The fundamental discovery of this project is the identification of the alpha7-nicotinic acetylcholine receptor as a strong candidate gene for an inherited physiological dysfunction in schizophrenia. The scientific work of the past 10 year-funding period has led to: (1) discovery of the alpha7-nicotinic receptor's neurobiological role in an inhibitory deficit associated with schizophrenia, (2) the first genetic linkage of the inhibitory deficit, as well as schizophrenia itself, to the chromosome 15q14 locus of the alpha7-nicotinic receptor gene, (3) the first evidence for decreased expression of this receptor in the hippocampus of schizophrenics, (4) the first description of the complex genomic structure of the human alpha7-nicotinic receptor gene, and (5) the first evidence for co-dominant inheritance of inhibitory deficits in childhood-on set schizophrenia. This renewal application seeks to replicate the current findings of linkage of an inhibitory neurophysiological deficit (Aims 1 and 2), and then extend the findings to a broader phenotype based on neuropsychological evaluation of probands and their relatives who do or do not carry genetic risk (Aim 3) and to a broader range of illnesses that have been associated with the alpha7-nicotinic receptor locus, viz. childhood-onset schizophrenia and bipolar disorder (Aims 4 and 5). The initial study used a neurobiological phenotype, i.e., the P50 inhibitory deficit, to find genetic linkage; in the replication, this new genetic information will now be used, first to improve precision, and then to broaden the description of this phenotype. Schizophrenia and bipolar disorder are complex illnesses with multiple genetic and non-genetic elements. The goal of this project is elucidate one of these elements as they are discovered.

R01MH038321

1984-04-01

2006-04-30