Epigenetics of major psychosis: progress, problems and perspectives

doi:10.1016/j.tig.2012.04.002

Trends in Genetics

Volume 28, Issue 9, September 2012, Pages 427-435

https://doi.org/10.1016/j.tig.2012.04.002 Get rights and content

Understanding the origins of normal and pathological behavior is one of the most exciting opportunities in contemporary biomedical research. There is increasing evidence that, in addition to DNA sequence and the environment, epigenetic modifications of DNA and histone proteins may contribute to complex phenotypes. Inherited and/or acquired epigenetic factors are partially stable and have regulatory roles in numerous genomic activities, thus making epigenetics a promising research path in etiological studies of psychiatric disease. In this article, we review recent epigenetic studies examining the brain and other tissues, including those from individuals with schizophrenia (SCZ) and bipolar disorder (BPD). We also highlight heuristic aspects of the epigenetic theory of psychiatric disease and discuss the future directions of psychiatric epigenetics.

Section snippets

Psychiatry meets epigenetics

Psychiatric disorders are characterized by severely debilitating behavioral abnormalities that often persist over a life time and are resistant to medical or psychotherapeutic interventions. Here, we focus on two major psychiatric diseases (SCZ and BPD) that have received the greatest attention in molecular biological studies. SCZ and BPD are severe forms of mental illness, each of which causes 1% of global disability [1]. SCZ is characterized by delusions, disturbances in reasoning,

Epigenetics is a new frontier in neurobiology

Epigenetic factors can influence genomic activities in the brain to produce long-term changes in synaptic signaling, organization, and morphology, which in turn underlie cognitive function [9]. For example, the phosphorylated form of methyl CpG binding protein 2 (MeCP2), a methyl-CpG-binding domain (MBD) protein that binds to methylated DNA and regulates transcription, binds broadly throughout the genome, affecting chromatin state, dendritic and synaptic development, and hippocampus-dependent

Epigenetic perspective on the ‘missing’ heritability, ephemeral environment, and non-Mendelian features of major psychosis

The second group of arguments supporting epigenetic applications in psychiatric research, and in other complex diseases, is a potential reinterpretation of the ‘DNA + environment’ paradigm of disease causation. Twin and family studies have demonstrated a genetic influence in all psychiatric diseases, with heritability reaching 80% in SCZ and BPD [20]. Despite high heritability estimates, common genetic risk factors mapped in genome-wide association studies (GWAS) [21] and rare DNA mutations,

The short (half a decade) history of epigenetic studies of SCZ and BPD

Both SCZ and BPD have been examined for disease-associated changes in DNA methylation [35]. Initial studies investigated methylation in candidate genes such as reelin 36, 37, sex-determining region Y (SRY)-box 10 [38], forkhead box P2 [39], and serotonin receptor 1A [40] using postmortem brains and peripheral blood samples; however, the findings from these studies were not always replicated [41]. The first epigenome-wide study characterizing DNA methylation in major psychosis surveyed 12 000

Future directions and challenges for identification of epimutations in major psychosis

As discussed above, epigenetics and epigenetic models of disease causation have numerous characteristics that distinguish them from genetic studies and, accordingly, the up-and-coming wave of epigenome-wide association studies (or ‘EWAS’) is being accompanied by thoughts on theoretical and experimental considerations for these studies [65]. Here, we focus on epigenomic research strategies that are directly relevant to the brain.

The instability of the epigenetic code is a double-edged sword, in

Concluding remarks

The coming decade is likely to see a large assortment of epigenomic assays of disease that have increased resolution, sample size, and scope of analysis. It is possible that epigenetic analysis in psychiatric disease will be inundated by the complexities of epigenetic maps, yielding small and non-replicable findings. However, the optimistic outlook is that this research will identify new molecular mechanisms to explain features of non-Mendelian biology and transform our understanding of the

Acknowledgments

This work was supported by the Canadian Institutes for Health and Research (186007), the National Institutes of Health (MH074127; MH088413), and the Krembil Foundation to AP. VL is supported by a Canadian Institutes of Health Research fellowship. AP is Senior Fellow, Ontario Mental Health Foundation, and Tapscott Chair in Schizophrenia Studies, University of Toronto.

Glossary

Copy number variation (CNV): is present when DNA sections (larger than 1 kb) show differences in copy number between individuals. These rare structural variations in the genome can result in the duplication, deletion, or disruption of gene copies.
DNA methyltransferases (DNMTs): enzymes that establish and maintain DNA methylation, using methyl-group donor compounds or cofactors. Main mammalian DNMTs are DNMT1, which maintains methylation state across DNA replication, and DNMT3a and DNMT3b, which

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Citation Excerpt :
However, the pathogenesis of SCZ could not be well defined based on existing findings yet. Despite multiple genetic variants have been reported, recent epigenetic analyses of SCZ are providing new insights into our understanding of the complex associations between epidemiological heritability and the phenotypic variation [10,11]. Epigenetic dysregulation of the genome has been shown to lead to chronic alterations of neurodevelopment, synaptic architecture, and cellular signaling.
Schizophrenia (SCZ) is a severe psychiatric disorder that affects approximately 0.75% of the global population. Both genetic and environmental factors contribute to development of SCZ. SCZ tends to run in family while both genetic and environmental factor contribute to its etiology. Much evidence suggested that alterations in DNA methylations occurred in SCZ patients.
To investigate potential inheritable pattern of DNA methylation in SCZ family, we performed a genome-wide analysis of DNA methylation of peripheral blood samples from 106 Chinese SCZ family trios. Genome-wide DNA methylations were quantified by Agilent 1 × 244 k Human Methylation Microarray.
In this study, we proposed a loci inheritance frequency model that allows characterization of differential methylated regions as SCZ biomarkers. Based on this model, 112 hypermethylated and 125 hypomethylated regions were identified. Additionally, 121 hypermethylated and 139 hypomethylated genes were annotated. The results of functional enrichment analysis indicated that multiple differentially methylated genes (DMGs) involved in Notch/HH/Wnt signaling, MAPK signaling, GPCR signaling, immune response signaling. Notably, a number of hypomethylated genes were significantly enriched in cerebral cortex and functionally enriched in nervous system development.
Our findings not only validated previously discovered risk genes of SCZ but also identified novel candidate DMGs in SCZ. These results may further the understanding of altered DNA methylations in SCZ.
None.
Toward personalized medicine in schizophrenia: Genetics and epigenetics of antipsychotic treatment
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Schizophrenia is a complex psychiatric disorder where genetic, epigenetic, and environmental factors play a role in disease onset, course of illness, and treatment outcome. Pharmaco(epi)genetic research presents an important opportunity to improve patient care through prediction of medication side effects and response. In this narrative review, we discuss the current state of research and important progress of both genetic and epigenetic factors involved in antipsychotic response, over the past five years. The review is largely focused on the following frequently prescribed antipsychotics: olanzapine, risperidone, aripiprazole, and clozapine. Several consistent pharmacogenetic findings have emerged, in particular pharmacokinetic genes (primarily cytochrome P450 enzymes) and pharmacodynamic genes involving dopamine, serotonin, and glutamate neurotransmission. In addition to studies analysing DNA sequence variants, there are also several pharmacoepigenetic studies of antipsychotic response that have focused on the measurement of DNA methylation. Although pharmacoepigenetics is still in its infancy, consideration of both genetic and epigenetic factors contributing to antipsychotic response and side effects no doubt will be increasingly important in personalized medicine. We provide recommendations for next steps in research and clinical evaluation.
Urbanicity and familial liability interact and influence auditory verbal hallucinations in first-episode schizophrenia patients
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In this study, we tested whether proxy genetic risk (defined as positive family history of schizophrenia in first- and second-degree relatives) and the level of urbanicity interact and influence the expression of auditory verbal hallucinations (AVH) in first-episode schizophrenia patients. We recruited 112 first-episode schizophrenia patients with age 29.24 ± 6.63 years old. The lifetime occurrence of AVH was also assessed using the The Operational Criteria for Psychotic Illness (OPCRIT), which includes the following categories of AVH: thought echo, third person auditory hallucinations, running commentary voices, abusive/accusatory/persecutory voices and other (nonaffective) auditory hallucinations. Hallucinatory behavior on the day of recruitment was evaluated using the P3 item of the Positive and Negative Syndrome Scale (PANSS). Our results show a significant effect of the interaction between family history of schizophrenia (i.e., genetic liability) and current place of residence on the total number of AVH categories (F = 4.41, p = 0.038) and the PANSS P3 item score (F = 4.21, p = 0.042). The implications of the findings are discussed within an epigenetic framework and in relation to the Differential Susceptibility Hypothesis (DSH), which states that individuals who are most at risk to adversity will most likely benefit from supportive environments. An integrative therapeutic approach is suggested as a means to improve the quality of life of first-episode schizophrenia patients living in urban environments.
Methylation of Brain Derived Neurotrophic Factor (BDNF) Val66Met CpG site is associated with early onset bipolar disorder
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The brain-derived neurotrophic factor (BDNF) rs6265 (Val66Met) Met allele is associated with early onset (≤ 19 years old) bipolar disorder (BD). Val66Met (G196A) creates a CpG site when the Val/G allele is present. We sought to study the methylation of the BDNF promoter and its interaction with Val66Met genotype in BD.
Sex/age-matched previously genotyped DNA samples from BD-Type 1 cases [N = 166: early onset (≤ 19 years old) n = 79, late onset (> 20 years old) n = 87] and controls (N = 162) were studied. Pyrosequencing of four CpGs in Promoter-I, four CpGs in promoter-IV, and two CpGs in Promoter-IX (CpG2 includes G= Val allele) was performed. Logistic regression adjusting for batch effect was used to compare cases vs. controls. Analyses also included stratification by disease onset and adjustment for Val66Met genotype. Secondary exploratory analyses for the association of life stressors, comorbid substance abuse, and psychotropic use with methylation patterns were performed.
Comparing all BD cases vs. controls and adjusting for Val66Met genotype, BD cases had significantly higher methylation in promoter -IX/CPG-2 (p = 0.0074). This was driven by early onset cases vs. controls (p = 0.00039) and not late onset cases vs. controls (p = 0.2).
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Early onset BD is associated with increased methylation of CpG site created by Val=G allele of the Val66Met variance. Further studies could include larger sample size and postmortem brain samples in an attempt to replicate these findings.
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Citation Excerpt :
In addition, environmental risk such as urbanicity (Pedersen and Mortensen, 2001), migrant status (Cantor-Graae and Selten, 2005), childhood maltreatment (Arseneault et al., 2011), prenatal infections (Brown and Derkits, 2010), and cannabis use (Moore et al., 2007) also contribute to schizophrenia susceptibility. These observations have led to the speculation that epigenetics is involved in the disease development (Labrie et al., 2012). Epigenetics is chemical modifications of the DNA or associated proteins that can affect gene regulation, without altering the nucleotide sequence.
Schizophrenia is a common mental disorder with high heritability. It is genetically complex and to date more than a hundred risk loci have been identified. Association of environmental factors and schizophrenia has also been reported, while epigenetic analyses have yielded ambiguous and sometimes conflicting results. Here, we analyzed fresh frozen post-mortem brain tissue from a cohort of 73 subjects diagnosed with schizophrenia and 52 control samples, using the Illumina Infinium HumanMethylation450 Bead Chip, to investigate genome-wide DNA methylation patterns in the two groups.
Analysis of differential methylation was performed with the Bioconductor Minfi package and modern machine-learning and visualization techniques, which were shown previously to be successful in detecting and highlighting differentially methylated patterns in case-control studies. In this dataset, however, these methods did not uncover any significant signals discerning the patient group and healthy controls, suggesting that if there are methylation changes associated with schizophrenia, they are heterogeneous and complex with small effect.
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Vitamin B₁₂ and omega-3 fatty acids are important nutrients required for neuronal functioning. We have demonstrated the beneficial effects of vitamin B₁₂ and omega-3 fatty acid supplementation on brain neurotrophins and cognition in the first and second generation offspring. However, there is a need to examine if the effects are sustained in the third generation offspring. This study reports the effects of vitamin B₁₂ and omega-3 fatty acid supplementation across three consecutive generations on brain neurotrophins like brain derived neurotrophic factor (BDNF); nerve growth factor (NGF) and cognitive performance in the third generation male offspring. Three successive generations of Wistar rats were assigned the following groups throughout pregnancy, lactation and adulthood: i) Control, ii) vitamin B₁₂ deficient (BD), iii) vitamin B₁₂ deficient + omega-3 fatty acid (BDO), iv) vitamin B₁₂ supplemented (BS) and v) vitamin B₁₂ supplemented + omega-3 fatty acid (BSO). The BD group demonstrated lower (p < 0.01) NGF in the cortex but not BDNF levels although the cognition was impaired (p < 0.01). In contrast, in the BDO group, higher NGF levels were observed in the hippocampus and animals demonstrated improved (p < 0.01) cognitive performance. Vitamin B₁₂ supplementation showed comparable BDNF levels in the hippocampus while their levels were lower in the cortex as compared to the control (p < 0.05). These animals showed more reference and working memory errors (p < 0.01) as compared to the control group. A combined supplementation of vitamin B₁₂ and omega-3 fatty acid showed higher (p < 0.01) levels of DHA and NGF in the hippocampus, higher BDNF in both hippocampus and cortex and improved cognitive performance. Our findings have implications for fortification of foods with vitamin B₁₂ and omega-3 fatty acids in improving brain development.

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^*: These authors contributed equally to this publication.

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Trends in Genetics

ReviewEpigenetics of major psychosis: progress, problems and perspectives

Section snippets

Psychiatry meets epigenetics

Epigenetics is a new frontier in neurobiology

Epigenetic perspective on the ‘missing’ heritability, ephemeral environment, and non-Mendelian features of major psychosis

The short (half a decade) history of epigenetic studies of SCZ and BPD

Future directions and challenges for identification of epimutations in major psychosis

Concluding remarks

Acknowledgments

Glossary

Neuron

Mol. Cell

Cell

Neuron

J. Biol. Chem.

Neuron

Cell

Trends Genet.

Biol. Psychiatry

J. Affect. Disord.

Biol. Psychiatry

Am. J. Hum. Genet.

Schizophr. Res.

Psychiatry Res.

J. Neurosci. Methods

Biol. Psychiatry

Schizophr. Res.

Neuron

Neuron

Lancet

Cell

Am. J. Hum. Genet.

Am. J. Hum. Genet.

Cell

Cell

Grand challenges in global mental health

Nature

Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies

Arch. Gen. Psychiatry

Psychiatric genetics: progress amid controversy

Nat. Rev. Genet.

Epigenetics as a unifying principle in the aetiology of complex traits and diseases

Nature

Environmental studies of schizophrenia through the prism of epigenetics

Schizophr. Bull.

Linking DNA methylation and histone modification: patterns and paradigms

Nat. Rev. Genet.

High-resolution analysis of parent-of-origin allelic expression in the mouse brain

Science

Epigenetics and the environment: emerging patterns and implications

Nat. Rev. Genet.

Loss of activity-induced phosphorylation of MeCP2 enhances synaptogenesis, LTP and spatial memory

Nat. Neurosci.

Neuronal activity modifies the DNA methylation landscape in the adult brain

Nat. Neurosci.

Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons

Nat. Neurosci.

Cortical DNA methylation maintains remote memory

Nat. Neurosci.

HDAC2 negatively regulates memory formation and synaptic plasticity

Nature

Heritability estimates for psychotic disorders: the Maudsley twin psychosis series

Arch. Gen. Psychiatry

Common polygenic variation contributes to risk of schizophrenia and bipolar disorder

Nature

Differences in the circuitry-based association of copy numbers and gene expression between the hippocampi of patients with schizophrenia and the hippocampi of patients with bipolar disorder

Arch. Gen. Psychiatry

Personal genomes: the case of the missing heritability

Nature

Evidence-based psychiatric genetics, AKA the false dichotomy between common and rare variant hypotheses

Mol. Psychiatry

The mystery of missing heritability: genetic interactions create phantom heritability

Proc. Natl. Acad. Sci. U.S.A.

Understanding transgenerational epigenetic inheritance via the gametes in mammals

Nat. Rev. Genet.

DNA methylation profiles in monozygotic and dizygotic twins

Nat. Genet.

DNA methylation analysis of multiple tissues from newborn twins reveals both genetic and intrauterine components to variation in the human neonatal epigenome

Hum. Mol. Genet.

Review
Epigenetics of major psychosis: progress, problems and perspectives