Common epigenetic variation in a European population of mentally healthy young adults (original) (raw)
Related papers
Patterns of methylation heritability in a genome-wide analysis of four brain regions
Nucleic Acids Research, 2013
DNA methylation has been implicated in a number of diseases and other phenotypes. It is, therefore, of interest to identify and understand the genetic determinants of methylation and epigenomic variation. We investigated the extent to which genetic variation in cis-DNA sequence explains variation in CpG dinucleotide methylation in publicly available data for four brain regions from unrelated individuals, finding that 3-4% of CpG loci assayed were heritable, with a mean estimated narrow-sense heritability of 30% over the heritable loci. Over all loci, the mean estimated heritability was 3%, as compared with a recent twin-based study reporting 18%. Heritable loci were enriched for open chromatin regions and binding sites of CTCF, an influential regulator of transcription and chromatin architecture. Additionally, heritable loci were proximal to genes enriched in several known pathways, suggesting a possible functional role for these loci. Our estimates of heritability are conservative, and we suspect that the number of identified heritable loci will increase as the methylome is assayed across a broader range of cell types and the density of the tested loci is increased. Finally, we show that the number of heritable loci depends on the window size parameter commonly used to identify candidate cis-acting single-nucleotide polymorphism variants.
2017
Epigenetic modifications confer stable transcriptional patterns in the brain, and both normal and abnormal brain function involve specialized brain regions, yet little is known about brain region-specific epigenetic differences. Here, we compared prefrontal cortex, anterior cingulate gyrus, hippocampus and nucleus accumbens from 6 individuals, performing whole genome bisulfite sequencing for DNA methylation. In addition, we have performed ATAC-seq for chromatin accessibility, and RNA-seq for gene expression in the nucleus accumbens and prefrontal cortex from 6 additional individuals. We found substantial neuron- and brain region-specific differences in both DNA methylation and chromatin accessibility which were largely non-overlapping, and were greatest between nucleus accumbens and the other regions. In contrast, glial methylation and chromatin were relatively homogeneous across brain regions, although neuron/glia ratios varied greatly, demonstrating the necessity for cellular frac...
Association of DNA Methylation Differences With Schizophrenia in an Epigenome-Wide Association Study
JAMA psychiatry, 2016
DNA methylation may play an important role in schizophrenia (SZ), either directly as a mechanism of pathogenesis or as a biomarker of risk. To scan genome-wide DNA methylation data to identify differentially methylated CpGs between SZ cases and controls. Epigenome-wide association study begun in 2008 using DNA methylation levels of 456 513 CpG loci measured on the Infinium HumanMethylation450 array (Illumina) in a consortium of case-control studies for initial discovery and in an independent replication set. Primary analyses used general linear regression, adjusting for age, sex, race/ethnicity, smoking, batch, and cell type heterogeneity. The discovery set contained 689 SZ cases and 645 controls (n = 1334), from 3 multisite consortia: the Consortium on the Genetics of Endophenotypes in Schizophrenia, the Project among African-Americans To Explore Risks for Schizophrenia, and the Multiplex Multigenerational Family Study of Schizophrenia. The replication set contained 247 SZ cases an...
Characterization of cross-tissue genetic-epigenetic effects and their patterns in schizophrenia
Genome medicine, 2018
One of the major challenges in current psychiatric epigenetic studies is the tissue specificity of epigenetic changes since access to brain samples is limited. Peripheral tissues have been studied as surrogates but the knowledge of cross-tissue genetic-epigenetic characteristics remains largely unknown. In this work, we conducted a comprehensive investigation of genetic influence on DNA methylation across brain and peripheral tissues with the aim to characterize cross-tissue genetic-epigenetic effects and their roles in the pathophysiology of psychiatric disorders. Genome-wide methylation quantitative trait loci (meQTLs) from brain prefrontal cortex, whole blood, and saliva were identified separately and compared. Focusing on cis-acting effects, we tested the enrichment of cross-tissue meQTLs among cross-tissue expression QTLs and genetic risk loci of various diseases, including major psychiatric disorders. CpGs targeted by cross-tissue meQTLs were also tested for genomic distributi...
Genome Biology, 2012
Background: Dynamic changes to the epigenome play a critical role in establishing and maintaining cellular phenotype during differentiation, but little is known about the normal methylomic differences that occur between functionally distinct areas of the brain. We characterized intra-and inter-individual methylomic variation across whole blood and multiple regions of the brain from multiple donors. Results: Distinct tissue-specific patterns of DNA methylation were identified, with a highly significant overrepresentation of tissue-specific differentially methylated regions (TS-DMRs) observed at intragenic CpG islands and low CG density promoters. A large proportion of TS-DMRs were located near genes that are differentially expressed across brain regions. TS-DMRs were significantly enriched near genes involved in functional pathways related to neurodevelopment and neuronal differentiation, including BDNF, BMP4, CACNA1A, CACA1AF, EOMES, NGFR, NUMBL, PCDH9, SLIT1, SLITRK1 and SHANK3. Although between-tissue variation in DNA methylation was found to greatly exceed between-individual differences within any one tissue, we found that some inter-individual variation was reflected across brain and blood, indicating that peripheral tissues may have some utility in epidemiological studies of complex neurobiological phenotypes.
PLOS Genetics
While population studies have resulted in detailed maps of genetic variation in humans, to date there are few robust maps of epigenetic variation. We identified sites containing clusters of CpGs with high inter-individual epigenetic variation, termed Variably Methylated Regions (VMRs) in five purified cell types. We observed that VMRs occur preferentially at enhancers and 3' UTRs. While the majority of VMRs have high heritability, a subset of VMRs within the genome show highly correlated variation in trans, forming co-regulated networks that have low heritability, differ between cell types and are enriched for specific transcription factor binding sites and biological pathways of functional relevance to each tissue. For example, in T cells we defined a network of 95 co-regulated VMRs enriched for genes with roles in T-cell activation; in fibroblasts a network of 34 co-regulated VMRs comprising all four HOX gene clusters enriched for control of tissue growth; and in neurons a network of 18 VMRs enriched for roles in synaptic signaling. By culturing genetically-identical fibroblasts under varying environmental conditions, we experimentally demonstrated that some VMR networks are responsive to the environment, with methylation levels at these loci changing in a coordinated fashion in trans dependent on cellular growth. Intriguingly these environmentally-responsive VMRs showed a strong enrichment for imprinted loci (p<10 −80), suggesting that these are particularly sensitive to environmental conditions. Our study provides a detailed map of common epigenetic variation in the human genome, showing that both genetic and environmental causes underlie this variation.
Genome biology, 2016
Schizophrenia is a highly heritable, neuropsychiatric disorder characterized by episodic psychosis and altered cognitive function. Despite success in identifying genetic variants associated with schizophrenia, there remains uncertainty about the causal genes involved in disease pathogenesis and how their function is regulated. We performed a multi-stage epigenome-wide association study, quantifying genome-wide patterns of DNA methylation in a total of 1714 individuals from three independent sample cohorts. We have identified multiple differentially methylated positions and regions consistently associated with schizophrenia across the three cohorts; these effects are independent of important confounders such as smoking. We also show that epigenetic variation at multiple loci across the genome contributes to the polygenic nature of schizophrenia. Finally, we show how DNA methylation quantitative trait loci in combination with Bayesian co-localization analyses can be used to annotate e...
Background: Psychiatric symptomatology during late childhood and early adolescence tends to persist later in life. In the present longitudinal study, we aimed to identify changes in genome-wide DNA methylation patterns that were associated with the emergence of psychopathology in youths from the Brazilian High-Risk Cohort (HRC) for psychiatric disorders. Moreover, for the differentially methylated genes, we verified whether differences in DNA methylation corresponded to differences in mRNA transcript levels by analyzing the gene expression levels in the blood and by correlating the variation of DNA methylation values with the variation of mRNA levels of the same individuals. Finally, we examined whether the variations in DNA methylation and mRNA levels were correlated with psychopathology measurements over time. Methods: We selected 24 youths from the HRC who presented with an increase in dimensional psychopathology at a 3-year follow-up as measured by the Child Behavior Checklist (CBCL). The DNA methylation and gene expression data were compared in peripheral blood samples (n = 48) obtained from the 24 youths before and after developing psychopathology. We implemented a methodological framework to reduce the effect of chronological age on DNA methylation using an independent population of 140 youths and the effect of puberty using data from the literature.
Human molecular genetics, 2017
Genetic association studies provide evidence for a substantial polygenic component to schizophrenia, although the neurobiological mechanisms underlying the disorder remain largely undefined. Building on recent studies supporting a role for developmentally regulated epigenetic variation in the molecular aetiology of schizophrenia, this study aimed to identify epigenetic variation associated with both a diagnosis of schizophrenia and elevated polygenic risk burden for the disease across multiple brain regions. Genome-wide DNA methylation was quantified in 262 post-mortem brain samples, representing tissue from four brain regions (prefrontal cortex, striatum, hippocampus and cerebellum) from 41 schizophrenia patients and 47 controls. We identified multiple disease-associated and polygenic risk score-associated differentially methylated positions and regions, which are not enriched in genomic regions identified in genetic studies of schizophrenia and do not reflect direct genetic effect...
Genome-Wide Methylation Profiling of Schizophrenia
Balkan Journal of Medical Genetics, 2014
Schizophrenia is one of the major psychiatric disorders. It is a disorder of complex inheritance, involving both heritable and environmental factors. DNA methylation is an inheritable epigenetic modification that stably alters gene expression. We reasoned that genetic modifications that are a result of environmental stimuli could also make a contribution. We have performed 26 high-resolution genomewide methylation array analyses to determine the methylation status of 27,627 CpG islands and compared the data between patients and healthy controls. Methylation profiles of DNAs were analyzed in six pools: 220 schizophrenia patients; 220 age-matched healthy controls; 110 female schizophrenia patients; 110 age-matched healthy females; 110 male schizophrenia patients; 110 age-matched healthy males. We also investigated the methylation status of 20 individual patient DNA samples (eight females and 12 males. We found significant differences in the methylation profile between schizophrenia an...