DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia

Hannon, Eilís; Dempster, Emma; Mansell, Georgina; Burrage, Joe; Bass, Nick; Bohlken, Marc M.; Corvin, Aiden; Curtis, Charles; Dempster, David; Forti, Marta Di; Dinan, Timothy G.; Donohoe, Gary; Gaughran, Fiona; Gill, Michael; Gillespie, Amy; Gunasinghe, Cerisse; Hulshoff, Hilleke E; Hultman, Christina M.; Johansson, Viktoria; Kahn, René S.; Kaprio, Jaakko; Kenis, Günter; Kowalec, Kaarina; MacCabe, James H.; McDonald, Colm; McQuillin, Andrew; Morris, Derek W.; Murphy, Kieran C.; Mustard, Colette J; Nenadić, Igor; O’Donovan, Michael; Quattrone, Diego; Richards, Alexander; Rutten, Bart P. F.; Clair, David St; Therman, Sebastian; Toulopoulou, Timothea; Os, Jim van; Waddington, John L.; Sullivan, Patrick F.; Vassos, Evangelos; Breen, Gerome; Collier, David A.; Murray, Robin M.; Schalkwyk, Leonard; Mill, Jonathan

doi:10.7554/elife.58430

Cited by 102 publications

(99 citation statements)

References 82 publications

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“…A systematic epigenome-wide association studies (EWAS) to analyse methylation profiles of DNA collected from blood sampled of seven different cohorts have identified 95 differentially methylated positions (DMPs) associated with psychosis and 1048 DMPs associated with treatment-resistant schizophrenia. This study also highlights the identification of potential biomarker candidate genes as well as open future avenues towards successful development of therapeutics [ 35 ].…”

Section: Maternal Dietary and Supplementary Intakesmentioning

confidence: 99%

DNA methylation and regulation of gene expression: Guardian of our health

Dhar

Saha

Mitra

et al. 2021

Nucleus

117

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One of the most critical epigenetic signatures present in the genome of higher eukaryotes is the methylation of DNA at the C-5 position of the cytosine ring. Based on the sites of DNA methylation in a locus, it can serve as a repressive or activation mark for gene expression. In a crosstalk with histone modifiers, DNA methylation can consequently either inhibit binding of the transcription machinery or generate a landscape conducive for transcription. During developmental phases, the DNA methylation pattern in the genome undergoes alterations as a result of regulated balance between de novo DNA methylation and demethylation. Resultantly, differentiated cells inherit a unique DNA methylation pattern that fine tunes tissue-specific gene expression. Although apparently a stable epigenetic mark, DNA methylation is actually labile and is a complex reflection of interaction between epigenome, genome and environmental factors prior to birth and during progression of life. Recent findings indicate that levels of DNA methylation in an individual is a dynamic outcome, strongly influenced by the dietary environment during germ cell formation, embryogenesis and post birth exposures. Loss of balances in DNA methylation during developmental stages may result in imprinting disorders, while at any later stage may lead to increased predisposition to various diseases and abnormalities. This review aims to provide an outline of how our epigenome is uniquely guided by our lifetime of experiences beginning in the womb and how understanding it better holds future possibilities of improvised clinical applications.

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Section: Maternal Dietary and Supplementary Intakesmentioning

confidence: 99%

DNA methylation and regulation of gene expression: Guardian of our health

Dhar

Saha

Mitra

et al. 2021

Nucleus

117

View full text Add to dashboard Cite

show abstract

“…Indeed, of the 641 context enriched genes, 114 were missed in the larger analysis illustrating how genes and terms associated with immune responses masked our ability to detect a greater depth of neurologically relevant signals. By way of example, we discovered a modest but significant overlap (Fisher's Exact Test p = 0.0492) between our context enriched gene set and genes highlighted in a recent meta-analysis of differentially methylated positions associated with psychosis, schizophrenia and treatmentresistant schizophrenia 49 which was not detectable using the full DE gene set.…”

Section: Recovery Of Neurologically Relevant Annotations Is Aided By a Novel Context Enrichment Approachmentioning

confidence: 77%

“…GO enrichment analysis was then performed on this subset per above using both the full GO ontology and NIGO, a neuro-immune focused GO subset developed using a clipping approach based on domain-specific relevance 47 obtained from BioPortal 70 . We obtained the list of genes with differentially methylated positions associated with psychosis, schizophrenia and treatment-resistant schizophrenia from supplementary material in Hannon et al 49 The expected overlap between this set and our context enriched set was assessed using Fisher's Exact Test assuming an estimated background frequency of 658/20,648 for SZassociated methylated mouse genes.…”

Section: Functional Analysismentioning

confidence: 99%

Toxoplasmainfection alters dopamine-sensitive behaviors and host gene expression patterns associated with neuropsychiatric disease

Cromar

Epp

Popović

et al. 2021

Preprint

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Toxoplasma gondii is a single celled parasite thought to infect 1 in 3 worldwide. During chronic infection, T. gondii can migrate to the brain where it promotes low-grade neuroinflammation with the capacity to induce changes in brain morphology and behavior. Consequently, infection with T. gondii has been linked with a number of neurocognitive disorders including schizophrenia (SZ), dementia, and Parkinson's disease. Beyond neuroinflammation, infection with T. gondii can modulate the production of neurotransmitters, such as dopamine. To further dissect these pathways and examine the impact of altered dopaminergic sensitivity in T. gondii-infected mice on both behavior and gene expression, we developed a novel mouse model, based on stimulant-induced (cocaine) hyperactivity. Employing this model, we found that infection with T. gondii did not alter fear behavior but did impact motor activity and neuropsychiatric-related behaviors. While both behaviors may help reduce predator avoidance, consistent with previous studies, the latter finding is reminiscent of neurocognitive disorders. Applying RNASeq to two relevant brain regions, striatum and hippocampus, we identified a broad upregulation of immune responses. However, we also noted significant associations with more meaningful neurologically relevant terms were masked due to the sheer number of terms incorporated in multiple testing correction. We therefore performed a more focused analysis using a curated set of neurologically relevant terms revealing significant associations across multiple pathways. We also found that T. gondii and cocaine treatments impacted the expression of similar functional pathways in the hippocampus and striatum although, as indicated by the low overlap among differentially expressed genes, largely via different proteins. Furthermore, while most differentially expressed genes reacted to a single condition and were mostly upregulated, we identified gene expression patterns indicating unexpected interactions between T. gondii infection and cocaine exposure. These include sets of genes which responded to cocaine exposure but not upon cocaine exposure in the context of T. gondii infection, suggestive of a neuroprotective effect advantageous to parasite persistence. Given its ability to uncover such complex relationships, we propose this novel model offers a new perspective to dissect the molecular pathways by which T. gondii infection contributes to neuropsychiatric disorders such as schizophrenia.

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“…In some studies, epigenetic variation induced by environmental exposure has been hypothesized as another mechanism by which non-genetic factors can affect risk for neuropsychiatric disorders including schizophrenia as well as efficacy of antipsychotic medication [103]. Hannon et al have shown that there are differences in DNA methylation patterns in patients with schizophrenia, taking into account patients' smoking status as well as drug treatment with clozapine or other antipsychotic drugs [104]. Much more research is required in order to fully understand the influence of smoking behavior on DNA methylation and possibly also on the efficacy of antipsychotic drugs, especially in treatment-resistant schizophrenia.…”

Section: Smoking-associated Pharmacokinetic Changes Due To Other Mechanismsmentioning

confidence: 99%

Therapeutic Drug Monitoring of Second- and Third-Generation Antipsychotic Drugs—Influence of Smoking Behavior and Inflammation on Pharmacokinetics

et al. 2021

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Both inflammation and smoking can influence a drug’s pharmacokinetic properties, i.e., its liberation, absorption, distribution, metabolism, and elimination. Depending on, e.g., pharmacogenetics, these changes may alter treatment response or cause serious adverse drug reactions and are thus of clinical relevance. Antipsychotic drugs, used in the treatment of psychosis and schizophrenia, should be closely monitored due to multiple factors (e.g., the narrow therapeutic window of certain psychotropic drugs, the chronicity of most mental illnesses, and the common occurrence of polypharmacotherapy in psychiatry). Therapeutic drug monitoring (TDM) aids with drug titration by enabling the quantification of patients’ drug levels. Recommendations on the use of TDM during treatment with psychotropic drugs are presented in the Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology; however, data on antipsychotic drug levels during inflammation or after changes in smoking behavior—both clinically relevant in psychiatry—that can aid clinical decision making are sparse. The following narrative review provides an overview of relevant literature regarding TDM in psychiatry, particularly in the context of second- and third-generation antipsychotic drugs, inflammation, and smoking behavior. It aims to spread awareness regarding TDM (most pronouncedly of clozapine and olanzapine) as a tool to optimize drug safety and provide patient-tailored treatment.

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DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia

Cited by 102 publications

References 82 publications

DNA methylation and regulation of gene expression: Guardian of our health

DNA methylation and regulation of gene expression: Guardian of our health

Toxoplasmainfection alters dopamine-sensitive behaviors and host gene expression patterns associated with neuropsychiatric disease

Therapeutic Drug Monitoring of Second- and Third-Generation Antipsychotic Drugs—Influence of Smoking Behavior and Inflammation on Pharmacokinetics

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