Miscellaneous associations

Additional schizophrenia associations include: GABBR1 (GABAb receptor) on chr6p21.3, a Ser9Gly polymorphism in the DA D3 receptor,40 the 5HT2A receptor, and CAPON (carboxy-terminal PDZ ligand of neuronal nitric oxide synthase). The reproducibility and uniqueness of these associations to schizophrenia is still under debate. The large number of studies focused on elucidating the genetic basis of schizophrenia and the multiple genetic foci thus far identified appear to be inversely proportional to the knowledge gained in understanding disease causality and treatment.27 Thus it is likely that another decade will be needed for the many interesting gene targets and their contribution to the hypotheses of disease causality will be put in an appropriate context. Schizophrenia is a complex genetic disorder with multiple risk genes of small effect that are made more complex by possible allelic heterogenicity and epistatic influences.7 In several instances (G72, GRM-3, and GRIN1) the genetic findings recapitulate (and are probably influenced by) existing hypotheses, in this instance, the glutamate hypothesis. In others, e.g., DISC1, the target for therapeutic intervention is unclear and in one, COMT, ignoring the multiple disease implications,82,83 both the disease associations and the drugs, e.g., COMT inhibitors, are available to prove the value of genome-based disease causality and its treatment. This has not occurred, a possible reflection of the currently available COMT inhibitors lacking access to the brain. In this context, it is also of considerable interest that there is minimal agenetic evidence to support the concept that DA receptor antagonists, i.e., the current treatment modalities for schizophrenia, would be useful in the treatment of schizophrenia.

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