Psychiatric Neurogenetics: CAMH Research Annual Report 2002

Genetic factors play a role in causing schizophrenia, bipolar affective disorder, anxiety disorders, alcoholism, eating disorders, autism, impulse control disorders, and some dementias. Researchers in the Psychiatric Neurogenetics Section, headed by Dr. James Kennedy, actively search for the abnormal genes involved in the cause, expression, treatment, and possible cure 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 from their families, allowing researchers to pursue diverse lines of inquiry and make extensive comparisons among mental illnesses. Aided by technology in molecular genetics, Psychiatric Neurogenetics researchers work to further our understanding of psychiatric disorders.

Psychiatric Epigenetics

Epigenetics deals with regulation of gene activity. It postulates that dysregulation of normal sequence genes may be as detrimental to a cell as the dna mutations that have been the primary target of traditional genetic linkage and association studies.

Epigenetic theory unifies a wide variety of biological and psychological theories, as well as empirical findings, that pertain to major psychosis. Over the past few years, we have been intensively investigating the role of epigenetic factors in major psychiatric illness. We performed an in-depth theoretical analysis of the epigenetic mechanisms that were assumed be operating in major psychosis (Petronis, 2001).

The epigenetic principles suggested for schizophrenia and bipolar disorder can be extrapolated and applied to a wide variety of other complex non-Mendelian disorders, such as diabetes, multiple sclerosis, rheumatoid arthritis and psoriasis, among others (Petronis, 2001).

In the laboratory, we have demonstrated that even genetically identical organisms such as monozygotic twins exhibit numerous epigenetic differences (Petronis et al. in press; submitted). This finding provides the basis for a series of new explorations in phenotypic discordance (non-identity for a disease) in identical twins, an unexplained phenomenon in human biology for more than 80 years.

Psychiatric epigenetics is an innovative development in psychiatric research, and to date, we represent the only group in the world fully dedicated to this development. With the support of the CAMH Foundation we are continuing to build a comprehensive CAMH Epigenetics Research Program in psychiatric and other human complex diseases.

Psychiatric Genetics

Three 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 knowing the brain processes involved. In the second, researchers test the structure of genes known or believed to be involved in the brain function in psychiatric diseases, such as dopamine receptor or serotonin receptor genes in schizophrenia. The third strategy analyses regulation of genes; dysregulation of normal genes may increase the risk for a disease.

Candidate Genes and Attention Deficit and Hyperactivity Disorder

We have investigated numerous candidate genes for their role in neuropsychiatric disorders. In collaboration with Dr. Cathy Barr (Research Scientist, the Toronto Western Hospital), we analysed genetic variation in the genes encoding adrenergic and dopamine receptors in people who have attention deficit and hyperactivity disorder (ADHD ) (Barr et al. 2001, a; b; c). Our results were consistent with those from other groups showing the dopamine transporter locus as a candidate gene for C.

Phenotype for Bipolar Disorder

In bipolar disorder we examined the second messengerG-protein beta 3 subunit gene that may be involved in the action of lithium. The bipolar patients were biochemically characterized in terms of calcium homeostasis by Dr. Jerry Warsh's group. This resulted in an innovative phenotype to examine in bipolar disorder (Corson et al. 2001).

Molecular Mechanisms of Major Psychosis

With Dr. Carlos Pato (Professor of Psychiatry, State University of New York at Syracuse), we detected further evidence that the alpha 7-nicotinic receptor gene (CHRNA7) contributes to the
risk of being affected with schizophrenia (Xu et al. 2001). In this study, we found that only paternal CHRNA7 is a risk factor to schizophrenia. This finding indicates the importance of epigenetic regulation in understanding the molecular mechanisms of major psychosis.

Trinucleotide Repeats in Portuguese Schizophrenia and Bipolar Patients

We continue to investigate the intriguing finding, first described by Vincent et al (2000), that unstable DNA in the form of trinucleotide repeats is increased in Portuguese schizophrenia and bipolar patients from the Azores Islands.

Serotonin System Genes and Bulimia Nervosa

In collaboration with Drs. Robert Levitan, Alan Kaplan, and Sid Kennedy, we evaluated the impact of genetic variation of the serotonin system genes (serotonin-1B receptor, HTR1B) on the body mass index in women affected with bulimia nervosa (Levitan et al. 2001). According to our data, we identified a possible association between HTR1B genetic polymorphism and body mass index. This finding may shed light on why, in response to dieting, some patients with bulimia nervosa are able to lose significant amounts of weight, whereas others have a natural limitation to their weight loss. Pending replication in a larger sample, these findings point to a possible genetic factor of fundamental importance to the bulimia nervosa population.

Psychiatric Pharmacogenetics

Although in its infancy, psychiatric pharmacogenetics will in the future aid clinical practice in the prediction of response and side-effects and minimize the current "trial and error" approach to prescribing medications.

Antidepressant -Induced Mania

Our group was the first to detect evidence that genetic variation in the serotonin transporter gene may account for abnormal response to medication in people with bipolar disorder (Mundo et al., 2001). We investigated "antidepressant-induced mania," a common side-effect in treatment of depression.

We found that carriers of a "short" version of the serotonin transporter gene exhibit a significantly higher probability of switching to a manic phase of the disease in comparison to people who carry a "long" serotonin transporter gene. A genetic test can help us identify patients at risk for the development of this potentially dangerous side-effect -- a finding that will considerably improve the clinical management of bipolar disorder.

Antipsychotic Response and Side-Effects

Individual people with schizophrenia vary widely in their response and side-effects to antipsychotic medications. Using one of the best characterized samples for antipsychotic treatment response and side-effects in the world, we continued our lines of pharmacogenetic research: response to the atypical antipsychotic, clozapine; weight gain induced by clozapine; and antipsychotic-induced tardive dyskinesia, a debilitating motor system disease characterized by abnormal and involuntary movements.

We have published numerous studies examining clozapine response and dna sequence variation across several key receptors from the serotonin and dopamine systems (Masellis et al., 2001; Ozdemir et al., 2001a, b). We evaluated the role of polymorphisms in dopamine D3 receptor (DRD3) and CYP1A2 genes for propensity to develop tardive dyskinesia in patients with schizophrenia. Combining pharmacogenetic analysis of pharmacokinetic and pharmacodynamic targets for antipsychotics should improve our ability to identify subpopulations that differ in drug safety profile.

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. Because of this, we have tested if and how dna sequence variants of the genes encoding brain receptors and the molecules involved in energy utilization are associated with susceptibility to weight gain (Basile et al., 2001).

To analyse patient susceptibility to clozapine-induced weight gain, we tested 10 genetic polymorphisms across nine candidate genes, including the serotonin 2C, 2A, and 1A receptor genes (HTR2C/2A/1A); the histamine H1 and H2 receptor genes (H1R/H2R); the cytochrome p450 1a2 gene (CYPIA2); the beta3- and alpha-adrenergic receptor genes (ADRB3/ADRA1A); and tumor necrosis factor alpha (TNF-alpha). We collected prospective weight gain data for 80 patients with schizophrenia who completed a structured clozapine trial. We observed promising trends for ADRB3, ADRA1A, TNF-alpha, and HTR2C.

This work is the first to provide a detailed methodological analysis of the literature on the obesity-related pathways and to develop rationale for other molecular genetic studies in this field of pharmacogenetics.