Prospects for DNA Methylation Research in Psychiatric Disorders
Mohammed A. Ibrahim
Recent advances in molecular genomic analysis showed the possibility of resolving the unexplained mysteries and problems of various biological phenomena. DNA methylation is one of three molecular epigenomic mechanisms involved in controlling gene expression during the process of cellular differentiation, development and aging. This genomic phenomenon has become of great interest in applied research of molecular medicine for its participation in development of various diseases. There is much evidence of possible connection between genomic DNA methylation profiles and psychiatric disorders. Recent studies have demonstrated possible role of DNA methylation in schizophrenia, depression, suicide and bipolar disorder. Aberrations in DNA methylation of several promoter regions of genes have been identified in the genomes of patients with psychiatric disorders. The aim of this effort is to review research work and looking into possible link between abnormal DNA methylation in genomic DNA and psychiatric disorders.
Received: June 08, 2010;
Accepted: June 15, 2010;
Published: October 13, 2010
Early studies showed the role of genetic factors and mutations in mood and
psychiatric disorders, these were found associated with sexual and aggressive
behavior, hysteria, depression, schizophrenia and others (Ibrahim,
1978; Klopfer, 1974). Recent studies proved that epigenetic
mechanisms, which are influenced by environmental factors, are involved in various
biological phenomena including behavioral and psychiatric disorders. Epigenetics
refers to phenotypic changes not explained by coded information in DNA and describes
patterns of gene expression caused by mechanisms other than changes in the nucleotide
sequence; as a result of active research in this field it was possible to reveal
three molecular epigenetic mechanisms which control gene expression: genomic
DNA methylation, histone modification and RNAi (Guil and
Esteller, 2009; Holliday, 2006; Kawasaki
and Taira, 2005; Sledz and Williams, 2005; Strahl
and Allis, 2000).
Genomic DNA methylation occurs because of addition of a methyl group at position
5 of the cytosine pyrimidine ring next guanine in CpG dinucleotides; in consequence,
DNA methylation disrupts the binding of transcription factors and draws methyl-binding
proteins, which are linked with gene silencing and chromatin packaging (Strathdee
and Brown, 2002; Weissbach, 1993). It is apparent
from foregoing published research results, the success of the human genome sequencing
project has created a wide-spread interest in exploring the human genome DNA
methylation profile (methylome) in order to elucidate how the genome executes
the information it holds (Beck and Rakyan, 2008; Eckhardt
et al., 2006; Hocquette, 2005; Lister
and Ecker, 2009; McKusick and Ruddle, 1987). One
of interesting aspects of methylomes is that although all humans nucleated
cells effectively contain the same genome, they contain very different methylomes
(Guil and Esteller, 2009). Specific DNA methylation
has been shown to reflect stable, long term characteristics and persistent commitment
along a cell type and lineage (Baron et al., 2006).
This epigenomic mechanism has been shown to lead to molecular changes which
are known to have most important input in development of various types of cancers
(Ibrahim, 2010; Jones and Baylin,
2002) and associated with several other developmental phenomena and syndromes
e.g., aging (Brunet and Rando, 2007; Ibrahim
et al., 2004; Richardson, 2003), fragile
X syndrome (Oostra and Willemsen, 2002), Beckwith-Weideman
syndrome (Maher and Reik, 2000) and Angelman syndrome
(Nicholls et al., 1998). Moreover, research in
molecular medicine has shown epigenomic mechanisms are major contributor in
the pathogenesis of psychiatric disorders including schizophrenia and bipolar
disorder (Tsankova et al., 2007). In this study
states of DNA methylations profiles of genes associated with psychiatric disorders
It had been reported that the estimated risk of developing schizophrenia
over one's lifetime range from 0.3-2.0% with an average of approximately 0.7%
(Saha et al., 2005), other studies showed that
population wide morbidity is approaching 1% (Grayson et
al., 2005; Kohlrausch et al., 2010). Schizophrenia
is the most genetically studied psychiatric disorder; however the results of
various studies on the genetics basis of schizophrenia have not provided a clarification
of underlying etiological factors that define the symptomatology of the disease
(Petronis, 2001; Petronis et
al., 2003). Another approach for investigating schizophrenia recognized
the role of epigenetic factors; this approach has shown possible molecular explanation
of this psychiatric disorder. The studies have been focused on possible potential
role of DNA methylation states of genes associated with the pathogenesis of
schizophrenia (Petronis, 2004; Tamminga
and Holcomb, 2005; Tremolizzo et al., 2002).
In this study epigenomic states of two types of mood disorders will be reviewed,
major depressive disorder and bipolar disorder, these two psychiatric disorders
are influenced by both genetic and environmental factors. Bipolar disorder is
a chronic illness characterized by shifts between states of mania and depression;
recent investigations showed that this disorder affects approximately 2.8% of
Americans population (Harvey et al., 2007; Kessler
et al., 2005). Mill et al. (2008)
indicated that epigenetic misregulation is consistent with various non-mendelian
features of bipolar disorder. The other mood disorder, major depressive disorder,
is described by an intense sadness, depressed mood and discouragement or loss
of interest that persists for at least two weeks; this state impairs the individuals
social functioning and it can also be accompanied by other symptoms, such as
irritability, changes in appetite, weight and sleep, decreased energy, feelings
of worthlessness or guilt and recurrent thoughts of death (Harvey
et al., 2007). One study showed that the incidence of depression
was observed in the range 0.9 to 2.0%, this range was distributed among participants
randomized to hypnotics (2%) as compared to 0.9% among those randomized in parallel
to placebo (Kripke, 2007). Other investigators reported
that the lifetime prevalence for mood disorders ranges between 6.6 and 11.9%
(Baumeister and Harter, 2007).
Suicide is a leading cause of death particularly in males and is considered
an act deliberately initiated and performed by a person with full knowledge
that a fatal outcome is probable; suicidal behavior is responsible for considerable
morbidity and mortality in schizophrenia and bipolar disorder (De
Luca et al., 2009; Mann, 2002; Turecki,
2001). It has been reported that according to calculations based on data
reported to World Health Organization by its Member States, in 1998 suicide
represented 1.8% of the global burden of disease and it is expected to increase
to 2.4% by the year 2020 and considered is among the 10 leading causes of death
for all ages and it is among the top three causes of death for people aged 15-34
years (Bertolote and Fleischmann, 2002). The results
reported in published research showed that alterations in epigenetic markers
in suicide victims, might suggest a link between mechanisms that regulate gene
expression and major depressive disorder (Autry and Monteggia,
States of DNA Methylation of Genes Associated with Psychiatricc Disorders
The data presented in Table 1 summarized the results of
the research work performed during last decade to investigate the possible involvement
of DNA methylation changes in gene expression of several psychic disorders.
In the following the involvement of DNA methylation states of genes associated
with psychiatric disorders will be reviewed.
It was noted that among greater than 100 different genes examined, reelin protein
gene (RELN ) and glutamic acid decarboxylase gene (GAD67) are the
most abnormal in the context of schizophrenia and bipolar illness (Torrey
et al., 2005). RELN gene is still under extensive investigation for
its role in schizophrenia and other psychiatric disorders; this gene is coding
for reelin protein, which is necessary for neuronal migration and synaptogenesis.
Reelin is a glycoprotein that is expressed during development and was found
important for appropriate neural positioning during brain development (Grayson
et al., 2005, 2006). An investigation was
carried out by Abdolmaleky et al. (2004, 2005)
showed that protein production of reelin is reduced in patients suffering schizophrenia
and bipolar disorder, suggesting hypermethylation of the promoter region in
these disorders. However, the results of a study performed by Tochigi
et al. (2008) did not confirm the hypermethylation of the RELN promoter
region in the brains of schizophrenic patients, in their investigation they
examined the DNA methylation status of the promoter region of RELN by using
the pyrosequencing method in the prefrontal cortices of 14 patients with schizophrenia
and 13 control subjects.
|| States of DNA methylation associated with psychiatric disorders
However, Tochigi and his collaborators noted that their results did not rule
out a possibility that DNA methylation of the RELN promoter region plays a role
in the pathophysiology of schizophrenia. It is worth mentioned that prefrontal
cortex and cerebellar expression of RELN mRNA was significantly decreased by
30 to 50% in patients with schizophrenia or bipolar disorder with psychosis,
but not in those with unipolar depression without psychosis when compared with
non psychiatric subjects (Guidotti et al., 2000).
It is worth noting the results of other research groups about DNA methylation
status of RELN gene. Chen et al. (2002) emphasized
on the evidence that the RELN promoter contains a large CpG island, this suggested
of possible role of DNA methylation in regulating its expression. Whereas, Grayson
et al. (2005) analyzed the extent and pattern of methylation within
the CpG island of the reelin promoter in genomic DNA isolated from cortices
of schizophrenia patients and non psychiatric subjects. Specific regions in
the promoter were amplified after bisulphite treatment and sequenced. Their
results showed that within the promoter region there were interesting regional
variations. There was increased methylation at positions -134 and -139; this
promoter region binds a protein present in neuronal precursor nuclear extracts
that express very low levels of reelin mRNA; i.e., an oligonucleotide corresponding
to this region and that contains methylated cytosines binds more tightly to
extracts from non expressing cells than the non methylated counterpart. Collectively,
their data showed that this promoter region has positive and negative properties
and that the function of this complex cis element relates to its methylation
status (Grayson et al., 2005).
Other investigators reported the effect of methionine administration on the
methylation status of promoter region of RELN gene, the results showed hypermethylation
of the promoter and this caused down regulation of reelin transcription in the
mouse model of schizophrenia (Dong et al., 2005;
Tremolizzo et al., 2002). In this context the
earliest observation was made thirty years ago by group of clinical investigators
who were able to observe the effects of methionine in schizophrenia (Antun
et al., 1971). By contrast, treatment with the methylation inhibitor
5-aza-2'-deoxycytidine upregulated reelin expression in vitro (Chen
et al., 2002).
Czesaka et al. (2008) investigated DNA methylation
profiles of the serotonin (5-HT) system which is strongly implicated in major
depression and suicide and the 5-HT1A receptor is considered a critical regulator
of serotonergic activity. They hypothesized increased DNA methylation of the
5-HT1A polymorphism may increase risk for depression or suicide. In their experiment
genomic DNA was isolated from cortical brain tissue and analyzed for methylation
aberration using modified bisulfite procedure. DNA methylation was examined
at two CpG sites: C(-1019) (POLY) and C(-1007) (HES) in the Deaf-1/ HES5 elements.
Methylation of POLY was low (< 10%), detected in schizophrenia, alcoholism
and controls. Methylation of HES ranged from 0 to15%, with three fold greater
methylation in schizophrenia vs. non schizophrenia or depressed patient samples.
HT2A gene is coding for serotonin 2A receptor, has been implicated in the pathogenesis
of suicidal behavior; De Luca and his associates were able to develop an improved
quantitative assay for the measurement of allele-specific methylation of the
5-HT2A gene and found that the methylation of the C allele in the pre-frontal
cortex of heterozygous suicide victims, was not significantly different in comparison
with the non-suicide group, but methylation analysis of the C allele in white
blood cell DNA from bipolar and schizophrenic attempters showed a significant
difference in the schizophrenic attempters but not in the bipolar attempters
(De Luca et al., 2009).
DRD2 gene which is coding for dopamine receptor D2 has been found to be over-expressed
in peripheral blood lymphocytes of schizophrenics (Zvara
et al., 2005). In addition, different methylation patterns in the
partial promoter region of DRD2 have been detected in the PBL of two pairs of
schizophrenic monozygotic twins (Petronis et al.,
2003). In contrast to this an investigation of the status of DNA methylation
in a typical CpGs island in the 5'-regulatory region of DRD2 was ascertained
by bisulphite sequencing in schizophrenics of 48 discordant sib pairs with schizophrenia,
did not support site-specific cytosine methylation of DRD2 as playing a role
in the psychopathology of schizophrenia (Zhang et al.,
Iwamoto et al. (2005) noticed that the cytosine-guanine
dinucleotide (CpG) island of sex-determining region Y-box containing gene SOX10,
coding for an oligodendrocyte-specific transcription factor, tended to be highly
methylated in brains of patients with schizophrenia, this is correlated with
reduced expression of SOX10. The authors concluded DNA methylation status of
the SOX10 CpG island could be an epigenetic sign of oligodendrocyte dysfunction
Murphy et al. (2005) investigated the methylation
status of COMT gene which is located on chromosome 22q11, the gene is coding
for catechol-o-methyltransferase. This gene has been considered a strong candidate
for schizophrenia susceptibility. They examined 31 brain regions and 51 individual
blood samples to ascertain the cytosine DNA methylation profile of the COMT
promoter, their results ruled out COMT promoter methylation as a common cause
of schizophrenia. But they reported unique observation of a completely methylated
cytosine at one site in one patient, this may have the potential to affect COMT
mRNA transcription and gene activity, but they indicated that this observation
remains to be evaluated.
Inoue and Oishi (2005) studied the effects of methylation
status of the promoter region of syt11 gene on the expression of human synaptotagmin
XI. This gene (syt11) is implicated in the onset of schizophrenia, sequence
analysis showed that cytosine residues not in the CpG sequence but still within
the promoter region of the gene, are partially methylated.
McGowan et al. (2008) studied the rRNA genes
that encode ribosomal RNA in the genome of suicide brain, these are the backbone
of the protein synthesis machinery and levels of rRNA gene promoter methylation
determine rRNA transcription. They found that coding region for rRNA was significantly
hypermethylated throughout the promoter and 5- regulatory region
in the brain of suicide subjects, consistent with reduced rRNA expression in
the hippocampus. This difference in rRNA methylation was not evident in the
cerebellum and occurred in the absence of genome-wide changes in methylation,
as assessed by nearest neighbor. They suggested that their data implicated the
epigenetic modulation of rRNA in the pathophysiology of suicide.
The involvement of DNA methyltransferases in psychiatric disorders has been
investigated, this is because addition of the methyl group at cytosine ring
of 5--CpG-3- sequence is catalyzed by one of three DNA
methyl transferases (DNMT1, DNMT3a and DNMT3b) with S-adenosyl methionine
as the methyl donor (Bird,1992). The DNMT3 family establishes
the initial CpG methylation pattern de novo, whereas DNMT1 maintains this pattern
during chromosome replication (Chen and Li, 2006; Cheng
and Blumenthal, 2008; Hermann et al., 2004).
Poulter et al. (2008) demonstrated that DNA methyltransferase
expression (DNMT3b) is increased in suicide completers compared with control
subjects in frontopolar cortex. Additionally the authors observed, this increase
was more pronounced in female versus male postmortem tissue and emphasized that
such sexual dimorphism is of note, since, Major Depression Disorder (MDD) is
twice as prevalent in women. Their study further revealed that DNMT3b upregulation
may contribute to hypermethylation of the gamma-aminobutyric acid type A (GABAA)
receptor promoter, thereby potentially explaining the down regulation of GABA-A
expression in suicide completers (Poulter et al.,
2008). It is worth noting that cortical dysfunction in schizophrenia is
associated with changes in GABAergic circuitry, including altered expression
of the 67 kDa isoform of glutamic acid decarboxylase (GAD67), an
enzyme for GABA synthesis in cortical interneurons (Benes
and Berretta, 2001) . Huang and Akbarian (2007)
reported significant decrease in CpG methylation at the proximal GAD1 promoter
in contrast to what was expected that subjects with schizophrenia should show
increased GAD1 DNA methylation. The authors suggested further studies are necessary
in order to determine if these changes are related to altered GAD1 gene transcription,
notably that the schizophrenia subjects in their study had lower GAD1 mRNA levels
in comparison to the matched control (Huang and Akbarian,
2007). In this respect it is worth noting that aberrant methylation of the
CpGs in regulatory region in genome of cancer patients affected gene expression
by changing binding affinity by means of transcription factors (Costello
et al., 2000).
An extensive study carried out by Siegmund and his group, they were able to
identify DNA methylation status at 50 loci, encompassing primarily 59 CpG islands
of genes related to CNS growth and development, in temporal neocortex of 125
subjects ranging in age from 17 weeks of gestation to 104 years old. Two psychiatric
diseases were included Alzheimer and schizophrenia. Disease-associated changes
were limited to 2/50 loci in the Alzheimers cohort, which appeared to
reflect an acceleration of the age-related change in normal brain. The methylation
of PAX8, a gene encoding a paired box containing transcription factor important
for CNS and thyroid development, was higher in schizophrenics than in controls
but this was not considered statistically significant , thus they concluded
that schizophrenia is not accompanied by consistent DNA methylation changes
at the 50 gene loci included in their study (Siegmund et
Epigenetic Therapy of Behavioral and Psychiatric Disorders
As mentioned earlier, the correlation between psychiatric disorders and
the states of genomic methylation is under extensive investigation. The reported
results by Mill et al. (2008) and other investigators
are consistent with possible epigenetic role of DNA methylation changes in schizophrenia,
bipolar disorder and others psychiatric disorders. Knowing that epigegnetic
mechanisms are reversible, hence it is possible to suggest that epigenetic defects
might be repaired. Thus there is possibility to discover and to use suitable
drugs that can amend epigenomic defects; this area of research is called pharmacogenomic
or epigenomic therapy (Zhang et al., 2008). It
is expected that epigenomic therapy can help preventing progression of the disease
caused by epigenetic defects. There are two groups of drugs which have received
the most attention, DNA methyltransferase inhibitors and histone deacetylase
inhibitors (Gavin and Sharma, 2010; Kirk
et al., 2008). In view of growing interest in the epigenetic therapies,
it is worth mentioned the success of epigenetic drugs in cancer treatment, already
there are applications of DNA methylation inhibitors in treatments of cancers.
Two types of DNA methylation inhibitors, azacitidine and decitabine, have generated
much interest in cancer therapies (Ibrahim, 2010).
It is possible to suggest there is a possibility that DNA methylation inhibitors
might have applications in psychiatric therapy. In this respect it was suggested
agents which can reactivate gene expression, such as inhibitors of DNMT1 might
therefore provide improved pharmacological treatment for schizophrenia (Grayson
et al., 2006). On the other hand there are indications of possible
use of other types of epigenetic drugs for treatment of psychiatric disorders.
Phiel et al. (2001) reported that valproic acid
which is one of epigenetic drugs is used widely to treat epilepsy and bipolar
and showed that valproic acid action is through inhibition of histone deacetylase
(HDAC1). The administration of valproate in conjunction with antipsychotic medication
had been shown to accelerate the onset of the antipsychotic effects in patients
with schizophrenia (Casey et al., 2003). It is
interesting to note that valproic acid has shown promising antineoplastic effects
when used concurrently and may increase the antitumor efficacy of current cytotoxic
agents (Chavez-Blanco et al., 2006).
There are reports which indicate that HDAC inhibitors reduce DNA methylation,
although the mechanisms by which HDAC inhibitors reduce DNA methylation are
unknown, it is thought that hyperacetylation can regulate the accessibility
of DNMT1 to promoter regions or that it might induce DNA demethylase activity
(Cervoni and Szyf, 2001; Cervoni
et al., 2002).
Some nutritional components such as S-adenosyl-methionine (SAM) and sulfophrane
can mitigate changes in DNA methylation and chromatin structure akin to those
observed by classical drugs used to treat psychopathology, such as valproic
acid and the monoamine oxidase inhibitors. Several investigators speculated
that nutritional components, especially those to which humans are exposed developmentally
or via sustained exposure, particularly to those which act to modify chromatin,
will have effects on mental health and risk for psychopathology. The possible
involvement of DNA methylation in schizophrenia implies that pharmacological
and nutritional agents, for example methionine treatment which increases SAM
levels in the brain, to aggravate schizophrenia (Brune and
Himwich, 1962; Israelstam et al., 1967).
Other research focused on folate deficiency, this seems to be associated with
depression; however the evidence for an association between aberrant folate
status and schizophrenia seems less convincing (Muntjewerff
and Blom, 2005). Another study showed the possible interactions between
dietary components that modify the DNA methylation machinery and their effects
on mental health in humans, this may be found in the effects of SAM in mood
disorders (McGowan and Kato, 2008). Other investigators
have found SAM to have antidepressive effects (Papakostas
et al., 2003). Interestingly, in one study, nine of 11 patients with
bipolar depression treated with SAM switched to mania, suggesting a specific
effect of SAM on bipolar depression (Carney et al.,
1989). Other investigators reported that methionine infusion reverses the
effect of maternal behavior on DNA methylation, nerve growth factor-inducible
protein-A binding to the exon 1(7) promoter, glucocorticoid receptor (GR) expression
and hypothalamic-pituitary-adrenal and behavioral responses to stress, suggesting
a causal relationship among epigenomic state, GR expression and stress responses
in the adult offspring. The investigators concluded that these results demonstrated
that, despite the inherent stability of the epigenomic marks established early
in life through behavioral programming, they are potentially reversible in the
adult brain (Weaver et al., 2005).
Impact of Environmental Factors on Psychiatric Disorders
Epigenetics provides the link between the environment and the development
of diseases (Sharma, 2005). Environmental factors are
capable of causing epigenetic changes in DNA that can potentially alter imprint
gene expression and that can result in genetic diseases including cancer and
behavioral disorders (Jirtle et al., 2000). The
influence of environmental factors on epigenetic mechanisms in general and DNA
methylation in particular, have been studied and well documented in recent published
literatures and there are indications which prove that these changes in turn
can be inherited by daughter cells during cell division and can also be inherited
through the germ line (Baccarelli and Bollati,2009;
Heindel et al., 2006; Perera
et al., 2009).
Environmental factors affecting DNA methylation include lifestyles, stress,
famine, diet, proteins, drugs, hormones and others. Investigators have provided
evidences on the affect of various environmental factors on the development
of psychiatric disorders. Twin, family and adoption studies have demonstrated
that schizophrenia is a multifactorial disorder in which genetic and environmental
elements contribute to overall risk (Corrigall and Murray,
1994; Ingraham and Kety, 2000; Sullivan
et al., 2003). The influences of famine and nutrition on prevalence
of psychiatric disorders have been under investigation. One study demonstrated
that prenatal exposure to famine significantly increases risk of schizophrenia
in later life (St Clair et al., 2005). On the
other hand several studies have supported the affect of nutrition, notably pre-natal
nutrition was found to exert a significant role in the etiology and severity
of schizophrenia (Abel, 2004; Davis
and Bracha, 1996; Dubertret et al., 2004;
Glatt and Jonsson, 2006; McDonald
and Murray, 2000).
There are indications that exposure to an unfavorable prenatal environment
considerably increases the risk of psychiatric and behavioral disorders later
in life, e.g., schizophrenia (Penner and Brown, 2007)
and autism (Kinney et al., 2008). Experiments
with laboratory animals indicated that prenatal stress can disrupt brain development
(Mulder et al., 2002), through several mechanisms
e.g., alteration of gene expression in neurons (Meaney and
A number of studies have demonstrated an effect of the pre-natal environment
upon susceptibility to eating disorders, with low birth weight repeatedly identified
as a risk factor (Cnattingius et al., 1999; Favaro
et al., 2006; Lindberg and Hjern, 2003; Procopio
and Marriott, 2007). Similarly, the pre-natal environment has been linked
to the risks of developing Attention-Deficit Hyperactivity Disorder (ADHD),
diagnosed among school children. This disorder is characterized by deficient
attention and problem solving, along with hyperactivity and difficulty with
holding incorrect responses; several biological and environmental factors have
also been proposed as risk factors for ADHD, including food additives, diet,
lead contamination, cigarette and alcohol exposure, maternal smoking during
pregnancy and low birth weight (Banerjee et al.,
Humans methylome has an important feature that is its response to
environmental factors. There is increasing evidence which suggests that environmental
exposures early in development have a role in susceptibility to disease in later
life, in addition, some of these environmental effects seem to be passed on
through subsequent generations (Baccarelli and Bollati,
2009; Heindel et al., 2006; Jirtle
and Skinner, 2007; Perera et al., 2009).
In this respect psychiatric disorders are affected by environmental factors
and this might due to epigenomic basis of these disorders and possibly DNA methylation
is at the epicenter of epigenomic mechanisms. It is expected epigenomic research
can give explanation for the relationship between an individual's epigenetic
background, the environment and mental health. It can do so because the epigenetic
state is affected by various external environmental factors, these will make
the methylome varies among individuals and during a lifetime, whereas the DNA
sequence remains essentially the same. It is worth mentioned an epigenetic contribution
to disease was first realized three decades ago, when it was possible to distinguish
human cancer from normal tissues based on DNA methylation levels (Feinberg
and Vogelstein, 1983) . To date, it appears that malignancy represents most
of the diseases for which epigenetic defects have been shown to contribute to
disease pathogenesis (Claus and Lubbert, 2003; Ibrahim,
2010). Thus, it is interesting to consider that epigenetic may play same
role in human mental health. Epidemiological research suggested that both an
individual's genes and the environment underlie the pathophysiology of psychiatric
disorders. There are published results, although some are divisive, have shown
possible role of aberrant DNA methylation profiles in promoter regions of genes
associated with schizophrenia and other psychiatric disorders. To clarify the
role of DNA methylation of the RELN promoter in schizophrenia, further molecular
studies are required. Disregulation of the serotonin (5-HT) system is strongly
implicated in major depression and suicide and the 5-HT1A receptor is a critical
regulator of serotonergic activity, it is expected to develop pharmacogenomic
drugs to reform this defect (Czesaka et al., 2008).
Research in this field is likely to lead to the development and discovery of
epigenetic drugs especially from plant origin (Kirk et
al., 2008) for treatment of various psychiatric disorders. Further more
future studies might investigate the possible role of genomic repetitive sequences
in psychiatric disorders (Batzer and Deininger, 2002;
Collier, 2002) and utilize molecular genomic markers
for early diagnosis and follow up therapy of psychiatric disorders; currently
possible use of specific DNA markers for diagnosis or prognosis is under active
investigation in cancer research (Ibrahim, 2010; Ibrahim
et al., 2009, 2010a, b;
Saleh et al., 2010).
Molecular studies gave evidence that epigenetic regulation is involved in psychiatric disorders such as schizophrenia; bipolar disorder, depression and suicide. DNA methylation profiles of promoter regions of a number of loci were found being altered in the genomes of individuals with psychiatric disorders. Epigenomic studies revealed that environmental conditions affect state of methylome and this has direct impact on gene expression of acquired mental health problems and might cause genomic imprinting allowing environmental effects to be passed through subsequent generations. Epigenomic therapy is promising and might assist in treatment and curing of these disorders.
The author would like to thank International Institute of Education (IIE) for the fellowship.
1: Abdolmaleky, H.M., C.L. Smith, S.V. Faraone, R. Shafa, W. Stone, S.J. Glatt and M.T. Tsuang, 2004. Methylomics in psychiatry: Modulation of gene-environment interactions may be through DNA methylation. Am. J. Med. Genet. B Neuropsychiatr. Genet., 127B: 51-59.
2: Abdolmaleky, H.M., K.H. Cheng, K.H., A. Russo, C.L. Smith and S.V. Faraone et al., 2005. Hypermethylation of the reelin (RELN) promoter in the brain of schizophrenic patients: A preliminary report. Am. J. Med. Genet. B Neuropsychiatr. Genet., 134B: 60-66.
3: Abel, K.M., 2004. Foetal origins of schizophrenia: Testable hypotheses of genetic and environmental influences. Br. J. Psychiatry, 184: 383-385.
4: Antun, F.T., G.B. Burnett, A.J. Cooper, R.J. Daly, J.R. Smythies and A.K. Zealley, 1971. The effects of L-methionine (without MAOI) in schizophrenia. J. Psychiatr. Res., 8: 63-71.
5: Autry, A.E. and L.M. Monteggia, 2009. Epigenetics in suicide and depression. Biol. Psychiatry, 66: 812-813.
6: Baccarelli, A. and V. Bollati, 2009. Epigenetics and environmental chemicals. Curr. Opin. Pediatrics, 21: 243-251.
7: Banerjee, T.D., F. Middleton and S.V. Faraone, 2007. Environmental risk factors for attention-deficit hyperactivity disorder. Acta Paediatr., 96: 1269-1274.
8: Baron, U., I. Turbachova, A. Hellwag, F. Eckhardt and K. Berlin et al., 2006. DNA methylation analysis as a tool for cell typing. Epigenetics, 1: 55-60.
9: Batzer, M.A. and P.L. Deininger, 2002. ALu repeats and human genomic diversity. Nat. Rev. Genet., 3: 370-380.
10: Baumeister, H. and M. Harter, 2007. Prevalence of mental disorders based on general population surveys. Soc. Psychiatry Psychiatr. Epidemiol., 42: 537-546.
11: Beck, S. and V.K. Rakyan, 2008. The methylome: Approaches for global DNA methylation profiling. Trends. Genet., 24: 231-237.
12: Benes, F.M. and S. Berretta, 2001. GABAergic interneurons: Implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology, 25: 1-27.
13: Bertolote, J.M. and A. Fleischmann, 2002. Suicide and psychiatric diagnosis: A worldwide perspective. World Psychiatry, 1: 181-185.
14: Bird, A., 1992. The essentials of DNA methylation. Cell, 70: 5-8.
15: Brune, G.G. and H.E. Himwich, 1962. Effects of methionine loading on the behavior of schizophrenic patients. J. Nerv. Ment. Dis., 134: 447-450.
16: Brunet, A. and T.A. Rando, 2007. Ageing: From stem to stern. Nature, 449: 288-291.
17: Carney, M.W., T.K. Chary, T. Bottiglieri and E.H. Reynolds, 1989. The switch mechanism and the bipolar/unipolar dichotomy. Br. J. Psychiatry, 154: 48-51.
18: Cervoni, N., N. Detich, S.B. Seo, D. Chakravarti and M. Szyf, 2002. The oncoprotein Set/TAF-1β, an inhibitor of histone acetyltransferase, inhibits activedemethylation of DNA, integrating DNA methylation and transcriptional silencing. J. Biol. Chem., 277: 25026-25031.
19: Cervoni, N. and M. Szyf, 2001. Demethylase activity is directed by histone acetylation. J. Biol. Chem., 276: 40778-40787.
20: Casey, D.E., D.G. Daniel, A.A. Wassef, K.A. Tracy and P. Wozniak et al., 2003. Effect of divalproex combined with olanzapine or risperidone in patients with an acute exacerbation of schizophrenia. Neuropsychopharmacology, 28: 182-192.
21: Chen, T. and E. Li, 2006. Establishment and maintenance of DNA methylation patterns in mammals. Curr. Top. Microbiol. Immunol., 301: 179-201.
22: Chen, Y., R.P. Sharma, R.H. Costa, E. Costa and D.R. Grayson, 2002. On the epigenetic regulation of the human reelin promoter. Nucleic Acids Res., 30: 2930-2939.
23: Cheng, X. and R.M. Blumenthal, 2008. Mammalian DNA methyltransferases: A structural perspective. Structure, 16: 341-350.
24: Claus, R. and M. Lubbert, 2003. Epigenetic targets in hematopoetic malignancies. Oncogene, 22: 6489-6496.
25: Cnattingius, S., C.M. Hultman, M. Dahl and P. Sparen, 1999. Very preterm birth, birth trauma and the risk of anorexia nervosa among girls. Arch. Gen. Psychiatry, 56: 634-638.
26: Collier, D.A., 2002. FISH, flexible joints and panic: Are anxiety disorders really expressions of instability in the human genome?. Br. J. Psychiatry, 181: 457-459.
27: Corrigall, R.J. and R.M. Murray, 1994. Twin concordance for congenital and adult-onset psychosis: A preliminary study of the validity of a novel classification of schizophrenia. Acta Psychiatr. Scand., 89: 142-145.
28: Costello, J.F., M.C. Fruhwald, D.J. Smiraglia, L.J. Rush and G.P. Robertson, 2000. Aberrant CpG-island methylation has non-random and tumour-type-specific patterns. Nat. Genet., 24: 132-138.
29: Czesaka, M., J. Lua, C.A. Stockmeierb, M.C. Austin, H.Y. Meltzer and P.R. Albert, 2008. DNA methylation at 5-HT1A receptor promoter C(−1019)G polymorphism CpG sites in schizophrenia and depression. J. Affective Disorders, 107: S53-S122.
30: Davis, J.O. and H.S. Bracha, 1996. Prenatal growth markers in schizophrenia: A monozygotic co-twin control study. Am. J. Psychiatry, 153: 1166-1172.
31: De Luca, V., E. Viggiano, R. Dhoot, J.L. Kennedy and A.H.C. Wong, 2009. Methylation and QTDT analysis of the 5-HT2A receptor 102C allele: Analysis of suicidality in major psychosis. J. Psychiatric Res., 43: 532-537.
32: Dong, E., R.C. Agis-Balboa, M.V. Simonini, D.R. Grayson, E. Costa and A. Guidotti, 2005. Reelin and glutamic acid decarboxylase67 promoter remodeling in an epigenetic methionine-induced mouse model of schizophrenia. Proc. Natl. Acad. Sci. USA., 102: 12578-12583.
CrossRef | PubMed | Direct Link |
33: Dubertret, C., L. Gouya, N. Hanoun, J.C. Deybach, J. Ades, M. Hamon and P. Gorwood, 2004. The 3 region of the DRD2 gene is involved in genetic susceptibility to schizophrenia. Schizophr. Res., 67: 75-85.
34: Eckhardt, F., J. Lewin, R. Cortese, V.K. Rakyan and J. Attwood et al., 2006. DNA methylation profiling of human chromosomes 6, 20 and 22. Nat. Genet., 38: 1378-1385.
35: Favaro, C., A.E. Tenconi and P. Santonastaso, 2006. Perinatal factors and the risk of developing anorexia nervosa and bulimia nervosa. Arch. Gen. Psychiatry, 63: 82-88.
36: Feinberg, A.P. and B. Vogelstein, 1983. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature, 301: 89-92.
37: Gavin, D.P. and R.P. Sharma, 2010. Histone modifications, DNA methylation and Schizophrenia. Neurosci. Biobehav. Rev., 34: 882-888.
38: Glatt, S.J. and E.G. Jonsson, 2006. The Cys allele of the DRD2 Ser311Cys polymorphism has a dominant effect on risk for schizophrenia: evidence from fixed- and random-effects metaanalyses. Am. J. Med. Genet. B Neuropsychiatr. Genet., 141B: 149-154.
39: Grayson, D.R., Y. Chen, E. Costa, E. Dong, A. Guidotti, M. Kundakovic and R.P. Sharma, 2006. The human reelin gene: Transcription factors (+), repressors (-) and the methylation switch (+/-) in schizophrenia. Pharmacol. Ther., 111: 272-286.
CrossRef | PubMed | Direct Link |
40: Grayson, D.R., X. Jia, Y. Chen, R.P. Sharma, C.P. Mitchell, A. Guidotti and E. Costa, 2005. Reelin promoter hypermethylation in schizophrenia. Proc. Natl. Acad. Sci. USA., 102: 9341-9346.
CrossRef | PubMed | Direct Link |
41: Guidotti, A., J. Auta, J.M. Davis, V. Di Giorgi-Gerevini and Y. Dwivedi et al., 2000. Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: A postmortem brain study. Arch. Gen. Psychiatry, 57: 1061-1069.
42: Guil, S. and M. Esteller, 2009. DNA methylomes, histone codes and miRNAs: Tying it all together. Int. J. Biochem. Cell Biol., 41: 87-95.
43: Harvey, M., P. Belleau and N. Barden, 2007. Gene interactions in depression: Pathways out of darkness. Trends. Genet., 23: 547-556.
44: Heindel, J.J., K.A. McAllister, L. Worth and F.L. Tyson, 2006. Environmental epigenomics, imprinting and disease susceptibility. Epigenetics, 1: 1-6.
Direct Link |
45: Hermann, A., H. Gowher and A. Jeltsch, 2004. Biochemistry and biology of mammalian DNA methyltransferases. Cell. Mol. Life Sci., 61: 2571-2587.
46: Hocquette, J.F., 2005. Where are we in genomics?. J. Physiol. Pharmacol., 56: 37-70.
47: Holliday, R., 2006. Epigenetics: A historical overview. Epigenetics, 1: 76-80.
48: Huang, H.S. and S. Akbarian, 2007. GAD1 mRNA expression and DNA methylation in prefrontal cortex of subjects with schizophrenia. PLoS ONE, 2: e809-e809.
49: Ibrahim, M.A., 1978. Genetics basis of behavior. Afaq Jamyia, 2: 37-40.
50: Ibrahim, M.A., 2010. Perspective of DNA methylation in cancer research. Int. J. Cancer Res., 6: 188-201.
CrossRef | Direct Link |
51: Ibrahim, M.A.K., M.A. Dhahee, M.B. Rabee, F.A. Baker and A. Jaber, 2004. DNA methylation polymorphism of aging human ovaries. Selected Res. Papers, 4: 42-49.
52: Ibrahim, M.A., N. Saleh, K.M. Mousawy, N. Al-Hmoud, E. Archoukieh, H.W. Al-Obaide and M.M. Al-Obaidi, 2009. Molecular analysis of RAPD-PCR genomic patterns in age related acute myeloid leukemia. Trends Med. Res., 4: 35-41.
CrossRef | Direct Link |
53: Ibrahim, M.A., N.M. Saleh, M.M. Al-Obaidi and E. Archoukieh, 2010. A RAPD-PCR study on DNA methylation patterns of chronic myeloid leukemia. Proceedings of 2nd AACR Dead Sea International Conference on Advances in Cancer Research, (ACR'10), USA., pp: 66-70
54: Ibrahim, M.A., N. Saleh, E. Archoukieh, H.W. Al-Obaide, M.M. Al-Obaidi and H.M. Said, 2010. Detection of novel genomic polymorphism in acute lymphoblastic leukemia by random amplified polymorphic DNA analysis. Int. J. Cancer Res., 6: 19-26.
55: Ingraham, L.J. and S.S. Kety, 2000. Adoption studies of schizophrenia. Am. J. Med. Genet., 97: 18-22.
56: Inoue, S. and M. Oishi, 2005. Effects of methylation of non-CpG sequence in the promoter region on the expression of human synaptotagmin XI (syt11). Gene, 348: 123-134.
57: Israelstam, D.M., A. Johnson and H.S. Winchell, 1967. Methionine and schizophrenia. J. Nucl. Med., 8: 325-326.
58: Iwamoto, K., M. Bundo, K. Yamada, H. Takao, Y. Iwayama-Shigeno, T. Yoshikawa and T. Kato, 2005. DNA methylation status of SOX10 correlates with its downregulation and oligodendrocyte dysfunction in schizophrenia. J. Neurosci., 25: 5376-5381.
59: Jirtle, R.L., M. Sander and J.C. Barreft, 2000. Genomic imprinting and environmental disease susceptibility. Environ. Health Perpect., 108: 271-277.
Direct Link |
60: Jirtle, R.L. and M.K. Skinner, 2007. Environmental epigenomics and disease susceptibility. Nat. Rev. Genet., 8: 253-262.
CrossRef | PubMed | Direct Link |
61: Jones, P.A. and S.B. Baylin, 2002. The fundamental role of epigenetic events in cancer. Nat. Rev. Genet., 3: 415-428.
CrossRef | PubMed | Direct Link |
62: Kawasaki, H. and K. Taira, 2005. Transcriptional gene silencing by short interfering RNAs. Curr. Opin. Mol. Ther., 7: 125-131.
63: Kessler, R.C., W.T. Chiu, O. Demler, K.R. Merikangas and E.E. Walters, 2005. Prevalence, severity, and comorbidity of twelve-month DSM-IV disorders in the National Comorbidity Survey Replication (NCS-R). Arch. General Psychiatry, 62: 617-627.
Direct Link |
64: Kinney, D.K., K.M. Munir, D.J. Crowley and A.M. Miller, 2008. Prenatal stress and risk for autism. Neurosci. Biobehav. Rev., 32: 1519-1532.
65: Kirk, H., W.T. Cefalu, D. Ribnicky, Z. Liu and K.J. Eilertsen, 2008. Botanicals as epigenetic modulators for mechanisms contributing to development of metabolic syndrome. Metabolism Clin. Exp., 57: S16-S23.
66: Klopfer, P.H., 1974. An Introduction to Animal Behavior. Prentice-Hall Publisher, New York, ISBN-10: 0134779355
67: Kohlrausch, F.B., A. Salatino-Oliveira, C.S. Gama, M.I. Lobato, P. Belmonte de Abreu and M. H. Hutz, 2010. Influence of serotonin transporter gene polymorphisms on clozapine response in Brazilian schizophrenics. J. Psychiatric Res.,
68: Kripke, D.F., 2007. Greater incidence of depression with hypnotic use than with Placebo. BMC Psychiatry, 7: 42-42.
69: Lindberg, L. and A. Hjern, 2003. Risk factors for anorexia nervosa: A national cohort study. Int. J. Eat Disord., 34: 397-408.
70: Lister, L. and J.R. Ecker, 2009. Finding the fifth base: Genome-wide sequencing of cytosine methylation. Genome Res., 19: 959-966.
71: Maher, E.R. and W. Reik, 2000. Beckwith-Weideman syndrome: Imprinting in cluster revisited. J. Clin. Invest., 105: 247-252.
PubMed | Direct Link |
72: McDonald, C. and R.M. Murray, 2000. Early and late environmental risk factors for schizophrenia. Brain Res. Brain Res. Rev., 31: 130-137.
73: McGowan, P.O. and T. Kato, 2008. Epigenetics in mood disorders. Environ. Health Prev. Med., 13: 16-24.
CrossRef | PubMed |
74: McGowan, P.O., A. Sasaki, T.C.T. Huang, A. Unterberger and M. Suderman, et al., 2008. Promoter-wide hypermethylation of the ribosomal RNA gene promoter in the suicide brain. PLoS ONE, 3: e2085-e2085.
75: McKusick, V.A. and F.H. Ruddle, 1987. Toward a complete map of the human genome. Genomics, 1: 103-106.
76: Mann, J.J., 2002. A current perspective of suicide and attempted suicide. Ann. Intern. Med., 136: 302-311.
77: Meaney, M.J. and M. Szyf, 2005. Environmental programming of stress responses through DNA methylation: Life at the interface between a dynamic environment and a fixed genome. Dialogues Clin. Neurosci., 7: 103-123.
78: Mill, J., T. Tang, Z. Kaminsky, T. Khare and S. Yazdanpanah et al., 2008. Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. Am. J. Human Genet., 82: 696-711.
CrossRef | PubMed |
79: Mulder, E.J., P.G. Robles de Medina, A.C. Huizink, B.R. van den Bergh, J.K. Buitelaar and G.H. Visser, 2002. Prenatal maternal stress: Effects on pregnancy and the (unborn) child. Early Hum. Dev., 70: 3-14.
80: Muntjewerff, J.W. and H.J. Blom, 2005. Aberrant folate status in schizophrenic patients: What is the evidence?. Prog. Neuropsychopharmacol. Biol. Psychiatry, 29: 1133-1139.
CrossRef | PubMed |
81: Murphy, B.C., R.L. OReilly and S.M. Singh, 2005. Site-specific cytosine methylation in S-COMT promoter in 31 brain regions with implications for studies involving schizophrenia. Am. J. Med. Genet. B Neuropsychiatr. Genet., 133: 37-42.
82: Nicholls, R.D., S. Saitoh and B. Horsthemka, 1998. Imprinting in prader-willi and angeleman syndromes. Trend Genet., 14: 194-200.
83: Oostra, B.A. and R. Willemsen, 2002. The X chromosome and fragile X mental retardation. Cytogenet. Gen. Res., 99: 257-264.
84: Papakostas, G.I., J.E. Alpert and M. Fava, 2003. S-adenosyl-methionine in depression: A comprehensive review of the literature. Curr. Psychiatry Rep., 5: 460-466.
85: Penner, J.D. and A.S. Brown, 2007. Prenatal infectious and nutritional factors and risk of adult schizophrenia. Expert Rev. Neurother, 7: 797-805.
86: Perera, F., W.Y. Tang, J. Herbstman, D. Tang and L. Levin et al., 2009. Relation of DNA methylation of 59-CpG island of ACSL3 to transplacental exposure to airborne polycyclic aromatic hydrocarbons and childhood asthma. PLoS ONE, 4: e4488-e4488.
87: Petronis, A., 2001. Human morbid genetics revisited: Relevance of epigenetics. Trends. Genet., 17: 142-146.
88: Petronis, A., 2004. The origin of schizophrenia: Genetic thesis, epigenetic antithesis and resolving synthesis. Biol. Psychiatry, 55: 965-970.
89: Petronis, A., I.I. Gottesman, P. Kan, J.L. Kennedy, V.S. Basile, A.D. Paterson and V. Popendikyte, 2003. Monozygotic twins exhibit numerous epigenetic differences: Clues to twin discordance?. Schizophr. Bull., 29: 169-178.
90: Phiel, C.J., F. Zhang, E.Y. Huang, M.G. Guenther, M.A. Lazar and P.S. Klein, 2001. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer and teratogen. J. Biol. Chem., 276: 36734-36741.
91: Poulter, M.O., L. Du, I.C. Weaver, M. Palkovits, G. Faludi and Z. Merali et al., 2008. GABAA receptor promoter hypermethylation in suicide brain: Implications for the involvement of epigenetic processes. Biol. Psychiatry, 64: 645-652.
92: Procopio, M. and P. Marriott, 2007. Intrauterine hormonal environment and risk of developing anorexia nervosa. Arch. Gen. Psychiatry, 64: 1402-1407.
93: Richardson, B., 2003. Impact of aging on DNA methylation. Ageing Res. Rev., 2: 245-261.
94: Saha, S., D. Chant, J. Welham and J. McGrath, 2005. A systematic review of the prevalence of schizophrenia. PLoS Med., 2: 413-433.
95: Saleh, N., M.A. Ibrahim, E. Archoukieh, A. Makkiya, M. Al-Obaidi and H. Alobydi, 2010. Identification of genomic markers by RAPD-PCR primer in leukemia patients. Biotechnology, 9: 170-175.
CrossRef | Direct Link |
96: Sharma, R.P., 2005. Schizophrenia, epigenetics and ligand-activated nuclear receptors: A framework for chromatin therapeutics. Schizophr. Res., 72: 79-90.
97: Siegmund, K.D., C.M. Connor, M. Campan, T. Long and D.J. Weisenberger et al., 2007. DNA methylation in the human cerebral cortex is dynamically regulated throughout the life span and involves differentiated neurons. PLoS One, 2: e895-e895.
98: Sledz, C.A. and B.R. Williams, 2005. RNA interference in biology and disease. Blood, 106: 787-794.
99: Strahl, B.D. and C.D. Allis, 2000. The language of covalent histone modifications. Nature, 403: 41-45.
100: St Clair, D., M. Xu, P. Wang, Y. Yu and Y. Fang et al., 2005. Rates of adult schizophrenia following prenatal exposure to the Chinese famine of 1959-1961. J. Am. Med. Assco., 294: 557-562.
101: Strathdee, G. and R. Brown, 2002. Aberrant DNA methylation in cancer: Potential clinical interventions. Expert. Rev. Mol. Med., 4: 1-17.
Direct Link |
102: Sullivan, P.F., K.S. Kendler and M.C. Neale, 2003. Schizophrenia as a complex trait: Evidence from a meta-analysis of twin studies. Arch. Gen. Psychiatry, 60: 1187-1192.
103: Tamminga, C.A. and H.H. Holcomb, 2005. Phenotype of schizophrenia: A review and formulation. Mol. Psychiatry, 10: 27-39.
104: Tochigi, M., K. Iwamoto, M. Bundo, A. Komori and T. Sasaki et al., 2008. Methylation status of the reelin promoter region in the brain of schizophrenic patients. Biol. Psychiatry, 63: 530-533.
105: Torrey, E.F., B.M. Barci, M.J. Webster, J.J. Bartko, J.H. Meador-Woodruff and M.B. Knable, 2005. Neurochemical markers for schizophrenia, bipolar disorder and major depression in postmortem brains. Biol. Psychiatry, 57: 252-260.
106: Tremolizzo, L., G. Carboni , W.B. Ruzicka, C.P. Mitchell and I. Sugaya et al., 2002. An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability. Proc. Natl. Acad. Sci. USA., 99: 17095-17100.
107: Tsankova, N., W. Renthal, A. Kumar and E.J. Nestle, 2007. Epigenetic regulation in psychiatric disorders. Nat. Rev. Neurosci., 8: 355-367.
108: Turecki, G., 2001. Suicidal behavior: Is there a genetic predisposition?. Bipolar, 3: 335-349.
109: Weaver, I.C., F.A. Champagne , S.E. Brown , S. Dymov and S. Sharma et al., 2005. Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: Altering epigenetic marking later in life. J. Neurosci., 25: 11045-11054.
110: Weissbach, A., 1993. A Chronicle of DNA Methylation, (1948-1975). In: DNA Methylation: Molecular Biology and Biological Significance, Jost, J.P. and H. Saluz (Eds.). Birkhauser Verlag, Berlin, pp: 1-10
111: Zhang, W., R.S. Huang and M.E. Dolan, 2008. Integrating epigenomics in to pharmacogenomic studies. Pharmacogenomics Personalized Med., 1: 7-14.
Direct Link |
112: Zhang, A.P., J. Yu, J.X. Liu, H.Y. Zhang and Y.Y. Du et al., 2007. The DNA methylation profile within the 5-regulatory region of DRD2 in discordant sib pairs with schizophrenia. Schizophrenia Res., 90: 97-103.
113: Zvara, A., G. Szekeres, Z. Janka, J.Z. Kelemen C. Cimmer, M. Santha and L.G. Puskas, 2005. Over-xpression of dopamine D2 receptor and inwardly rectifying potassium channel genes in drug-naive schizophrenic peripheral blood lymphocytes as potential diagnostic markers. Dis. Markers, 21: 61-69.
114: Chavez-Blanco, A., C. Perez-Plasencia, E. Perez-Cardenas, C. Carrasco-Legleu and E. Rangel-Lopez et al., 2006. Antineoplastic effects of the DNA methylation inhibitor hydralazine and the histone deacetylase inhibitor valproic acid in cancer cell lines. Cancer Cell Int., Vol. 6.
CrossRef | Direct Link |