Psychiatric Neurogenetics
Head: Dr. James L. Kennedy
Genetic factors play a role in causing schizophrenia, bipolar affective
disorder, some anxiety disorders, alcoholism, eating disorders, autism,
impulse control disorders and some dementias. Researchers in the Psychiatric
Neurogenetics Section, headed by Dr. J. Kennedy, are actively searching
for the abnormal genes involved in the causes, expression, treatment and
possible cures of these disorders. The section houses one of the world's
most comprehensive collections of interview data and DNA samples from
patients with psychiatric disorders, and their families, allowing researchers
to pursue diverse lines of inquiry and make extensive comparisons among
mental illnesses. Aided by new technology in molecular genetics, Psychiatric
Neurogenetics researchers have contributed significantly to advances in
the understanding of a variety of psychiatric disorders.
Two general strategies are used in the lab. In one strategy, investigators
scan all the human chromosomes, using a wide array of DNA markers, in
the hope of discovering a disease gene without prior knowledge of the
brain processes involved. In the second, researchers test genes known
or believed to be involved in the brain function in psychiatric diseases,
such as dopamine receptor genes in schizophrenia.
Trinucleotide Repeat
Expansion Mutation in Major Psychosis
We have identified a new gene on chromosome 13, termed SCA8, where unstable
DNA has been suggested to be involved in a very rare form of autosomal
dominant movement disorder (Vincent et al., 2000, 2001). In contrast with
other researchers' hypotheses regarding the rare SCA8 disorder, we observed
across a sample of 1,800 individuals that about one per cent of DNA samples
from control individuals, and about two per cent of patients with schizophrenia,
have the expansion mutation at this site.
Psychiatric Pharmacogenetics:
Antipsychotic Response and Side-Effects
There is a great deal of variability in response and side-effects to
antipsychotic medications among individual patients who have schizophrenia.
At clinically relevant doses, some patients will fully respond to antipsychotic
medications, while others will fail to respond, and have poor outcomes
as a result. In addition, a subset of patients will develop significant
side-effects to antipsychotic therapy, which impairs patient compliance
and might also increase their risk for comorbid conditions and even death.
Using one of the best characterized samples for antipsychotic treatment
response and side-effects in the world, we have generated significant
and intriguing pharmacogenetic data along three fronts: response to the
atypical antipsychotic, clozapine; weight gain induced by clozapine; and
antipsychotic-induced tardive dyskinesia (TD), a debilitating motor system
disease characterized by abnormal and involuntary movements.
With respect to clozapine response, we have published numerous studies
examining DNA sequence variation across several key receptors from the
serotonin and dopamine systems (Masellis et al., 1998; 2001; Ozdemir et
al., 1999). A particular DNA variant in the serotonin 2A (5-HT2A) receptor
gene was found to significantly predict non-response to clozapine (Masellis
et al., 1998). We have recently summarized the results across all pharmacogenetic
studies of clozapine response and have provided a critical discussion
of this body of literature (Masellis et al., 2000). This has resulted
in the generation of a series of recommendations, which, when initiated,
should lead to improved study design and quality of the collected pharmacogenetic
data.
Weight gain is a serious side-effect of antipsychotic therapy. Clozapine,
in particular, has the highest propensity of all antipsychotics to lead
to increased weight. As a result, we have tested the hypothesis that DNA
sequence variant across key neurotransmitter genes and those expressing
molecules involved in energy utilization are associated with susceptibility
to weight gain (Basile et al., in press). This work is the first to provide
a comprehensive analysis of the literature and to develop rationale for
each of the studied candidate genes. Preliminary results suggest that
genetic variation in adrenergic receptor subtypes, ß3 and *1a, the
serotonin 2C receptor, and the Tumour Necrosis Factor a genes may be involved
in clozapine-induced weight gain.
Some patients are more susceptible than others to TD, even when they
receive similar doses of antipsychotics. This suggests genetic factors
may be involved in the liability to developing this side-effect.
We have previously shown that a DNA sequence difference in an important
brain gene, the dopamine D3 receptor, is a susceptibility factor for TD
(Basile et al., 1999). This finding has subsequently been replicated by
a number of other groups around the world, and appears to be an important
factor in predicting this serious side-effect. Furthermore, the gene CYP1A2,
involved in the metabolism of antipsychotic drugs by the body, shows predictive
power for risk of TD in our sample (Basile et al, 2000).
Psychiatric Epigenetics
The data on the human DNA sequences are of enormous value in revolutionizing
biological research and clinical medicine; however, the complete genome
sequence is only a beginning in understanding the human genome. One of
the greatest mysteries is how the potential of the 35,000 human genes
present within each cell of the organism is regulated and controlled.
Despite their genetic identity, cells from different tissues look different
and perform very different functions.
It is now believed that this precise level of regulation is achieved
by the so-called epigenetic regulation of genes. The essence of epigenetics
consists in the ability to keep some genes active in one type of cell
but switched off in another type of cell. For example, although dopamine
system genes are present both in brain and blood cells, such genes are
active only in the neurons but not in the blood cells. The opposite scenario
applies to the gene encoding hemoglobin, which is "active" in
the erythrocytes but is "dormant" in the brain cells. This simple
example indicates the primary importance of epigenetic regulation for
the normal functioning of every cell. Disruption of the normal epigenetic
regulation of a gene can be very harmful to a cell and may result in a
disease. Epigenetics is a relatively young field of study, but it is proving
to be an important branch of human biology.
Over the past few years, we have been intensively investigating the role
of epigenetic factors in major psychiatric illness. We began our epigenetic
studies with theoretical re-analysis of the main etiological hypotheses
of schizophrenia and bipolar disorder, and concluded that epigenetics
is able to explain various seemingly unrelated clinical and molecular
findings in these major psychotic disorders. A significant advantage of
the epigenetic theory is its ability to unify a wide variety of biological
and psychological theories as well as empirical findings that pertain
to major psychosis under the epigenetic "umbrella." Epigenetics
may become the "master key" to numerous "locks" of
major psychosis. We also operationalized the main laboratory techniques
of epigenetics, and have performed a series of studies investigating epigenetic
regulation of dopamine receptor genes in people with schizophrenia, epigenetic
differences in identical twins and experimental animals and epigenetic
changes after treatment with antipsychotics, among others. Our papers
on epigenetics of schizophrenia and bipolar disease were published in
the top psychiatry and genetics journals, such as Neuropsychopharmacology,
Schizophrenia Bulletin, Molecular Psychiatry, The American Journal of
Human Genetics and Trends in Genetics, among numerous others.
Psychiatric epigenetics is an innovative development in psychiatric research,
and to our knowledge, we are the only group in the world fully dedicated
to this development. Psychiatric epigenetic projects may contribute significantly
to understanding the molecular basis of mental illness and addictions,
and may lead to detection of epigenetic disease markers, which would help
to identify individuals who are at risk of developing psychiatric diseases.
If epigenetic changes are detected, the next logical step is to design
epigenetic therapeutic agents. Since epigenetics represents the "interface"
between the cell (genome) and the environment, such a program would also
facilitate the integration of biological and clinical research, and more
specifically the understanding of biological reactions to hazardous environmental
factors. With the support of the CAMH Foundation, we are now in the process
of building a comprehensive CAMH Epigenetics Research Program in psychiatric
and other human complex diseases.
Testing People Who Have
Bipolar Disorder and Their Relatives
After we collected one of the world's largest samples of patients with
bipolar disorder and their immediate relatives, we collaborated with the
Mood Disorders Program and tested, with promising results, several genes
of neurotransmitter systems (dopamine, serotonin, glutamate) that may
confer susceptibility to bipolar disorder.
In the context of our psychiatric pharmacogenetic research, we studied
the genes that may confer susceptibility to the side-effect of antidepressant-
induced mania. Recently, we have found that one of the variants of a gene
in the serotonin system (the serotonin transporter protein gene) plays
an important role in conferring risk to antidepressant-induced manic episodes
in people who have bipolar disorder (Mundo et al, 2000, 2001). Using a
genetic test to identify patients at risk of developing of this dangerous
side-effect will considerably improve the clinical management of bipolar
disorder.
The Genetics of Obsessive-Compulsive
Disorder
In collaboration with Dr. Richter of the Anxiety Disorders Clinic, we
are continuing our search for genes for obsessive-compulsive disorder
(OCD).
The main hypothesis for OCD is that genes in the serotonin system are
involved in determining risk and medication response. We found that a
variant of one of these genes (the 5-HT1Dbeta) appears to increase the
risk of developing OCD (Mundo et al, 2000).
In January 2001, Dr. Mundo was funded the Dean's Fund Competition for
New Staff Grant by the University of Toronto to study the role of the
5HT1Dbeta gene in determining the severity of symptoms and other relevant
clinical features of OCD. This same neurotransmitter system is also implicated
in our collaborative study with Drs. Levitan, Kaplan and Sid Kennedy examining
the molecular genetics of seasonal affective disorder
and eating disorders.
Also, we are taking a genetic approach to studying the autoimmune disorder,
associated with OCD, that resembles the etiology of Sydenham's Chorea.
We have preliminary positive results with the cytokine activating Myelin
Oligodenrocyte Glycoprotein gene. These results were presented by Dr.
Richter in the Late Breaking News section of the International Society
for Psychiatric Genetics in St. Louis, Missouri.
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