Connecting genomic findings in schizophrenia and intermediate phenotypes

There is evidence for a strong genetic component in the etiology of schizophrenia, as demonstrated by family, twin and adoption studies. The risk of developing the disease increases exponentially with the genetic relatedness to an individual suffering from the disorder. Furthermore, schizophrenic patients, and their unaffected relatives display alterations in brain function (intermediate phenotypes). We use complementary strategies to approach the pathobiology and genetics of schizophrenia including genetic association studies as well as animal and cell culture models. We first aim to identify schizophrenia genes in a large case-control and family-based study. Over 1000 patients, 200 first degree relatives and 2500 community-based healthy volunteers entered the study. Furthermore, the use of schizophrenia-related intermediate phenotypes represents a complementary approach which has been used in this study. These comprise, among others, neuropsychological (e.g. working memory, attention/vigilance, verbal/visual learning and memory, speed of processing, and problem solving) intermediate phenotypes. Additionally, we use an NMDA-receptor antagonist animal model which mimics aspects of psychosis to identify candidate genes which can be used in human studies. High-throughput targeted and genome-wide genotyping was performed.