Alternative phenotypes for the complex genetics of schizophrenia

The complexity of the genetics of schizophrenia has been described by many investigators. In the absence of simple Mendelian inheritance, genetic linkage has not achieved the definitive results found in other illnesses, where such methods have led to the identification of responsible genes. Alternative phenotypes for linkage analysis are proposed as one solution to this problem. These phenotypes, representative of discrete biological deficits in schizophrenia, may more closely reflect the effect of a single gene than the illness itself. The Mendelian inheritance of one alternative phenotype, failure to inhibit the P50 auditory evoked response to repeated stimuli, has resulted in successful linkage of the deficit to the locus of a candidate gene, the α7-nicotinic acetylcholine receptor on chromosome 15q14. Further support for this linkage has recently been found in families from the NIMH Schizophrenia Genetics Initiative, using schizophrenia as the phenotype. Alternative phenotypes based on discrete biological deficits in schizophrenia have enhanced power for linkage analysis. Such analyses can not only facilitate understanding of the genetic transmission of schizophrenia, but they also provide further support for neurobiological characterizations of the pathophysiology of schizophrenia; however, identification of responsible genetic mutations is necessary before definitive conclusions can be reached.