PLEIOTROPIC EFFECTS OF GENES LINKED TO SCHIZOPHRENIA

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DESCRIPTION (provided by applicant): For many years this laboratory has focused intensively on characterizing schizophrenia-related traits (SRTs) as qualitative and quantitative phenotypes for schizophrenia. Three of these SRTs - thought disorder with schizophrenic features, eye tracking dysfunction and a craniofacial anomaly involving the frontonasal-maxilllary junction - stand out as especially probative for clarifying the neurobiological interpretation of schizophrenia susceptibility loci. Each of these traits has a much higher recurrence in relatives of schizophrenics than in schizophrenics. Moreover, unlike schizophrenia, which is generally thought to involve a number of co-acting genes, the family data on the SRTs are consistent with monogenic transmission models, and may therefore clarify the complex genetics of schizophrenia. The massive investment by NIMH in searching for genes for schizophrenia has resulted in an impressive number of promising candidate genes and chromosomal regions. Our progress in characterizing SRTs places us in an ideal position to determine whether any of these SRTs is linked to identified genes and "warm spot" regions for schizophrenia. We recognize, of course, that not all of the reported linkages will be replicable, but the probability is high that some of them are authentic, and the added cost of taking an inclusive view of the candidate loci is modest. Our power analyses show that the density of individuals affected with the SRTs in families of a schizophrenic proband is sufficiently high that, given a candidate locus associated with the SRT, the probability of our being able to detect that relationship is very high. If any of the genetic loci that have been linked to schizophrenia can be shown to be linked to any of the SRTs, it would open the way for building a neurobiological bridge between the disease phenotype and its genetic underpinnings, and it would add considerably to the confidence one can have in the reported linkages. Because of our laboratory's long involvement in investigating schizophrenia-related traits, the substantial number of families already acquired and thoroughly studied with respect to these traits and the expertise of our statistical and molecular genetics collaborators, our laboratory is uniquely positioned to carry out these studies.