CLINICAL HANDBOOK OF SCHIZOPHRENIA

62 I. CORE SCIENCE AND BACKGROUND INFORMATIONgrees is that the disorder is not transmitted in a Mendelian fashion. For example, if a singledominant gene caused schizophrenia, 50% of individuals with one parent with schizophreniawould develop the disorder themselves; yet only 13% of such individuals actuallybecome affected. Alternatively, if the disorder were caused by a single recessive gene, everyindividual with two affected parents would develop schizophrenia, but less than 50%of these individuals actually do.It is also quite clear that, unlike Huntington’s disease or other diseases caused by mutationsin a single gene, schizophrenia has multiple genetic determinants. Models thatposit a single major locus for schizophrenia are unable to predict accurately the incidenceof the disorder in the parents, siblings, MZ twins, and DZ twins of a patient with schizophrenia.Through the analysis of segregation of schizophrenia through families, such amode of inheritance has been rejected in favor of polygenic and multifactorial models.The evidence to support this etiological model is substantial. For example, such a modelcan account for varying degrees of severity of the disorder and, thus, the inheritance ofsubthreshold schizophrenia spectrum conditions in schizophrenia pedigrees. Furthermore,the risk for schizophrenia is related to both the number of cases and the severity ofschizophrenia among an individual’s relatives. The nonlinearity of the relationship betweenrisk and biological relation to a patient with schizophrenia observed in family andtwin studies is also strong evidence for a polygenic mechanism. A multifactorial polygenicexplanation of this finding is strengthened further by allowing for epistasis among the putativerisk genes.Linkage AnalysesThe results of no less than 18 independent genomewide linkage analyses have been publishedto date. Each of these studies has identified at least one chromosomal region inwhich some evidence for linkage between a marker and a putative schizophrenia-relatedgene was observed. Although the findings from these genomewide linkage scans do notentirely overlap, this is not unexpected given the methodological differences between thestudies, including the regional distribution and lineage of ascertained target populations,the type and spacing of genotyped markers, and the various phenotypic definitions ofschizophrenia applied to subjects. To narrow down the search for genetic linkage withschizophrenia, Badner and Gershon (2002) performed a meta-analysis of all previousgenomewide linkage scans. The results of this pooled analysis identified loci on chromosomes8p, 13q, and 22q as the best candidates to harbor schizophrenia-relevant riskgenes. Other promising regions included chromosomes 1q, 2q, 6q, and 15q, but evidencefor linkage at these loci was weaker, indicating a need for further replication. The resultsof these genome scans, and especially the more powerful meta-analysis, should informsubsequent efforts to examine linkage within finite, densely mapped regions of individualchromosomes. The alleles of specific genes that may eventually be identified from suchmethods can then be tested directly for association with the disorder.Association AnalysesMany genes have been tested for an association with schizophrenia, because they eithercode for proteins thought to be involved in the pathology of the disorder or map to achromosomal region implicated in the disorder by linkage analysis. In the former group,several genes have been verified in large, pooled samples to have a small but reliable influenceon risk for the disorder. Some of these include the genes coding for the serotonin