Schizophrenia is an often devastating neuropsychiatric illness whose etiology remains unknown despite considerable study. Genetic factors have been strongly and consistently implicated in its etiology via the quasi- experimental tools of family, adoption, and twin studies. Historically, the molecular genetics of schizophrenia has been controversial due to a disturbing pattern of highly publicized single studies followed by multiple non-replications. Developments in the scientific literature over the past two years very strongly suggest a fundamental shift in the field. By our count, there are 12 genes for which there is compelling evidence from multiple different samples/types of evidence for involvement in the etiology of schizophrenia. Therefore, it seems evident that research into the molecular genetics of schizophrenia has """"""""turned the corner"""""""". However, the field is at a critical juncture. To avoid uncertainty, confusion, and disillusionment, there is an urgent need for additional study of these genes in large and well-characterized samples. To achieve this end, we propose here an efficient, brief, inexpensive, but highly rigorous exploration of these 12 candidate genes for schizophrenia. Our overarching goals are essentially twofold, to add to the body of data on these genes in one of the largest case-control studies yet conducted for schizophrenia and to extend this work using additional phenotypes in a well-characterized sample. We propose a genetic case-control association study of 800 genetic markers in 12 candidate genes for schizophrenia. All of these genes are expressed in brain regions relevant to schizophrenia and have substantial evidence via prior linkage and association studies. Our marker coverage is more systematic and complete than in any prior study. Cases are ~1,000 individuals with schizophrenia who participated in CATIE (a large, NIMH-funded trial of multiple antipsychotic medications). Controls are from a US national sample and will be matched by age band, gender, and ancestry. Ascertainment, phenotyping, blood sampling, and cell line creation were all funded via other NIMH grants and all samples will be available at the start of this project. The analytic methods are advanced and take into account the known weaknesses of this study design. Therefore, we request support for only genotyping and data analysis. We believe that the results of our study will be highly informative and are essential to the field at this critical juncture in the hunt for genes mediating liability to schizophrenia. ? ?
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