ABSTRACT

Abstract .................................................................................................................. 209 15.1 Introduction .................................................................................................. 210 15.2 Defining the Phenotype ............................................................................... 210 15.3 Does Genetic Variation Contribute to the Etiology

of Schizophrenia?......................................................................................... 211 15.3.1 Family Studies.................................................................................. 211 15.3.2 Twin Studies..................................................................................... 213 15.3.3 Adoption Studies.............................................................................. 214

15.4 What Is the Nature of Genetic Effects on Schizophrenia? ......................... 216 15.4.1 Only Genetic Effects? ...................................................................... 216 15.4.2 How Many Genes?........................................................................... 217

15.5 Where on the Chromosomes Are Schizophrenia Liability Genes Located? ............................................................................. 219

15.6 Which Genes Contribute to Schizophrenia Liability? ................................ 220 15.7 Conclusions .................................................................................................. 222 References.............................................................................................................. 222

Genetic research on the phenotype of schizophrenia is reviewed to illustrate the strategies, problems, and findings encountered in the study of a genetically complex, relatively common, dysfunctional behavioral phenotype. Schizophrenia provides an excellent case history for these purposes because it has one of the longest histories and most socially costly presence of any psychopathological phenotype. Family, twin, and adoption studies are consistent in indicating that genetic effects on schizophrenia are both important and complex. Genetic “model-fitting” to risk data for different relative classes also suggests that: (1) environmental experiences that are uncorrelated among siblings probably interact with the relevant genotypes to contribute to (or protect from) schizophrenia, (2) action of “abnormal” alleles in multiple genes seems likely

for most schizophrenia cases, and (3) phenotypically normal (non-schizophrenic) individuals with “unexpressed” genetic liability exist, confusing molecular genetic studies as false negatives. Genetic linkage and association studies attempting to locate and identify individual genes of probably modest effect have to-date produced numerous positive and negative findings with frequent failures to replicate. However, a second generation of more sophisticated studies suggests increased reasons for cautious optimism that the nature of the genetic effects on schizophrenia will be revealed in the foreseeable future.