DNA methylation as a potential mediator of environmental risks in the development of childhood acute lymphoblastic leukemia

5-year survival rate for childhood acute lymphoblastic leukemia (ALL) has risen to approximately 90%, yet the causal disease pathway is still poorly understood. Evidence suggests multiple 'hits' are required for disease progression; an initial genetic abnormality followed by additional secondary 'hits'. It is plausible that environmental influences may trigger these secondary hits, and with the peak incidence of diagnosis between 2 and 5 years of age, early life exposures are likely to be key. DNA methylation can be modified by many environmental exposures and is dramatically altered in cancers, including childhood ALL. Here we explore the potential that DNA methylation may be involved in the causal pathway toward disease by acting as a mediator between established environmental factors and childhood ALL development

Multi-omics integration reveals molecular networks and regulators of psoriasis.

BackgroundPsoriasis is a complex multi-factorial disease, involving both genetic susceptibilities and environmental triggers. Genome-wide association studies (GWAS) and epigenome-wide association studies (EWAS) have been carried out to identify genetic and epigenetic variants that are associated with psoriasis. However, these loci cannot fully explain the disease pathogenesis.MethodsTo achieve a comprehensive mechanistic understanding of psoriasis, we conducted a systems biology study, integrating multi-omics datasets including GWAS, EWAS, tissue-specific transcriptome, expression quantitative trait loci (eQTLs), gene networks, and biological pathways to identify the key genes, processes, and networks that are genetically and epigenetically associated with psoriasis risk.ResultsThis integrative genomics study identified both well-characterized (e.g., the IL17 pathway in both GWAS and EWAS) and novel biological processes (e.g., the branched chain amino acid catabolism process in GWAS and the platelet and coagulation pathway in EWAS) involved in psoriasis. Finally, by utilizing tissue-specific gene regulatory networks, we unraveled the interactions among the psoriasis-associated genes and pathways in a tissue-specific manner and detected potential key regulatory genes in the psoriasis networks.ConclusionsThe integration and convergence of multi-omics signals provide deeper and comprehensive insights into the biological mechanisms associated with psoriasis susceptibility

Traumatic Brain Injury Induces Genome-Wide Transcriptomic, Methylomic, and Network Perturbations in Brain and Blood Predicting Neurological Disorders.

The complexity of the traumatic brain injury (TBI) pathology, particularly concussive injury, is a serious obstacle for diagnosis, treatment, and long-term prognosis. Here we utilize modern systems biology in a rodent model of concussive injury to gain a thorough view of the impact of TBI on fundamental aspects of gene regulation, which have the potential to drive or alter the course of the TBI pathology. TBI perturbed epigenomic programming, transcriptional activities (expression level and alternative splicing), and the organization of genes in networks centered around genes such as Anax2, Ogn, and Fmod. Transcriptomic signatures in the hippocampus are involved in neuronal signaling, metabolism, inflammation, and blood function, and they overlap with those in leukocytes from peripheral blood. The homology between genomic signatures from blood and brain elicited by TBI provides proof of concept information for development of biomarkers of TBI based on composite genomic patterns. By intersecting with human genome-wide association studies, many TBI signature genes and network regulators identified in our rodent model were causally associated with brain disorders with relevant link to TBI. The overall results show that concussive brain injury reprograms genes which could lead to predisposition to neurological and psychiatric disorders, and that genomic information from peripheral leukocytes has the potential to predict TBI pathogenesis in the brain

Epigenetic Biomarkers for Environmental Exposures and Personalized Breast Cancer Prevention.

Environmental and lifestyle factors are believed to account for >80% of breast cancers; however, it is not well understood how and when these factors affect risk and which exposed individuals will actually develop the disease. While alcohol consumption, obesity, and hormone therapy are some known risk factors for breast cancer, other exposures associated with breast cancer risk have not yet been identified or well characterized. In this paper, it is proposed that the identification of blood epigenetic markers for personal, in utero, and ancestral environmental exposures can help researchers better understand known and potential relationships between exposures and breast cancer risk and may enable personalized prevention strategies

A DNA Methylation Biomarker of Alcohol Consumption

The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal=13 317; 54% women; mean age across cohorts 42–76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90–0.99) for current heavy alcohol intake (≥ 42 g per day in men and ≥ 28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P \u3c 1 × 10−7. Analysis of the monocyte-derived DNA (n = 1251) identified 62 alcohol-related CpGs at P \u3c 1 × 10-7. In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the γ-Aminobutyric acid-A receptor delta and γ-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption

Impact of Long‐Term Alcohol Consumption and Relapse on Genome‐Wide DNA Methylation Changes in Alcohol‐Dependent Subjects: A Longitudinal Study

Background: Genetic factors play an important role in the development and maintenance of alcohol use disorder (AUD). Significant and widespread differences in methylation levels of multiple regions within the genome have been reported between AUD patients and healthy controls in large epigenome-wide association studies (EWASs). Also, within patient populations, methylation changes over time (both during and after withdrawal) have been identified as sensitive indicators for disease activity. The detection of changes in methylation levels is a powerful tool to further explore and understand the biological correlates and underpinnings of AUD. Although there is strong and convincing evidence for differences in methylation of various sites between AUD patients and controls, only few studies assessed changes within patients over longer periods of time while taking into account alcohol consumption, relapse, and abstinence. So far, the longest period assessed as a within-subject design using EWASs was 4 weeks. Methods: Here, we investigated changes in whole-genome methylation levels within a sample of 69 detoxified AUD patients over a period as long as 12 months for the first time, comparing patients that relapsed within the follow-up period to those that remained abstinent. Results: Whole-genome methylation patterns of individual CpG sites over time did not differ between abstinent and relapsing patients. However, there was a negative association between global mean methylation at the 12-month follow-up and alcohol consumption within our sample. Conclusion: Although the present study represents the largest study of methylation levels in a sample of AUD patients with a follow-up period of 1 year and accounting for alcohol consumption and relapse to date, the sample size might still not be large enough to detect genome-wide significant effects. Therefore, large-scale, long-term studies with AUD subjects are needed to determine the utility of DNA methylation for the assessment and monitoring of persons with alcohol use disorders

DNA methylation pattern for insufficient sleep and recovery

Chronic insufficient sleep affects basic physiological processes and increases risk for various mental and somatic disorders. Despite the growing number of omics-studies, sleep laboratory studies conducted in human samples, as well as various experiments in animals, the biological mechanisms underlying the health consequences of curtailed sleep are not fully understood. This thesis was inspired by the hypothesis that the consequences of sleep loss may be reflected as changes in the epigenetic processes, with DNA methylation (DNAm) selected as the most feasible to study. The aim of this thesis was to elucidate biological pathways associated with chronic insufficient sleep, as well as to explore how transient and reversible DNAm changes triggered by sleep loss are. In the first study, a cross sectional genome-wide DNAm analysis (Epigenome-wide Association Analysis, EWAS) was performed in relation to self-reported insufficient sleep in individuals from a population-based sample and in relation to insufficient sleep (shift work disorder) among shift-workers from an occupational cohort. No genome-wide significant differences in DNAm were observed in cases versus controls. The study revealed that insufficient sleep was accompanied by the loss of methylation and DNAm alterations in genes enriched in nervous system development pathway. The karyoplot evidenced for several clusters of CpGs on various chromosomes, including a cluster of 12 CpGs on chromosome 17. The genes corresponding to these CpGs were previously associated with a rare genetic condition accompanied by disturbed sleep and inverted circadian rhythm. The second study examined dynamic DNAm changes in relation to recovery from a shift work disorder in the occupational cohort of shift workers across the genome. The results indicated that recovery during vacation leads to the restoration of DNAm and specifically affects genes involved in the activity of N-methyl-d-aspartate (NMDA) glutamate receptors. These findings provide evidence for the dynamic nature of human methylome and suggest CpG sites in genes Glutamate Ionotropic Receptor NMDA Type Subunit 2C (GRIN2C), cAMP Responsive Element Binding Protein 1 (CREB1), and Calcium/calmodulin Dependent Protein Kinase II Beta (CAMK2B) as putative indicators of recovery in a shift worker with shift work disorder. In the third study, we studied the effect of depressed sleep on DNAm in a sample of adolescents with comorbid depression and insomnia as compared to healthy controls. No genome-wide significant differences in DNAm appeared in cases versus controls. However, the top findings of DNAm analyses were enriched in the synaptic long-term depression (LTD) pathway, emphasizing the role of sleep in synaptic plasticity and the widespread physiological consequences of disturbed sleep. Based on these findings, it can be concluded that chronic insufficient sleep is associated with a specific DNAm pattern in blood leukocytes, evidencing for the systemic physiological wide-spread consequences of curtailed sleep. Some of these specific DNAm alterations appeared to be reversible, once individuals restored sleep during two weeks of vacation. Altogether, this thesis contributes to an understanding of the changes triggered by sleep loss in a highly complex and dynamic regulatory mechanism, human DNA methylome.Univaje on terveydelle haitallista ja lisää pitkäaikaisena psykiatristen ja somaattisten sairauksien riskiä. Univajeen patofysiologisia mekanismeja on tutkittu erilaisissa tutkimusasetelmissa ja kokeellisissa malleissa, mutta sen aiheuttamien terveyshaittojen taustalla olevat molekyylibiologiset mekanismit ovat vielä pitkälti tuntemattomia. Tämän väitöskirjan kantavana hypoteesina oli, että univaje johtaa epigeneettisten prosessien – erityisesti DNA:n metylaation – muutoksiin. Selvitimme ensimmäisessä osatyössä riittämättömän unen ja veren valkosolujen DNA-metylaation välisiä yhteyksiä yleisväestössä ja vuorotyötä tekevillä. Tutkimus osoitti, että riittämättömään yöuneen liittyy matalampia DNA:n metylaatiotasoja ja metylaatiotasojen muutoksia hermoston kehitykseen ja toimintaan liittyvissä geeneissä. Osa poikkeavasti metyloituneista geeneistä on liitetty aiemmin sellaisiin harvinaisiin perinnöllisiin sairauksiin, joiden oireina on unen ja vuorokausirytmin häiriöitä. Tarkastelimme toisessa osatyössä valkosolujen DNA:n metylaation dynaamisia muutoksia vuorotyötä tekevillä työjakson aikana sekä vuosiloman jälkeen. Tulokset osoittivat, että vuorotyö-unihäiriöstä kärsivillä oireiden väistyminen ja palautuminen lomajakson aikana johti myös DNA-metylaatiomuutosten palautumiseen. Työssä osoitettiin DNA:n metylaation dynaaminen luonne erityisesti NMDA-glutamaattireseptorien kohdalla ja siten niiden mahdollinen merkitys vuorotyöunihäiriön synty- ja palautumismekanismeissa. Selvitimme kolmannessa tutkimuksessa DNA-metylaatiomuutoksia nuorilla masennuksesta ja unettomuudesta kärsivillä potilailla. Polkuanalyysit antoivat viitteitä siitä, että muistimekanismeihin liittyvän synaptisen polun geenien metylaatiotasot olivat potilailla poikkeavat terveisiin verrokkeihin verrattuna. Löydös sopii hyvin siihen, että riittävä yöuni on tärkeää muistin ja oppimisen toiminnan kannalta. Tulosten perusteella voidaan päätellä, että pitkäaikaiseen univajeeseen liittyy veren valkosolujen DNA-metylaation muutoksia, jotka voivat välittää univajeeseen liittyviä laajoja fysiologisia seuraamuksia. Osa muutoksista oli palautuvia lepojakson jälkeen. Kaiken kaikkiaan väitöskirjatutkimus lisää osaltaan ymmärrystä siitä, kuinka univajeen fysiologiset vaikutukset välittyvät epigeneettisten mekanismien ja erityisesti DNA:n metylaation kautta

Epigenome-wide association study of alcohol consumption in N = 8161 individuals and relevance to alcohol use disorder pathophysiology:identification of the cystine/glutamate transporter SLC7A11 as a top target

Alcohol misuse is common in many societies worldwide and is associated with extensive morbidity and mortality, often leading to alcohol use disorders (AUD) and alcohol-related end-organ damage. The underlying mechanisms contributing to the development of AUD are largely unknown; however, growing evidence suggests that alcohol consumption is strongly associated with alterations in DNA methylation. Identification of alcohol-associated methylomic variation might provide novel insights into pathophysiology and novel treatment targets for AUD. Here we performed the largest single-cohort epigenome-wide association study (EWAS) of alcohol consumption to date (N = 8161) and cross-validated findings in AUD populations with relevant endophenotypes, as well as alcohol-related animal models. Results showed 2504 CpGs significantly associated with alcohol consumption (Bonferroni p value < 6.8 × 10(−8)) with the five leading probes located in SLC7A11 (p = 7.75 × 10(−108)), JDP2 (p = 1.44 × 10(−56)), GAS5 (p = 2.71 × 10(−47)), TRA2B (p = 3.54 × 10(−42)), and SLC43A1 (p = 1.18 × 10(−40)). Genes annotated to associated CpG sites are implicated in liver and brain function, the cellular response to alcohol and alcohol-associated diseases, including hypertension and Alzheimer’s disease. Two-sample Mendelian randomization confirmed the causal relationship of consumption on AUD risk (inverse variance weighted (IVW) p = 5.37 × 10(−09)). A methylation-based predictor of alcohol consumption was able to discriminate AUD cases in two independent cohorts (p = 6.32 × 10(−38) and p = 5.41 × 10(−14)). The top EWAS probe cg06690548, located in the cystine/glutamate transporter SLC7A11, was replicated in an independent cohort of AUD and control participants (N = 615) and showed strong hypomethylation in AUD (p < 10(−17)). Decreased CpG methylation at this probe was consistently associated with clinical measures including increased heavy drinking days (p < 10(−4)), increased liver function enzymes (GGT (p = 1.03 × 10(−21)), ALT (p = 1.29 × 10(−6)), and AST (p = 1.97 × 10(−8))) in individuals with AUD. Postmortem brain analyses documented increased SLC7A11 expression in the frontal cortex of individuals with AUD and animal models showed marked increased expression in liver, suggesting a mechanism by which alcohol leads to hypomethylation-induced overexpression of SLC7A11. Taken together, our EWAS discovery sample and subsequent validation of the top probe in AUD suggest a strong role of abnormal glutamate signaling mediated by methylomic variation in SLC7A11. Our data are intriguing given the prominent role of glutamate signaling in brain and liver and might provide an important target for therapeutic intervention