Ming T. Tsuang, MD, PhD, DSc

The term “epigenetic” was first coined by Waddington in 1939 to describe diverse reprogramming of the same genetic materials to generate a multicellular organism from a single cell. With new technologies and knowledge, several types of epigenetic modifications-such as DNA methylation, histone modifications, RNA editing, and RNA interference-have been discovered. These modifications are involved in the regulation of gene expression without changing the sequence of DNA. In fact, while genetic codes determine the structure of proteins, epigenetic codes define the time, duration, and amount of protein synthesis in a specific cell or tissue.

Epigenetics has evolved to become the science that explains how the differences in the patterns of gene expression in diverse cells or tissues are executed and inherited. Although heritable, epigenetic programming is influenced by micro and macro environmental factors, and it provides a short-term and generation-specific cellular memory to adapt to variable conditions. It can also be considered as a buffering mechanism to compensate for genetic defects. This dynamic pattern of gene regulation might be a response to internal cues (eg, hormones, neurotransmitters, cellular metabolic states) as well as external cues (eg, neuronal activation, climate changes, seasons, drugs, malnutrition, contaminants). Some epigenetic changes induced by external cues can be transferred to next generation, leading to a disease state.

Many psychiatric disorders, such as bipolar disorder and major depression, are episodic and may spontaneously remit. The episodic nature of these diseases suggests that they are unlikely to be pure genetic diseases, which in general are responsible for the genesis of life-long illness. A multitude of genome-wide association scans of thousands of patients with schizophrenia or bipolar disorder and controls have revealed that while genetic mutations of hundreds of genes appear to be associated with severe mental illness, the effective contribution of each gene is very small (1% to 2%).

 This, along with the fact that the majority of affected individuals do not exhibit any single pattern of genetic mutations, implies that major psychiatric disorders are multifactorial and may involve epigenetic alterations.

In contrast to genetic marks that cannot be restored (at least with the current techniques), epigenetic marks are more amenable to preventive and/or therapeutic modifications using a variety of agents, such as enzymes, hormones, vitamins, nutrients, and drugs (

). The common types of epigenetic modifications are discussed in brief, to provide a rationale for their suitability to design therapeutics.

DNA methylation as a target for epigenetic therapy

DNA methylation, a common epigenetic alteration of the cytosine residue in the context of CpG dinucleotides, has long been detected in mammals. Methylated CpGs are targets for DNA-binding domain proteins such as MBD1, MBD3, MBD4, and MeCP2, which correspond to silencing of gene expression, genomic imprinting, suppression of transposable elements, and X inactivation in females. In the early embryonic stage, DNA methylation marks are erased to generate virtual totipotent cells that then acquire a tissue-specific epigenome that defines the identity and destination of the differentiated cells. Any interference in the process, including the unavailability of the various factors or nutrients (eg, methyl groups, folic acid) may result in an aberrant DNA methylome in the derivative cells.

Hormones or environmental cues can cause demethylation and de novo methylation to alter the inherited pattern of DNA. While DNA methyltransferases convert unmethylated cytosine residues to 5-methylcytosine (5mC), the TET and IDH family proteins convert 5mC to 5-hydroxymethylcytosine (5hmC), a transitional product during demethylation (

). Interestingly, in the brain, a significant fraction of the methylated cytosines are in fact 5hmC and correspond to the induction of gene expression. A dynamic exchange of 5mC and 5hmC may be a key mechanism for functional plasticity of neuronal cells, and an imbalance in the exchange between 5mC and 5hmC may lead to epigenetic dysregulation of many genes underlying psychotic manifestations.

The results of a postmortem study of the human brain showed that 5hmC levels at the 

 promoter in the inferior parietal lobule of patients with schizophrenia and bipolar disorder were increased compared with levels in controls.

 are associated with a greater than 2-fold increase in TET1 expression. An increase in 

 expression (which is involved in DNA demethylation) was also seen in psychotic patients.

A recent whole genome DNA methylation microarray analysis found that methylation values at 2868 CpG sites in DNA extracted from the saliva of 96 maltreated children were significantly different from those of controls.

 Another genome-wide DNA methylation analysis of the peripheral blood DNA in humans uncovered disease-associated aberrant DNA methylation of numerous CpGs in twins affected by schizophrenia and bipolar disorder versus discordant twins, among whom hypomethylation of the 

 gene promoter was observed in postmortem brain tissue from those with psychosis.

 show aberrant promoter DNA methylation of specific genes, including 

 in postmortem brain samples of patients who had major psychiatric disorders.

 Recent whole genome DNA methylation studies of postmortem brain samples (H. M. Abdolmaleky and S. Thiagalingam, unpublished data, 2013) and of peripheral leukocytes identified specific DNA methylation changes

; and global DNA hypomethylation became attenuated with haloperidol treatment.

 Melas and colleagues9 found hypermethylation of soluble catechol-

-methyltransferase (s-COMT) in schizophrenia; another study suggested that s-COMT promoter DNA methylation is influenced by the 158Val/Met polymorphism as well as by physical activity.

 These observations support evidence that in addition to drugs and genetic polymorphisms, external cues may also modify epigenetic codes.

While more studies are required to identify the major affected pathways and genes, the existing data have influenced the use of drugs with epigenetic effects in treating patients with psychiatric disorders. At this time, the most remarkable drug seems to be sodium valproate, an “epigenetic softener” that indirectly decreases promoter DNA methylation through the inhibition of histone deacetylase (HDAC) enzymes. However, in the case of DNA hypomethylation (eg, in malnutrition, MDD, Alzheimer disease), the use of folic acid, vitamin B12, and L-methionine has been considered.

Histone modifications and current therapeutics

Histone modifications are major epigenetic mechanisms closely tied with DNA methylation and frequently considered as a therapeutic target for various diseases. An octamer of positively charged histone core proteins (H2A, H2B, H3, H4) with the H1 linker histone (which are wrapped by 147 base pairs of DNA strands with a negative electric charge) constitutes the nucleosome (the building unit of chromatin assembled in chromosomes). Histone tails are subjected to various modifications, such as methylation, acetylation, and phosphorylation, that determine the transcriptionally active status of the chromatin as well as the accessibility to transcription factors. Several enzymes are involved in diverse types of histone modifications and, thus, induction or suppression of gene expression (

). For instance, histone methyltransferases add and histone demethylases remove methyl groups of histone tails that, in turn, can, depending on the sequence context of the amino-acid residue, switch on or switch off gene expression. The target amino acids of histone tails can be mono-methylated, bi-methylated, or tri-methylated, making their functional status more complex (

Activation or suppression of some of the enzymes that mediate epigenetic modifications have been used to treat many diseases, including major psychiatric disorders (

). Valproate is an HDAC inhibitor, and it increases the level of histone acetylation. Lithium also increases the levels of histone H3 acetylation and phosphoacetylation in the central nucleus of the amygdala, which is associated with the induction of c-Fos.

 Haloperidol, clozapine, and benzamides have similar effects. Imipramine, amitriptyline, fluoxetine, escitalopram, tranylcypromine, and opioids are also epigenetic modifiers (see 

 for more details). Although the expression of HDAC1, HDAC2, and HDAC5 is higher with lurasidone than with valproate treatment, concomitant use of valproate led to higher brain-derived neurotrophic factor (BDNF) expression in the ventral hippocampus compared with either drug alone.

RNA editing that includes substitution, deletion, or insertion of ribonucleotides corresponding to a coding DNA sequence can generate multiple variants of a single protein in diverse tissues, particularly in the brain as the result of neuronal activity. Multiple forms of serotonin, glutamate, and Î³-aminobutyric acid (GABA) receptors with different functional and pharmacological properties that originate from RNA editing have been recognized in humans. Hence, some drugs that in-hibit or stimulate these targets in other tissues may fail to act in the human brain.

 In fact, the diversity of RNA editing in the human brain may underlie region-specific effects of modern antipsychotic drugs that are known for fewer adverse effects. A better understanding of this mechanism of epigenetic modification could provide opportunities for designing better drugs to target the exact variants of specific receptors, channels, or enzymes in particular areas of the brain in affected individuals.

Non-coding RNAs, such as microRNAs (miRNAs), which are 20 to 25 bases in length, are another important feature of epigenetic regulation. In general, miRNAs bind to target messenger RNAs (mRNAs) and inhibit the translation or degrade mRNAs and prevent protein synthesis. Remarkably, each gene can be targeted by multiple miRNAs and each miRNA (approximately 1000 known) may target hundreds of mRNAs. In addition to intracellular regulation of gene expression, miRNAs can affect the expression of various genes (eg, metabolic genes) far from the locations from which they were generated in the form of circulating miRNAs.

A number of studies have uncovered close to 2 dozen miRNAs affected in psychiatric disorders (

). A microarray analysis showed decreased expression of 16 miRNAs in the frontal lobe of postmortem brains in patients with schizophrenia and schizoaffective disorder.

 The assay included miR-24, miR-26b, miR-30e, and miR-92, and results were confirmed by quantitative real-time polymerase chain reaction analysis.

Increased miRNA biogenesis in the superior temporal gyrus and dorsolateral prefrontal cortex and overexpression of miR-15a, miR-15b, miR-195, and miR-107 were also found in patients with schizophrenia. These miRNAs have the capacity to regulate the expression of target genes, including 

ATXN2, BDNF, CHRM1, DRD1, GABR1, GRIN1, GRM7, HTR4, NRG1,

 which are known to be affected in schizophrenia.15 Overexpression of miR-181b was found to be associated with reduced expression of 

 (which regulates the activity of adenylyl cyclase) and 

 (glutamate receptor, ionotropic, AMPA 2) in the gray matter of the temporal cortex in postmortem brain samples of patients with schizophrenia. Subsequent studies verified that the expression of 

 is suppressed by synthetic miR-181b in cell culture experiments.

Other targets of miR-181b are genes coding receptors for GABA (

), which contribute to the pathogenesis of mental diseases. 

 and miR-346, which are localized to the intron 2 of 

exhibited reduced expression in postmortem brain samples of patients with schizophrenia.

Recent findings suggest an increased expression of exosomal miR-497 and miR-29c in the postmortem prefrontal cortices of patients with schizophrenia and bipolar disorder, respectively, and a decrease in circulating miR-134 in the plasma of drug-free patients in the manic phase of bipolar disorder.

Collectively, the progress made in miRNA studies not only indicates that these non-coding regulatory RNAs may contribute to the pathogenesis of psychiatric diseases and mediate the effects of mood stabilizers but also suggests the potential use of circulating miRNAs as diagnostic biomarkers and the use of synthetic miRNAs (that mimic the activity of circulating or brain specific miRNAs) as therapeutic tools.

The major challenges for epigenetic therapies are target specificity of the drugs-an issue that is also true for most of the currently used drugs in medicine, especially in psychiatry. Recent discoveries on the use of zinc finger proteins and other tools such as TALEN (transcription activator-like effector nucleases) that recognize specific DNA sequences have paved the way for the recruitment of regulatory proteins, enzymes, and drugs to gene promoters for site-specific epigenetic modifications.

 However, the mechanisms that deliver the modifiers to specific neuronal nuclei or pathways are still to be identified.

Concurrent activation of a desired pathway using transcranial magnetic stimulation (TMS) or other tools may help to deliver the specific epigenetic modifiers to the activated pathways or neuronal nuclei by the mediation of glucose or other molecules that are utilized at a higher rate by the activated cells. Given that electroconvulsive therapy–induced neuronal activity is a powerful epigenetic modifier in the adult brain and that the abnormal epigenomic brain map for psychiatric disorders is under development, epigenetic modifications of specific brain regions using noninvasive methods such as TMS may be among the epigenetic therapies coming over the horizon.

Dr Abdolmaleky is a Visiting Professor/Research Associate in the departments of medicine and genetics and genomics at Boston University School of Medicine, and Research Associate at the Harvard Institute of Psychiatric Epidemiology and Genetics in Boston. Dr Shafa is Scientific Director at Metrowest CNS Research Center, Pharmacogenomics, in Natick, Mass. Dr Tsuang is Distinguished Professor of Psychiatry and Behavioral Genomics Endowed Chair and Director, Center for Behavioral Genomics, department of psychiatry, University of California, San Diego. Dr Tsuang is also Director of the Harvard Institute of Psychiatric Epidemiology and Genetics, Boston. Dr Thiagalingam is an Associate Professor in the departments of medicine, genetics and genomics, and pathology and laboratory medicine at Boston University School of Medicine. The authors report no conflicts of interest concerning the subject matter of this article.

 Hamshere ML, Walters JT, Smith R, et al. Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC. 

Dong E, Gavin DP, Chen Y, Davis J. Upregulation of TET1 and downregulation of APOBEC3A and APOBEC3C in the parietal cortex of psychotic patients. 

 Gavin DP, Sharma RP, Chase KA, et al. Growth arrest and DNA-damage-inducible, beta (GADD45b)-mediated DNA demethylation in major psychosis [published correction appears in 

 Yang BZ, Zhang H, Ge W, et al. Child abuse and epigenetic mechanisms of disease risk. 

 Dempster EL, Pidsley R, Schalkwyk LC, et al. Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder. 

 Abdolmaleky HM, Zhou JR, Thiagalingam S, Smith CL. Epigenetic and pharmacoepigenomic studies of major psychoses and potentials for therapeutics. 

Abdolmaleky HM, Yaqubi S, Papageorgis P, et al. Epigenetic dysregulation of HTR2A in the brain of patients with schizophrenia and bipolar disorder. 

 Nishioka M, Bundo M, Koike S, et al. Comprehensive DNA methylation analysis of peripheral blood cells derived from patients with first-episode schizophrenia. 

 Melas PA, Rogdaki M, Ãsby U, et al. Epigenetic aberrations in leukocytes of patients with schizophrenia: association of global DNA methylation with antipsychotic drug treatment and disease onset. 

 Lott SA, Burghardt PR, Burghardt KJ, et al. The influence of metabolic syndrome, physical activity and genotype on catechol-O-methyl transferase promoter-region methylation in schizophrenia. 

 Kwon B, Houpt TA. Phospho-acetylation of histone H3 in the amygdala after acute lithium chloride. 

 Calabrese F, Luoni A, Guidotti G, et al. Modulation of neuronal plasticity following chronic concomitant administration of the novel antipsychotic lurasidone with the mood stabilizer valproic acid. 

 Sanjana NE, Levanon EY, Hueske EA, et al. Activity-dependent A-to-I RNA editing in rat cortical neurons. 

Perkins DO, Jeffries CD, Jarskog LF, et al. microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder. 

 Beveridge NJ, Gardiner E, Carroll AP, et al. Schizophrenia is associated with an increase in cortical microRNA biogenesis. 

 Beveridge NJ, Tooney PA, Carroll AP, et al. Dysregulation of miRNA 181b in the temporal cortex in schizophrenia. 

Zhu Y, Kalbfleisch T, Brennan MD, Li Y. A microRNA gene is hosted in an intron of a schizophrenia-susceptibility gene. 

Banigan MG, Kao PF, Kozubek JA, et al. Differential expression of exosomal microRNAs in prefrontal cortices of schizophrenia and bipolar disorder patients. 

 Rong H, Liu TB, Yang KJ, et al. MicroRNA-134 plasma levels before and after treatment for bipolar mania. 

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Articles

The major challenges for epigenetic therapies are target specificity of the drugs-an issue that is also true for most of the currently used drugs in medicine, especially in psychiatry. 

Psychiatric Epigenetics: A Key to the Molecular Basis of and Therapy for Psychiatric Disorders

Many people who have family members afflicted by psychiatric disorders wonder if mental illness is inherited. In fact, over the last several decades, research has provided clinicians with information and empirical risk estimates for some psychiatric disorders. Despite the large body of work, clinical implications of psychiatric genetic data have only recently become apparent. This reflects both increased media attention to genetics, as well as the growing sophistication of patients and their families.

In this article we will address two clinical applications of genetic information. First, we will discuss genetic counseling, which provides general principles to help clinicians communicate genetic risks to patients and family members. Genetic counseling is a well-established medical subspeciality, typically applicable to many rare non-psychiatric medical disorders. Second, we will discuss the potential adverse consequences and the ethical implications raised by the availability of genetic testing. We will illustrate ethical issues using lessons learned from genetic testing in classical Mendelian diseases and discuss established guidelines that may apply to psychiatric disorders.

There has been explosive growth in the number of disease genes identified over the past several years, giving clinicians more information about the heritability of many diseases. However, new knowledge can-and often does-create confusion. There are still several misconceptions concerning human genetics and psychiatric illness. The primary purpose of genetic counseling, therefore, is to correct misunderstandings about the heritability of psychiatric disorders, such as:

 If a disorder is genetic, it inevitably occurs in those who carry the harmful gene(s).

 The influence of genetic factors in psychiatric disorders is highly variable. More commonly, environmental and genetic interactions influence most psychiatric conditions. Furthermore, genetic and environmental influences are likely to differ between individuals and have variable impacts on each individual. Thus, the expression of a single disorder is not necessarily the same in each affected individual. It is also possible that an individual who carries the susceptible gene will not develop the disorder.

If a disorder is genetic, it is untreatable.

 Although many genetic conditions are currently untreatable (for example, Huntington's disease), most psychiatric disorders respond to some form of treatment. Similarly, while the underlying genetics cannot yet be changed, the expression of those genes can be treated. Individuals with identified psychiatric genetic disorders may mitigate the effects of the disorder through medical treatment, psychotherapeutic intervention and lifestyle changes. In addition, much scientific effort has been invested in gene therapy, with the eventual goal of reversing the effects of the deleterious gene. While this may sound like science fiction, gene therapy may become a reality in the future.3.) 

Genetic counseling is associated with eugenics and genocide. 

In fact, contemporary genetic counseling is non-directive, with an emphasis on individual autonomy and informed decision-making. The goal of genetic counseling is to disseminate current scientific knowledge concerning the disorder at hand and to aid the consultand (the person seeking genetic counseling) in making the best possible decision.As with other medical conditions, some psychiatric disorders are inherited while others are not. Genetic counseling serves to educate consultands and provide them with information concerning the disorder of interest. The Table* outlines the seven stages of genetic counseling. Multiple visits may be necessary to complete all stages. Genetic counseling should be tailored to the specific needs of the individual and their family. Interested readers are referred to the chapter entitled "Clinical Applications of Psychiatric Genetics" in Genetics in Mental Disorders: A Guide for Students, Clinicians, and Researchers (1999; Guilford Press) for additional details.

DNA-based tests are the newest technique in testing for genetic disorders. These techniques require direct examination of the DNA molecule (e.g., determination of the number of repeated DNA sequences in the Huntington's disease gene). Other genetic tests include those that detect gene products (e.g., biochemical tests, such as one that screens for phenylketonuria) and those that detect chromosomal changes by microscopic examination of fluorescent chromosomes (e.g., fluorescent in-situ hybridization techniques to screen for velocardiofacial syndrome). Genetic tests are currently used in a variety of situations, including:

presymptomatic testing for prediction of adult-onset disorders;

presymptomatic testing for estimating the risk of developing adult-onset diseases;

diagnostic testing for symptomatic individuals; 

>, genetic tests are currently available for over 700 diseases. For many at-risk individuals, the availability of genetic tests gives them the opportunity to relieve uncertainty and to appropriately plan for their future.

For treatable disorders, a positive test can result in a higher level of surveillance as well as intervention to reduce risk. Unfortunately, only a few genetic tests are definitive (e.g., the test for Huntington's disease, which is 99% predictive). In other single-gene disorders, although the presence of a mutation is highly predictive of the disorder (as in some forms of familial early-onset Alzheimer's disease [AD], in which age of onset is consistently before the age of 60), genetic testing is more complicated. Testing for mutations in one of the three known causative genes (presenilin 1) is clinically available. Testing is recommended only in individuals with age of onset of AD younger than 60 and who have another affected family member with early-onset AD. Although apparent sporadic cases of early-onset AD exist, there is still the possibility of false paternity or early death of an asymptomatic parent who carried the mutation. Testing is not recommended for people with late-onset AD, both sporadic and familial.

When testing at-risk individuals, an affected family member should be tested first to confirm the molecular diagnosis of the family. In the absence of this information, a negative test could simply indicate that the family has another genetic form of dementia. Testing for mutations in the two other genes (amyloid precursor protein and presenilin 2) is only available on a research basis. Testing for mutations causative for AD is not useful in predicting the age of onset, severity or type of clinical symptoms, or rate of progression of the disease.

The apolipoprotein E4 (APO E4) should not be used in presymptomatic testing. Although 35% to 60% of AD cases have an E4 allele, its presence is not highly diagnostic of AD. Furthermore, epidemiologic data in presymptomatic individuals with longitudinal follow-up are not well-established. In addition, there is consensus that children at risk for adult-onset disorders should not be tested in the absence of clinical symptoms. Additional information on testing guidelines for AD and other genetic disorders is available on GeneClinics' Web site <

In more common diseases, such as adult-onset cancers and coronary artery disease, only age-adjusted risk estimates can be provided. Likewise, most psychiatric disorders are presumed to be multifactorial (e.g., due to multiple genes and gene-environmental interactions). Many uncertainties regarding future presymptomatic testing in psychiatric disorders remain. Testing guidelines for individual disorders depends on who is at risk for specific disorders, the accuracy of risk prediction, the best age to provide test results and how the genetic test results are to be used to improve the lives of those tested.

Informed consent is the guiding principle behind the ethics of clinical practice and genetics research and testing. Consultands who choose to undergo genetic testing for clinical reasons should be thoroughly informed about the risks and benefits of the procedure and should always have the option to terminate the process. The counselor should discuss the potential social consequences of genetic testing with consultands. Unlike other laboratory tests, genetic tests may also reveal information about other family members, who, in turn, may or may not want access to this information. Part of the consent process should routinely describe the confidentiality of the data, although clinicians must inform the consultand that the genetic information is part of their medical records. Since stigmatization may occur as a consequence of test results, consultands should review their life and disability insurance prior to testing, as insurance companies have argued that they should have access to presymptomatic genetic testing results.

To compute the costs of health and life insurance, actuaries take into account many factors known to predict disease and death. Few people can argue with the rationale that smokers should pay higher health insurance premiums than non-smokers. Does a parallel argument justify the use of genetic information? Theoretically, insurance companies should have access to genetic profiles of individuals who apply for insurance. Should those who are at risk for untreatable or chronically debilitating disorders pay higher insurance premiums? Should insurance companies have the right to deny coverage to those individuals?

In the same vein, employers may want access to employee records regarding medical information including risk factors for genetic disorders since potential at-risk employees could eventually become less productive, and they may increase health care costs. Understandably, there is reason for concern that discrimination based on genetic testing could occur. Proponents have argued that employers should have access to genetic test results for disorders that may impair judgment and job performance in occupations involving the safety of the general public (e.g., commercial airline pilots and physicians).

The implications of the Human Genome Project have not escaped the attention of legislators. In the United States, several states have already enacted genetic privacy laws. In general, these laws limit the use of genetic data by insurance companies. However, the idea that genetic data should be treated differently from other clinical data has been hotly debated. Society can anticipate additional ethical and legal debates. Indeed, such debates are likely to intensify as the ability to predict behavioral and personality traits becomes a reality. Society will then have to decide the ethical, legal and social implications of this new knowledge. Much work is ongoing as part of the Ethical, Legal, and Social Implications Program of the Human Genome Project. (For additional information, please visit <

The Human Genome Project will undoubtedly provide an abundance of data to assist researchers in identifying the genes that contribute to human behavioral disorders. With the working draft of the human genome in hand, identification of genes relevant to human behavior continues. The implications of genetic data for diagnosing and treating psychiatric disorders remain speculative. Clinical applications often arise during the mature phases of a scientific discipline. As psychiatric genetics enters into the gene identification era, more clinical applications will be discovered. Although the future of psychiatric genetics will answer many scientific and clinical questions, it will also raise many questions about the legal, ethical and social implications of these answers. Medical and scientific advances may bring many gifts to society in the form of new knowledge; as clinicians and scientists, we should approach this new knowledge with caution, as one of these gifts could be a Pandora's box.

The Human Genome project has provided an abundance of genetic information, including identification of many disease-causing genes. Clinical applications, genetic counseling and the potential ethical issues raised by the availability of genetic testing are all areas of concern in gene research. Will genetic counseling in classical genetic diseases help to provide guidelines for behavioral disorders?

Ming T. Tsuang, MD, PhD, DSc

Articles

Psychiatric Epigenetics: A Key to the Molecular Basis of and Therapy for Psychiatric Disorders

Clinical Uses and Ethical Implications of Psychiatric Genetic Counseling