Joe Burrage

• University of Exeter

The human cortex undergoes extensive epigenetic remodelling during development, although the precise temporal and cell-type-specific dynamics of DNA methylation remain incompletely understood. In this study, we profiled genome-wide DNA methylation across human cortex tissue from donors aged 6 post-conception weeks (pcw) to 108 years of age. We obse...

Recent studies on the role of epigenetics in disease have focused on DNA methylation profiled in bulk tissues limiting the detection of the cell-type affected by disease related changes. Advances in isolating homogeneous populations of cells now make it possible to identify DNA methylation differences associated with disease in specific cell-types....

The rising prevalence and legalisation of cannabis worldwide have underscored the need for a comprehensive understanding of its biological impact, particularly on mental health. Epigenetic mechanisms, specifically DNA methylation, have gained increasing recognition as vital factors in the interplay between risk factors and mental health. This study...

The second-generation antipsychotic clozapine is used as a medication for treatment-resistant schizophrenia. It has previously been associated with epigenetic changes in pre-clinical rodent models and cross-sectional studies of treatment-resistant schizophrenia. Cross-sectional studies are susceptible to confounding, however, and cannot disentangle...

Development of the human pancreas requires the precise temporal control of gene expression via epigenetic mechanisms and the binding of key transcription factors. We quantified genome-wide patterns of DNA methylation in human fetal pancreatic samples from donors aged 6 to 21 post-conception weeks. We found dramatic changes in DNA methylation across...

Background Due to interindividual variation in the cellular composition of the human cortex, it is essential that covariates that capture these differences are included in epigenome-wide association studies using bulk tissue. As experimentally derived cell counts are often unavailable, computational solutions have been adopted to estimate the propo...

The second-generation antipsychotic clozapine is used as a medication for treatment-resistant schizophrenia. It has previously been associated with epigenetic changes in pre-clinical rodent models and cross-sectional studies of treatment-resistant schizophrenia. Cross-sectional studies are susceptible to confounding, however, and cannot disentangle...

Major Depression (MD) is a leading cause of global disease burden, and both experimental and population-based studies suggest that differences in DNA methylation (DNAm) may be associated with the condition. However, previous DNAm studies have not so far been widely replicated, suggesting a need for larger meta-analysis studies. In the present study...

Development of the human pancreas requires the precise temporal control of gene expression via epigenetic mechanisms and the binding of key transcription factors. We quantified genome-wide patterns of DNA methylation in human fetal pancreatic samples from donors aged 6 to 21 post-conception weeks. We found dramatic changes in DNA methylation across...

Increased understanding of the functional complexity of the genome has led to growing recognition about the role of epigenetic/transcriptional variation in health and disease. Current analyses of the human brain, however, are limited by the use of “bulk” tissue, comprising a heterogeneous mix of different neural cell types. As epigenetic processes...

INTRODUCTION: Given the established association between DNA methylation and the pathophysiology of dementia and its plausible role as a molecular mediator of lifestyle and environment, blood-derived DNA methylation data could enable early detection of dementia risk. METHODS: In conjunction with an extensive array of machine learning techniques, we...

The rising prevalence and legalization of cannabis worldwide have underscored the need for a comprehensive understanding of its biological impact, particularly on mental health. Epigenetic mechanisms, specifically DNA methylation, have gained increasing recognition as vital factors in the interplay between risk factors and mental health. This study...

Background Due to inter-individual variation in the cellular composition of the human cortex, it is essential that covariates that capture these differences are included in epigenome-wide association studies using bulk tissue. As experimentally derived cell counts are often unavailable, computational solutions have been adopted to estimate the prop...

Abtract Studies conducted in psychotic disorders have shown that DNA-methylation (DNAm) is sensitive to the impact of Childhood Adversity (CA). However, whether it mediates the association between CA and psychosis is yet to be explored. Epigenome wide association studies (EWAS) using the Illumina Infinium-Methylation EPIC array in peripheral blood...

Background Human aggression is influenced by an interplay between genetic predisposition and experience across the life span. This interaction is thought to occur through epigenetic mechanisms, inducing differential gene expression, thereby moderating neuronal cell and circuit function, and thus shaping aggressive behaviour. Methods Genome‐wide DN...

Disadvantaged socio-economic position (SEP) is associated with greater biological age, relative to chronological age, measured by DNA methylation (positive ‘age acceleration’, AA). Social mobility has been proposed to ameliorate health inequalities. This study aimed to understand the association of social mobility with positive AA. Diagonal referen...

The majority of epigenetic epidemiology studies to date have generated genome-wide profiles from bulk tissues (e.g., whole blood) however these are vulnerable to confounding from variation in cellular composition. Proxies for cellular composition can be mathematically derived from the bulk tissue profiles using a deconvolution algorithm; however, t...

Induced pluripotent stem cells (iPSCs) and their resultant neurons are popular models for studying diseases of aging, such as Alzheimer’s disease (AD). One hallmark of aging is the decreasing length of telomeres, the repetitive, protective DNA sequences at the end of each chromosome. We have previously demonstrated that whilst epigenetic age does i...

Studies conducted in psychotic disorders have shown that DNA-methylation (DNAm) is sensitive to the impact of Childhood Adversity (CA). However, whether it mediates the association between CA and psychosis is yet to be explored. Epigenome-wide association studies (EWAS) using the Illumina Infinium-Methylation EPIC array in peripheral blood tissue f...

Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by the progressive accumulation of amyloid-beta and neurofibrillary tangles of tau in the neocortex. We profiled DNA methylation in two regions of the cortex from 631 donors, performing an epigenome-wide association study of multiple measures of AD neuropathology. We meta...

The majority of epigenetic epidemiology studies to date have generated genome-wide profiles from bulk tissues (e.g. whole blood) however these are vulnerable to confounding from variation in cellular composition. Proxies for cellular composition can be mathematically derived from the bulk tissue profiles using a deconvolution algorithm however, the...

Genome‐wide association studies (GWAS) have identified multiple genomic regions associated with schizophrenia, although many variants reside in noncoding regions characterized by high linkage disequilibrium (LD) making the elucidation of molecular mechanisms challenging. A genomic region on chromosome 10q24 has been consistently associated with sch...

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by the progressive accumulation of amyloid-beta and neurofibrillary tangles of tau in the neocortex. Utilizing extensive neuropathology data from the Brains for Dementia Research (BDR) cohort we performed the most systematic epigenome-wide association study (EWAS) of mult...

Induced pluripotent stem cells (iPSCs) and their differentiated neurons (iPSC-neurons) are a widely used cellular model in the research of the central nervous system. However, it is unknown how well they capture age-associated processes, particularly given that pluripotent cells are only present during the earliest stages of mammalian development....

In development, differentiation from a pluripotent state results in global epigenetic changes, although the extent to which this occurs in induced pluripotent stem cell-based neuronal models has not been extensively characterized. In the present study, induced pluripotent stem cell colonies (33Qn1 line) were differentiated and collected at four tim...

Most epigenome-wide association studies (EWAS) quantify DNA methylation (DNAm) in peripheral tissues such as whole blood to identify positions in the genome where variation is statistically associated with a trait or exposure. As whole blood comprises a mix of cell types, it is unclear whether trait-associated DNAm variation is specific to an indiv...

Several epigenome-wide association studies of DNA methylation have highlighted altered DNA methylation in the ANK1 gene in Alzheimer's disease (AD) brain samples. However, no study has specifically examined ANK1 histone modifications in the disease. We use chromatin immunoprecipitation-qPCR to quantify tri-methylation at histone 3 lysine 4 (H3K4me3...

We performed a systematic analysis of blood DNA methylation profiles from 4,483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell pro...

Accumulating evidence suggests that individuals exposed to victimization at key developmental stages may have different epigenetic fingerprints compared to those exposed to no/minimal stressful events, however results are inconclusive. This study aimed to strengthen causal inference regarding the impact of adolescent victimization on the epigenome...

Human DNA methylation data have been used to develop biomarkers of ageing, referred to as ‘epigenetic clocks’, which have been widely used to identify differences between chronological age and biological age in health and disease including neurodegeneration, dementia and other brain phenotypes. Existing DNA methylation clocks have been shown to be...

Induced pluripotent stem cells (iPSCs) and their differentiated neurons (iPSC-neurons) are a widely used cellular model in the research of the central nervous system. However, it is unknown how well they capture age-associated processes, particularly given that pluripotent cells are only present during the early stages of mammalian development. Epi...

Induced pluripotent stem cells (iPSCs) and their differentiated neurons (iPSC-neurons) are a widely used cellular model in the research of the central nervous system. However, it is unknown how well they capture age-associated processes, particularly given that pluripotent cells are only present during the early stages of mammalian development. Epi...

Background Most epigenome-wide association studies (EWAS) quantify DNA methylation (DNAm) in peripheral tissues such as whole blood to identify positions in the genome where variation is statistically associated with a trait or exposure. As whole blood comprises a mix of cell types, it is unclear whether trait-associated variation is specific to an...

Human DNA-methylation data have been used to develop biomarkers of ageing - referred to epigenetic clocks - that have been widely used to identify differences between chronological age and biological age in health and disease including neurodegeneration, dementia and other brain phenotypes. Existing DNA methylation clocks are highly accurate in blo...

Objective: Psychosis - a complex and heterogeneous neuropsychiatric condition characterized by hallucinations and delusions - is a common feature of schizophrenia. There is evidence for altered DNA methylation (DNAm) associated with schizophrenia in both brain and peripheral tissues. We aimed to undertake a systematic analysis of variable DNAm asso...

Surgery is an invasive procedure evoking acute inflammatory and immune responses that can influence risk for postoperative complications including cognitive dysfunction and delirium. Although the specific mechanisms driving these responses have not been well-characterized, they are hypothesized to involve the epigenetic regulation of gene expressio...

Suicide is the second leading cause of death globally among young people representing a significant global health burden. Although the molecular correlates of suicide remains poorly understood, it has been hypothesised that epigenomic processes may play a role. The objective of this study was to identify suicide-associated DNA methylation changes i...

Background: The Horvath epigenetic clock is widely used. It predicts age quite well from 353 CpG sites in the DNA methylation profile in unknown samples and has been used to calculate "age acceleration" in various tissues and environments. Results: The model systematically underestimates age in tissues from older people. This is seen in all exam...

Background: Surgery is an invasive procedure evoking acute inflammatory and immune responses that are believed to mediate risk for postoperative complications including cognitive dysfunction and delirium. Although the specific mechanisms driving these responses have not been well-characterized, they are hypothesized to involve the epigenetic regula...

Schizophrenia (SCZ) is associated with high mortality. DNA methylation levels vary over the life course, and pre-selected combinations of methylation array probes can be used to estimate “methylation age” (mAge). mAge correlates highly with chronological age but when it differs, termed mAge acceleration, it has been previously associated with all-c...

Background Alzheimer’s disease is a progressive neurodegenerative disorder that is hypothesized to involve epigenetic dysfunction. Previous studies of DNA modifications in Alzheimer’s disease have been unable to distinguish between DNA methylation and DNA hydroxymethylation. DNA hydroxymethylation has been shown to be enriched in the human brain, a...

Background Schizophrenia is a severe, highly heritable, neuropsychiatric disorder characterized by episodic psychosis and altered cognitive function. Despite recent successes in identifying genetic variants robustly associated with susceptibility, there remains uncertainty about the causal genes involved in disease pathogenesis and how their functi...

Background Schizophrenia is a neuropsychiatric disorder with a prevalence of 1%, characterised by episodes of psychosis and an alteration in cognitive function. The aetiology of Schizophrenia is still largely unknown but evidence suggests an underlying neurodevelopmental aspect despite onset occurring in adulthood as well as a considerable genetic...

Recent epigenome-wide association studies in Alzheimer’s disease have highlighted consistent robust neuropathology-associated DNA hypermethylation of the Ankyrin 1 (ANK1) gene in the cortex. The extent to which altered ANK1 DNA methylation is also associated with other neurodegenerative diseases is not currently known. In the current study, we used...

Characterizing the complex relationship between genetic, epigenetic, and transcriptomic variation has the potential to increase understanding about the mechanisms underpinning health and disease phenotypes. We undertook a comprehensive analysis of common genetic variation on DNA methylation (DNAm) by using the Illumina EPIC array to profile samples...

Motivation The datasets generated by DNA methylation analyses are getting bigger. With the release of the HumanMethylationEPIC micro-array and datasets containing thousands of samples, analyses of these large datasets using R are becoming impractical due to large memory requirements. As a result there is an increasing need for computationally effic...

Variation in DNA methylation is being increasingly associated with health and disease outcomes. Although DNA methylation is hypothesized to be a mechanism by which both genetic and non-genetic factors can influence the regulation of gene expression, little is known about the extent to which DNA methylation at specific sites is influenced by heritab...

Sites at which DNA methylation is strongly influenced by additive genetic effects are often associated with mQTL variation. (XLSX)

Estimated contribution of additive genetic and environmental influences to estimated age and blood cell proportion estimates derived from DNA methylation data. (PDF)

Estimates of additive genetic and environmental effects on levels of DNA methylation at 176 differentially methylated positions associated with BMI. (PDF)

The proportion of variance in DNA methylation explained by additive genetic effects (A), shared environmental effects (C) and unshared (or unique) environmental effects (E) across autosomal sites after adjusting for cellular composition. Panels a-c show density distributions for estimates of A, C, and E across all 420,857 autosomal DNA methylation...

The contribution of genetic and environmental influences on DNA methylation at autosomal sites differs as a function of the variability in DNA methylation level. Shown are estimates of additive genetic effects (A), shared environmental effects (C) and non-shared (or unique) environmental effects (E) plotted as a function of the variability in DNA m...

The contribution of genetic and environmental influences on DNA methylation at autosomal sites annotated to specific genic features. Shown is a density plot of estimates of A) additive genetic, B) shared environmental, and C) non-shared environmental influences on DNA methylation at autosomal sites stratified by gene feature annotation. (PDF)

There is a strong correlation between the extent to which inter-individual variation in DNA methylation co-varies across tissues with the influence of additive genetic variation on DNA methylation. Scatterplot of the amount of variance in DNA methylation explained by additive genetic effects (y-axis) against the level of blood-brain covariation in...

The contribution of genetic and environmental influences on DNA methylation at sites on the X-chromosome differs as a function of the variability in DNA methylation level, with notable differences between males and females. Shown are estimates of additive genetic effects (A), shared environmental effects (C) and unshared (or unique) environmental e...

The contribution of genetic and environmental influences on DNA methylation at sites on the X-chromosome is modestly correlated between males and females. Shown are scatterplots of the A) additive genetic, B) shared environmental, and C) non-shared environmental contribution to DNA methylation for sites on the X chromosome in female (x-axis) and ma...

The extent to which DNA methylation levels at sites annotated to specific genic features and CpG island features are enriched for the influence of additive genetic or environmental factors. (PDF)

Estimates of additive genetic and environmental influences on levels of DNA methylation at the 97 differentially methylated positions (P < 1x10-7) associated with tobacco smoking. (PDF)

Genome-wide patterns of DNA methylation are highly correlated between siblings, with significantly higher average similarity in monozygotic (MZ) twin-pairs than dizygotic (DZ) twin-pairs. Shown are violin plots for the average correlations of DNA methylation within each sibling pair (stratified by relatedness) averaged across A) all autosomal DNA m...

The contribution of genetic and environmental influences on DNA methylation is not strongly influenced by blood cell heterogeneity. Scatterplots of additive genetic effects (A), shared environmental effects (C) and non-shared (or unique) environmental effects (E) for all autosomal DNA methylation sites (n = 420,857), comparing DNA methylation data...

The influence of genetic and environmental factors on DNAm varies across regulatory features and chromatin states. Violin plots showing the proportion of variance explained by additive genetic factors (A; red), common environmental factors (C; green), and unique environmental factors (E; blue) where DNA methylation sites are stratified by their loc...

The contribution of genetic and environmental influences on DNA methylation at sites on the X-chromosome differs as a function of mean DNA methylation with notable differences between males and females. Shown for A) males and B) females are estimates of additive genetic effects (A), shared environmental effects (C) and non-shared (or unique) enviro...

Twin-pair correlations for estimates of DNA methylation age and blood cell composition derived from DNA methylation data. Shown are co-twin correlations for A) DNA methylation age, B) estimated plasma blast abundance, C) estimated CD8+CD28-CD45RA- T cell abundance, D) estimated naïve CD8 T cell abundance, E) estimated naive CD4 T cell abundance (al...

Examples of DNA methylation sites associated with smoking that are influenced by both additive genetic and environmental factors. Scatterplot of DNA methylation values at cg05575921 for A) monozygotic (MZ) twin pairs and B) dizygotic (DZ) twin pairs, and cg26703534 for C) MZ twin pairs and D) DZ twin pairs. Colors depict the concordance for current...

Sites with intermediate levels of DNAm are associated with larger DNA methylation trait quantitative trait loci (mQTL) effects. Line graph of the moving mean mQTL effect on DNA methylation (measured as the % DNA methylation change per allele; y-axis) as a function of mean DNA methylation (%; x-axis). The gray area indicates the 95% interquantile ra...

Example of a site at which DNA methylation is highly heritable (A = 96.9%) and associated with genotype at a DNA methylation trait quantitative trait loci (mQTL). Panel A) shows a boxplot of the association between DNA methylation at cg02573566 and genotype at rs11548104 (P = 5.95x10-179). Panel B) shows the correlation in DNA methylation at cg0257...

Sex differences for the proportion of variance in DNA methylation explained by additive genetic and environmental influences for sites on the X chromosome. Shown are density plots of estimates of additive genetic effects (A), shared environmental effects (C) and non-shared (or unique) environmental effects (E) stratified by sex (red = females, gree...

An example of a site (cg00195237) on the X chromosome at which DNA methylation is strongly influenced by additive genetic factors in females (A = 56.8%) but not males (A = 6.70%). The scatterplots show DNA methylation values in A) female MZ, B) female DZ, D) male MZ, and E) male DZ twin pairs. Each point represents an individual twin-pair. At this...

The proportion of variance in DNA methylation explained by additive genetic and environmental influences for sites on the X chromosome. Shown are density plots of estimates of additive genetic effects (A), shared environmental effects (C) and non-shared (or unique) environmental effects (E) stratified by sex and within females stratified by sites l...

DNA methylation at sites associated with body mass index (BMI) is influenced by additive genetic factors. Density plots for estimates of A) additive genetic effects (A), B) shared environmental effects (C), and C) non-shared environmental effects (E) at 176 differentially methylated positions (DMPs) recently associated with BMI (green)[47]. (PDF)

There is considerable overlap between the set of autosomal DNA methylation sites defined as being ‘variable’ and having intermediate levels of DNA methylation. (TIFF)

The contribution of genetic and environmental influences on DNA methylation at autosomal sites are not evenly distributed across genic regions. Shown is a line graph depicting the extent to which variation in DNA methylation is influenced by genetic and environmental factors across a canonical gene region. Genetic influences on DNA methylation are...

The contribution of genetic and environmental influences on DNA methylation at autosomal sites annotated to specific CpG island features. Shown is a density plot of estimates of A) additive genetic, B) shared environmental, and C) non-shared environmental influences on DNA methylation at sites stratified by CpG island feature annotation. (PDF)

Sites at which DNA methylation is more strongly influenced by genetic factors are more likely to be associated with genotype at a mQTL. Shown is a line graph of the percentage of DNA methylation sites significantly associated with an mQTL variant in our whole blood dataset[29] (y-axis) as a function of increasing cut-offs for estimates of additive...

Distribution of DNA methylation levels across sites on the X chromosome. A) Shown is a density plot of DNA methylation across sites on the X chromosome stratified by sex. B) Shown is a scatterplot comparing mean DNA methylation at sites across the X-chromosome in females (x-axis) and males (y-axis). (PDF)

An example of a site (cg19782749) on the X chromosome at which DNA methylation is strongly influenced by additive genetic factors in males (A = 58.9%) but not females (A = 3.76%). The scatterplots show DNA methylation values in A) female MZ, B) female DZ, D) male MZ, and E) male DZ twin pairs. Each point represents an individual twin-pair. At this...

The contribution of additive genetic and environmental influences to age and blood cell-count estimates derived from the DNA methylation data. AAR = age acceleration residual derived from the DNA methylation age clock. (PDF)

Effect sizes at DNA methylation sites associated with tobacco smoking in the E-risk cohort overlap with those previously identified in adult cohorts. A) The mean difference between current smokers and never smokers from the E-risk cohort (x-axis) against a similar study in adults taken from Joehanes et al[44] (y-axis). B) Shown is the correlation o...

Accelerated DNA methylation age is linked to all-cause mortality and environmental factors, but studies of associations with socioeconomic position are limited. Studies generally use small selected samples, and it is unclear how findings with two commonly used methylation age calculations (Horvath and Hannum) translate to general population samples...

Heterozygous mutation of the transcription factor HNF1B is the most common cause of monogenetic developmental renal disease. Disease-associated mutations fall into two categories: HNF1B intragenic mutations and a 1.3 Mb deletion at chromosome 17q12. An increase in neurodevelopmental disorders has been observed in individuals harbouring the 17q12 de...