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Psychiatric Genetics: Schizophrenia

Molecular genetics of schizophrenia

Investigators: B. Lerer, K. Kanyas, O. Karni, Y. Kohn, R.H. Segman, N. Turetsky. A. Yakir (with D.B. Wildenauer, University of Bonn, A. Hamdan and M. Kaadan, Taibe Mental Health Center and Schizophrenia Working Group, Israel Consortium for Molecular Psychiatry).

There is strong evidence from family, twin and adoption studies implicating a major genetic component in the pathogenesis of schizophrenia. Current research efforts are aimed at locating and identifying the genes involved. This work has been a major focus of the Laboratory since its inception. The strategies that are implemented include:

  • Linkage studies in large samples consisting of families with more than one affected member.
  • A separate linkage study (genome scan) in a unique, inbred, ethnically homogeneous family sample recruited from the Arab population of Israel. [SEE RESEARCH NEWS]
  • Association studies in population-based case control samples and family based association samples.
Our linkage studies, conducted in collaboration with the University of Bonn, have culminated in a recently completed genome scan. This shows suggestive evidence of linkage in 6 chromosomal regions (5q, 6p, 6q, 10p, 18q, 22q). The genome scan on our Arab family sample (recruited in collaboration with Dr. Adnan Hamdan) is currently being performed in Jerusalem in collaboration with Prof. Bathsheva Kerem and Dr. Mira Korner of the Hebrew University, Life Sciences Institute. One of the largest of the kindreds that are included in the genome scan is shown in simplified form in the accompanying diagram.

Our case control association studies of schizophrenia overlap intriguingly with our studies on the molecular genetics of tardive dyskinesia that are described separately.

Identity by descent haplotype sharing in psychiatric patients from a genetic isolate in Israel: Localization of genes involved in the inheritance of psychotic disorders.

Investigators: Y. Kohn, B. Lerer (with Dr. E. Danilowitz, Eitanim Mental Health Center, Jerusalem)

Identical By Descent (IBD) haplotype sharing is a non-parametric method which is suited to the identification of genes responsible for disorders in small and genetically isolated populations. Compared to more traditional methods of genetic analysis, it requires a smaller number of individuals who have to be studied because of a putative common mutation responsible for the disease. The aim of this project is to study the genetics of psychotic disorders with a known genetic component, such as schizophrenia, bipolar disorder and schizoaffective disorder, in one Moslem Arab village using the method of IBD haplotype sharing. In this village, which is genetically isolated, psychiatric morbidity is high. As many psychiatric patients as can be identified in the village are being recruited for the project. IBD haplotype sharing will be sought in affected individuals in order to find a common mutation. 35 patients have already been ascertained in the first steps of this project. Increased IBD haplotype sharing would indicate a possible location for genes contributing to these psychiatric disorders, and will allow further fine mapping of these regions.

Refining the clinical phenotype of schizophrenia for genetic studies

Investigators: A. Yakir, K. Kanyas, O. Karni, N. Turetsky, B. Lerer

Linkage analysis of affected sibling pairs is a core strategy in current efforts to establish the molecular genetic basis of schizophrenia. The samples studied generally include probands and affected siblings with schizophrenia (SCZ), schizoaffective disorder (SA) and unspecified functional psychosis (UFP) (according to Research Diagnostic Criteria) or schizophreniform disorder according to DSM-IV. This strategy presupposes a shared genetic basis for SCZ, SA and UFP (or schizophreniform disorder). If this is so, it is reasonable to assume that probands and affected sibs with any one of the above diagnoses will resemble each other in core clinical characteristics of their illness. To explore this question, we are studying pairs of siblings made up of subjects affected with SCZ, SA or UFP according to Research Diagnostic Criteria (RDC). We are using bivariate and multivariate approaches to analyze clinical features including factor analysis. In an extension of this project we are examining the clinical and neurocognitive characteristics of unrelated probands who carry alleles reported as associated with schizophrenia or tardive dyskinesia.