CLINICAL HANDBOOK OF SCHIZOPHRENIA

58 I. CORE SCIENCE AND BACKGROUND INFORMATIONthe familial transmission of schizophrenia. If genes are important, then the familial transmissionof the illness should occur in the biological family but not in the adoptive family.In contrast, if culture, social learning, or other sources of environmental transmissioncause schizophrenia, familial transmission should occur in the adoptive family but not inthe biological family.Question 3: What Is the Mode of Transmission?Once twin and/or adoption studies demonstrate that the familial transmission of a disorderis due at least in part to genetic factors, it becomes necessary to identify the manner inwhich those genetic factors exert their influence. The mode of transmission of schizophreniathrough multiply affected families can be modeled statistically through the use of segregationanalysis. A model of familial transmission translates assumptions about geneticand environmental causes into mathematical equations. These equations are then used topredict the distribution of a disorder that we observe in pedigrees. If the pattern of disorderpredicted by a given model is close to what we observe, then this provides evidence infavor of that model. In contrast, if the predicted pattern of disorder differs from what isobserved in the pedigree, then we reject the model and seek another mechanism of transmission.Segregation analysis is a flexible procedure that can test various known and hypothesizedmodes of genetic transmission; the familiar Mendelian model of single-gene transmissionof a trait is only one of many transmission mechanisms that can be tested. In general,these alternative models can be assigned to three classes: single major gene,oligogenic, and multifactorial polygenic models. The word major indicates that one genecan account for most of the genetic transmission of a disorder, while other genes and environmentalconditions may play minor roles in modifying the expression of the disease.In contrast, an oligogenic model assumes that the combined actions of several genes causeillness. These genes may combine in an additive fashion, such that the probability of illnessis a function of the number of pathogenic genes; alternatively, the mechanism may beinteractive. The multifactorial polygenic (MFP) model proposes that a large, unspecifiednumber of genes and environmental factors combine in an additive fashion to causeschizophrenia. The difference between oligogenic and polygenic models is one of degree;the former test for effects of “several” genes (e.g., less than 10), whereas the latter evaluatea “large number” of genes (e.g., 100).Although the MFP model posits that many genes and environmental factors contributeadditively to development of a disorder, these individual factors are not directly modeled.According to the model, liability toward developing the disorder is normally distributed,and individuals above a certain threshold on the liability scale manifest the illness. Morethan one threshold may be placed along the liability continuum, representing varying degreesof severity. Thus, individuals beyond the threshold may develop a severe form of thedisorder; those under the threshold may have minor problems or be unaffected; and thosewhose liability falls between the two thresholds may have an intermediate form of thedisorder.Question 4: Where are the Genes Located?Knowing the manner in which a heritable psychiatric disorder is transmitted throughfamilies is useful for designing optimal molecular genetic studies to reveal the chromosomallocation. To identify regions of chromosomes that have a high likelihood of harboringrisk genes for schizophrenia, linkage analysis is a highly appropriate strategy.Families are ascertained for linkage analysis through a proband affected with schizophre-