S-55-01

Theory and practice in quantitative genectics: The use of endophenotypes in detecting QTLs for schizophrenia

D. Posthuma. Department of Biological Psych, Amsterdam, Netherlands

S-55-02

Genetic variations underlying electrophysiological endophenotypes in schizophrenia

F. Thibaut. INSERM EM19906, 1RFMP, Facult, Rouen, France

Objective: Twin and adoption studies, as well as familial clustering, have supported a genetic aetiology for schizophrenia. A model involving numerous interactive genes with minor effects interacting with environmental factors is hypothesized. The complexities of the genetics of schizophrenia and the lack of precise phenotype definition have made classical genetic studies quite unproductive.

Methods: Alternative genetic strategies have been used such as the endophenotype strategy. As suggested by previous studies, abnormal sensory gating, measured by the P50 paradigm, could be an endophenotype predisposing to schizophrenia. In addition, we have measured simultaneously three electrophysiological paradigms in schizophrenic patients, non schizophrenic firstdegree relatives and normal controls: P50 inhibition, antisaccade paradigm and smooth pursuit. We have evaluated the concordance rates among these 3 markers.

Results: We have shown a significant association between the presence of at least one -2 bp deletion located within exon 6 of the alpha7-1ike nicotinic receptor subunit gene and the P50 sensory gating deficit in the general population. We have also reported a significant association between the promoter -194C polymorphism of the nicotinic alpha7 receptor (CHRNA7) gene and a normal P50 sensory gating. The concordance rates among the three electrophysiological markers will be reported.

Conclusion: A recent study has reported polymorphisms located in the core promoter region of the CHRNA7 gene as risk factors for the sensory gating deficit. This -194C allele polymorphism is probably in linkage disequilibrium with other causal variations for the P50 sensory gating deficit. The three different paradigms measure different aspects of central inhibition.

S-55-03

Genetic analyses using eye movement disturbances as endophenotypic marker in schizophrenia

F. Rybakowski, A. Borkowska, P. Czerski, J. Hauser. Poznan University of Med. Sci. Psychiatry, Poznan, Poland

Objective: Eye movement disturbances occurring during fixation and smooth pursuit task have been suggested as endophenotypic marker for genetic studies of schizophrenia. The aim of this study was to find a possible relationship of these disturbances with polymorphism of selected genes of dopaminergic system, using candidate gene approach, in schizophrenic patients.

Methods: Eye movement disturbances during fixation and smooth pursuit task were measured by infrared reflectometry system. Genotyping of Ser9Gly polymorphism of dopamine receptor D3 (DRD3) gene, Vall58Met polymorphism of gene for catechol-Omethyltransferase (COMT) and SNP polymorphism in the first intron of cytosolic phospholipase A2 (cPLA2) gene were performed.

Results: An association was found between the intensity of abnormal eye tracking and Ser9Gly polymorphism of DRD3 gene: higher intensity of both kinds of disturbances was associated with Ser allele. The study of Val158Met polymorphism of gene for COMT, the enzyme metabolizing dopamine in prefrontal cortex, revealed an association between Met allele and lower intensity of eye movement disturbances in male schizophrenic patients. A connection was found between a greater degree of eye movement abnormalities and A2/A2 genotype ofcPLA2, the key enzyme of the phospholipid metabolism, also influencing dopaminergic activity.

Conclusion: The results obtained may show an association between eye movement disturbances and genes of dopaminergic system in schizophrenia. Abnormal eye tracking can be viewed as one pleiotropic manifestation of schizophrenia and association of polymorphism of various genes with eye movement disturbances may be stronger that with the illness itself.

S-55-04

Endophenotypes for molecular genetic studies in schizophrenia

D. Rujescu. Department of Psychiatry, Ludwig-Maximilians- University, Munich, Germany.

Clinical classification systems in psychiatric disorders, including schizophrenia, may describe heterogeneous disorders implying that the current clinical psychiatric classification might not be optimal for genetic studies. Therefore, simpler, quantifiable measures of neuropsychiatric functioning may be more useful in gene discovery. This approach helps to circumvent questions about etiological models. The rationale for the use of endophenotypes in gene discovery is that the endophenotypes associated with a psychiatric disorder are more elementary compared to clinical phenotypes. This also implies that the number of genes required to produce variations in these traits may be fewer than those involved in producing a psychiatric diagnostic entity. Endophenotypes are thus likely to bridge the gap between genes and clinical phenotypes. We describe our strategy which includes a broad range of schizophrenia endophenotypes and present new data.