Psychiatric Genetics:
Affective and Other Disorders
Molecular genetics of bipolar disorder
Investigators: B. Lerer, K. Kanyas, O. Karni, R.H. Segman, N. Turetsky (with M. Baron, Columbia University, New York and the European Collaborative Project on Affective Disorders)
Like schizophrenia, bipolar disorder has a strong genetic component which has been demonstrated by family twin and adoption studies. Strategies to seek the genes involved also employ linkage and association approaches. For linkage studies of BPD we are recruiting a series of multiply affected families that are being genotyped in collaboration with Dr. Miron Baron of Columbia University, New York. This is a long standing collaboration whose most prominent finding has been fairly well replicated evidence for a predisposing locus on chromosome 21q. We have also recruited a case control sample for association studies of bipolar disorder and are implementing this approach in the collaborative context of the European Collaborative Project for Affective Disorders (Biomed II) of which our Laboratory is a prominent member.
Genetic susceptibility to eating disorders
Investigators: R. Segman, K. Kanyas, B. Lerer (With: E. Berry, Dept. of
Nutrition; Y. Latzer and M. Bloch, Rambam Hospital, Haifa).
Eating disorders (ED) constitute a severe illness affecting adolescents and young woman, showing a growing incidence and high morbidity and mortality. The etiology of ED is multifactorial. Genetic vulnerability may predispose some individuals to develop extremely abnormal eating behavioral patterns. Functionally significant genetic polymorphisms altering the expression or function of proteins encoded by relevant genes may predispose to ED or modify the clinical characteristics and severity of these behavioral patterns. The objective of this study is to search for association of candidate genes with ED. In order to increase the efficacy of the search for contributing genes, we are concentrating on a narrow extreme phenotype of Anorexia Nervosa and are using a haplotype relative risk design. The putative contribution of candidate genes to the diagnosis of anorexia nervosa as well as to selective behavioral dimensions within this extreme phenotype, are being examined.
Genetics of Attention Deficit and Hyperactivity Disorder
Investigators: R. Segman, E. Galili - Wiesstub
Attention Deficit and Hyperactivity Disorder (ADHD), is an idiopathic disorder affecting 4%-10% of school aged children. Without early detection and treatment, ADHD affects learning and social interaction and consequently personality development and self-esteem at a critical period of development. Previous studies have shown considerable heritability in the transmission of ADHD, however the mode of inheritance and actual genes involved are unknown. The aim of the current study is to identify candidate genes contributing to the risk for ADHD. The study recruits children diagnosed as suffering from ADHD treated at the Child Psychiatry center and Child Neurology Units. Children and their parents undergo a comprehensive diagnostic process and a blood sample is taken for DNA extraction and genetic analysis of allelic transmission employing haplotype relative risk (HRR) and transmission disequilibrium analyses. We are examining the contribution of the dopamine transporter as well as other candidate loci. Findings could aid in the development of predictors for early detection of children at risk and could contribute to the development of more effective and safer medications.
Human brain gene expression correlates of common genetic variation in serotonergic genes
Investigators: R. H. Segman, I. Ariel (Pathology)
The study of common functional genetic variations in the context of hypothesis driven search for genetic association with psychiatric disorders is based on the assumption that such variations will have a direct biological contribution to the phenotype under investigation. However the actual functional significance in normal brain tissue for the majority of polymorphic sites commonly employed for association with psychiatric disorders in recent years, has not been directly examined. Therefore, the actual biological implications and appropriate method of analysis for heterozygosity and homozygosity status cannot be established in the numerous genetic association studies of psychiatric disorders published to date. The serotonergic system has been the focus of intensive study in psychiatric research, mainly owing to its crucial role as a target for psychotropic drugs. The serotonin transporter and serotonin 2a/c receptors are the focus of considerable interest. The genes encoding these key proteins have been found to posses common genetic variations that may result in altered gene expression. We are examining the impact of these mutations on mRNA expression in post mortem samples of normal human fetal brain tissue employing reverse transcription PCR. Results will expand our understanding of the functional significance of common genetic variation in the normal brain and will inform genetic association studies of complex phenotypes.
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