This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Keywords: schizophrenia, genetics, linkage analysis, sequence analysis Abstract: Schizophrenia is a common disabling disorder, with a lifetime prevalence of 1%. Its pathogeneis is unknown and treatment remains pallitative. Because non-genetic eniological factors are obscure and the heritability is relatively high (60-70%), genetic investigations may hold the key to understanding etiology. Yet conlcusive findings remain elusive. In common with other complex disorders, linkage studies have not been consistent. While linkage studies are a sound approach when searching for liability genes, they have low resolution. These challenges are compounded int he USA by difficulties in recruiting large pedigrees. On the other hand, candidate gene association studies have been even less successful, presumably because the selected genes have low prior probability of conferring liability. We will build on the strengthes of both approaches by screening positional candidate genes, chosen because of a plausible hypothesis of schizophrenia liability. Our hypothesis is simple to motivate. Extensive functional, pharmacological and biochemical data implicate dysfunctional dopamine (DA) transmission in the pathogenesis of schizophrenia. Indeed, we and others have detected credible linkage and association with DA genes. Thus we hypothesize that a substantial portion of liability to schizophrenia is due to genes influencing DA neurotransmission. This hypothesis, however, implicates a forbiddingly large list of genes, which is why it is critical to assess only positional candidates- those for which is larger prior probablity.
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