CLINICAL HANDBOOK OF SCHIZOPHRENIA

60 I. CORE SCIENCE AND BACKGROUND INFORMATIONsis subsequent to linkage analysis as a means to follow up on evidence for increased geneticsimilarity at a locus among affected individuals in a family (i.e., a “positional candidategene” approach). Alternatively, specific genes can be examined in the absence oflinkage information if there is some compelling reason to suspect that the gene influencesrisk for a given disorder (i.e., a “functional candidate gene” approach). For example, dopaminesystem genes, such as receptors and transporters, are commonly examined asfunctional candidates for schizophrenia. In contrast to linkage analysis, which uses randomDNA markers as proxies for nearby risk genes, genetic association analysis is the appropriatemethod for determining whether a particular gene variant has a direct effect onrisk for schizophrenia, or is very tightly linked to such a gene.If a gene influences risk for schizophrenia, then this should be detectable as an increasedfrequency of the risk allele of the gene (or a tightly linked marker allele in anearby gene) in cases relative to controls. Within the context of the family, this would bedetectable as an increased likelihood of a patient with schizophrenia receiving the risk alleleof the gene from his or her parent, even when both the risk and normal forms of thegene were present in the parent and could have been transmitted with equal frequencyand likelihood.In a case–control association study, we simply count the number of each type of alleleof a gene that is found in cases and compare these counts with the allele distributionseen in the control group (this process can also be performed for genotypes). A simplestatistical test can then be used to determine whether the distribution of alleles observedin the group of cases is different from that seen in the control group. If it is different, thenwe have found evidence for a genetic association with schizophrenia, where the allele thatis overrepresented in the group of cases is considered the risk allele. The degree ofoverrepresentation of the risk allele in cases relative to controls can be used to derive anodds ratio, which gives a numeric indication of an individual’s chance of being affectedby a disorder if he or she possesses the risk allele. In family-based studies, we can useanalogous statistics to determine whether any difference from the expected equal inheritanceof risk and normal alleles of a gene is detected in affected probands who could havereceived either allele from their parent. In a family-based study, the odds ratio estimatesthe haplotype relative risk, which represents the increase in the probability of the affectedoffspring receiving the risk allele relative to the normal allele.Family StudiesMAJOR FINDINGSThe results of many family studies of schizophrenia strongly support the hypothesis thatschizophrenia has a genetic etiology. Anecdotal evidence of the familial nature of schizophreniawas first offered more than a century ago by Kraepelin, who noted that as manyas 70% of his patients with dementia praecox were familial cases. It was not until 1916,however, that the first systematic assessment of familial patterns of schizophrenia was undertakenby Rüdin (1916). In this first of many family studies of schizophrenia, the closerelatives of an affected individual were found to have a sixfold increase in risk for developingthe illness themselves. Subsequent reports routinely replicated a pattern of higherschizophrenia prevalence among the relatives of patients with schizophrenia. A quantitativereview of 40 family studies of schizophrenia revealed a consistent pattern of elevatedrisk among relatives of affected individuals, with the degree of risk contingent upon thedegree of biological relation to the patient. It is noteworthy, however, that this relationshipwas not linear: The risk to first-degree relatives was more than twice that to second-