This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Schizophrenia (SZ) susceptibility has a large genetic component, and in another preliminary study, the PI performed initial genetic testing of GCH1, the first gene in the BH4 biosynthesis pathway, genotyping a polymorphism for association with SZ in a sample of 132 subjects (86 SZ and 46 control). They found that GCH1 was strongly associated with SZ: odds ratio, 5.0, p = 0.0057. They also been found that GCH1 allele status predicts low biopterin in SZ patients. Based on these very positive preliminary data, and the fact that some SZ subjects without the GCH1-associated genotype have a biopterin deficit, this exploratory study is designed to test the hypothesis that DNA variants in the GCH1 and other BH4 biosynthesis-related genes are associated with and influence biopterin levels and are candidate SZ susceptibility loci. The investigators will employ Re-Sequencing Arrays to search for DNA variants that may influence gene expression and/or protein function. Sequence data generated in this study will be analyzed for association with low biopterin levels and subject diagnosis. They propose to compare bloods obtained from a group of 90 SZ patients with a group of 90 controls and compare the plasma tetrahydrobiopterin levels with the expression of genes of the biopterin pathways. For the relatively small group of medication-na ve SZ patients there will be a repeat blood draw after treatment and before and after contrasts. The investigators recognize that diet can have a large effect on the biopterin level and propose a statistical control for this confound. Although this is an exploratory study, a positive finding will suggest the possibility of a dramatically different set of therapeutic targets.
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