A R T I C L E Inhibitory Neurophysiological Deficit as a Phenotype for Genetic Investigation of Schizophrenia ROBERT FREEDMAN,* C.E. ADAMS, LAWRENCE E. ADLER, PAULA C. BICKFORD, JUDITH GAULT, JOSETTE G. HARRIS, HERBERT T. NAGAMOTO, ANN OLINCY, RANDAL G. ROSS, KAREN E. STEVENS, MERILYNE WALDO, AND SHERRY LEONARD Many investigators have proposed that biological endophenotypes might facilitate the genetic analysis of schizophrenia. A deficit in the inhibition of the P50 evoked response to repeated auditory stimuli has been characterized as a neurobiological deficit in schizophrenia. This deficit is linked to a candidate gene locus, the locus of the 7-nicotinic cholinergic receptor subunit gene on chromosome 15q14. Supportive evidence has been found by other investigators, including: 1) linkage of schizophrenia to the same locus; 2) linkage of bipolar disorder to the locus; and 3) replication of the existence of this neurobiological deficit and its relation to broader neuropsychological deficits in schizophrenia. It is certain that there are many genetic factors in schizophrenia and bipolar disorder; what is needed is a complete and precise description of the contribution of each individual factor to the pathophysiology of these illnesses. J. Med. Genet. (Semin. Med. Genet.) 97:58–64, 2000.  2000 Wiley-Liss, Inc. KEY WORDS: schizophrenia; genetics; nicotinic receptors; inhibition; auditory evoked potential INTRODUCTION A complex illness is one that does not result from a single genetic abnormality. Complexity is not only obvious from schizophrenia’s non-Mendelian inheri- tance pattern, but it is also the likely situation for an illness that has no single defined biological deficit [Tsuang et al., 1990]. After several major efforts, the current findings consist of many linkage signals of moderate effect on several dif- ferent chromosomes [Cao et al., 1997; Blouin et al., 1998]. Similarly, despite intensive studies using a variety of dif- ferent techniques, no single biological abnormality has emerged as the major pathogenic factor. These two conun- drums may well reflect the same prob- lem, i.e., schizophrenia likely results from the interaction of several genetic and non-genetic pathogenic factors. A central thesis of our work has been that one solution to the dual genetic and biological complexity is to attempt to solve both of them simultaneously for discrete elements within schizophrenia itself. Linkage of a putative brain deficit in schizophrenia to a specific chromo- somal site provides strong evidence that the deficit is indeed a discrete neu- robiological dysfunction in the illness. Conversely, the most powerful pheno- types for linkage are likely to be dis- crete neurobiological deficits that result from the effect of a single gene. Al- though this strategy has not been widely used in schizophrenia, it has been successful in a number of other genetic illnesses, that, like schizophre- nia, cluster in families but do not have Mendelian inheritance. Hemochroma- tosis is perhaps the best known; serum ferritin proved to be a better marker of genetic affection than the illness itself [Borecki et al., 1990]. Another example is colon cancer, where the expression of polyps, rather than clinical cancer itself, is the inherited phenotype [Leppert et al., 1990]. Robert Freedman is Professor of Psychiatry and Pharmacology at the University of Colorado and co-director of the Denver VA Medical Center Schizophrenia Research Center, where the other authors are also affiliated. He is a NARSAD distinguished investigator and a psychia- trist interested in the neurobiological basis of schizophrenia. Cathy Adams, Assistant Professor of Psychiatry, is a neurobiologist interested in the neuroanatomy and neuroembryology of schizophrenia. Lawrence E. Adler, Professor of Psychiatry, is a psychiatrist interested in the neuro- pharmacology of schizophrenia. Paula C. Bickford, Associate Professor of Pharmacology, studies the neurobiology of sensory processing in animal models of schizophrenia and other illnesses. Judith Gault, Instructor of Psychiatry, is a NARSAD young investigator and geneticist, who is interested in the genetic transmission of schizophrenia. Josette Harris, Assistant Professor of Psychiatry, is a neuropsychologist interested in the inheritance of neuropsychological dysfunction in schizophrenia. Ann Olincy, Assistant Professor of Psychiatry, is a NARSAD young investigator and a VA Research Career psychiatrist, who is interested in nicotinic receptor function in schizophre- nia. Randal G. Ross, Assistant Professor of Psychiatry, is a NARSAD mid career investigator and a VA Research Career psychiatrist, who is interested in children at risk for schizophre- nia. Karen Stevens, Assistant Professor of Psychiatry, is a neuropharmacologist who is interested in animal models of schizophrenia. Merilyne Waldo, Assistant Professor of Psychiatry and NARSAD young investigator, is a psychologist interested in cross cultural studies of schizophrenia. Sherry Leonard is Associate Professor of Psychiatry and VA Research Career Scientist and co-director of the VA Schizophrenia Center. She is interested in the molecular biology of nicotinic receptors and their relevance to the genetics of schizophrenia. *Correspondence to: Professor of Psychiatry and Pharmacology, Vice-chairman, De- partment of Psychiatry, Campus Box C-268-71, University of Colorado Health Sciences Cen- ter, 4200 East Ninth Avenue, Denver CO 80262. E-mail: Robert.Freedman@uchsc.edu AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) 97:58–64 (2000) © 2000 Wiley-Liss, Inc.