuals of African and European descent -- detected in primary monocytes that were used as a model of a major innate immunity cell type. Most of these differences (~70%) were driven by DNA sequence variants nearby CpG sites (meQTLs), which account for ~60% of the variance in DNA methylation. We also identify several master regulators of DNA methylation variation in trans, including a regulatory hub nearby the transcription factor-encoding CTCF gene, which contributes markedly to ancestry-related differences in DNA methylation. Furthermore, we establish that variation in DNA methylation is associated with varying gene expression levels following mostly, but not exclusively, a canonical model of negative associations, particularly in enhancer regions. Specifically, we find that DNA methylation highly correlates with transcriptional activity of 811 and 230 genes, at the basal state and upon immune stimulation, respectively. Finally, using a Bayesian approach, we estimate causal mediation effects of DNA methylation on gene expression in ~20% of the studied cases, indicating that DNA methylation can play an active role in immune gene regulation. Using a system-level approach, our study reveals substantial ancestry-related differences in DNA methylation and provides evidence for their causal impact on immune gene regulation.

genomics↗

bioRxiv2018

A novel, biologically-informed polygenic score reveals role of mesocorticolimbic insulin receptor gene network on impulsivity and addiction

ImportanceActivation of brain insulin receptors occurs on mesocorticolimbic regions, modulating reward sensitivity and inhibitory control. Variations in the functioning of this mechanism likely associate with individual differences in the risk for related psychopathologies (attention-deficit hyperactivity disorder, addiction), an idea that agrees with the high comorbidity between insulin resistant states and psychiatric conditions. While genetic studies comprise an interesting tool to explore neurobiological mechanisms in community samples, the conventional genome-wide association studies and polygenic risk score methodologies completely ignore the fact that genes operate in networks, and code for precise biological functions in specific tissues.\n\nObjectiveWe propose a novel, biologically informed genetic score reflecting the mesocorticolimbic insulin receptor-related gene network, and investigate if it predicts dopamine-related psychopathology (impulsivity and addiction) in community samples.\n\nDesignBirth cohort (Maternal Adversity, Vulnerability and Neurodevelopment, MAVAN) and adult cohort (Study of Addiction, Genes and Environment, SAGE).\n\nSettingGeneral community.\n\nParticipants212 4-year-old children (MAVAN), and 1626 adults (SAGE).\n\nExposureThe biologically informed, mesocorticolimbic specific, insulin receptor polygenic score was created based on levels of co-expression with the insulin receptor in striatum and prefrontal cortex, and calculated in the two samples using the genotype data (Psychip/Psycharray).\n\nMain outcomechildhood impulsivity in the Information Sampling task, and risk for early addiction onset.\n\nResultsThe insulin receptor polygenic score showed improved prediction of childhood impulsivity in boys and risk for early addiction onset in males in comparison to conventional polygenic risk scores for attention-deficit hyperactivity disorder or addiction.\n\nConclusions and relevanceThis novel genomic approach reveals insulin action as a relevant biological process involved in the risk for dopamine-related psychopathology.\n\nKey pointsO_ST_ABSQuestionC_ST_ABSConsidering the modulation of mesocorticolimbic dopaminergic pathways by insulin through the action on its receptors (IR), we investigated if a novel, region specific polygenic score on the IR-related gene network (ePRS-IR) is associated with dopamine-related behaviors (impulsivity and addiction).\n\nFindingsThe ePRS-IR showed improved prediction of childhood impulsivity and risk for early addiction onset in comparison to conventional polygenic risk scores for ADHD or addiction.\n\nMeaningThis novel genomic approach reveals insulin action as a biological process involved in the risk for dopamine-related psychopathology.

neuroscience↗