Genetics of Schizophrenia and the New Millennium: Progress and Pitfalls

Abstract

Schizophrenia (MIM 181500) is a severe and common psychiatric disorder afflicting 1% of the world population. The disease is characterized by psychotic symptoms and by cognitive, affective, and psychosocial impairment. As a leading cause of psychiatric admissions, schizophrenia accounts for a considerable portion of health-care expenditures and is viewed as a major public health concern. Despite extensive research, our knowledge of the structural or functional pathology of schizophrenia is limited. The only etiological factor with a reasonably firm foundation is inheritance, as evidenced by family, twin, and adoption studies that point to substantial heritability (Gottesman and Shields 1982; Gottesman 1991; Kendler and Diehl 1993). In the premolecular era, attempts to discern the underlying genetic mechanism consisted of (1) segregation analysis, testing the fit of observed familial patterns to specific genetic formulations (e.g., single–major-locus, oligogenic, and multifactorial-polygenic models); (2) searching for genetic susceptibility traits, also known as “biological markers,” that segregate with the disorder in families (e.g., neurotransmitter enzymes, receptor proteins, or metabolites; attentional and electroencephalographic measures; and indices based on brain imaging); and (3) linkage studies that used classical gene markers (e.g., leukocyte antigens, blood groups, or serum proteins). However, in spite of numerous studies, the genetic underpinnings of schizophrenia remain elusive. The disorder, which is confounded by a host of factors (e.g., phenotypic diversity, etiologic heterogeneity, incomplete penetrance, unknown mode of inheritance, uncertainty about the number of loci involved and about their interactions, and the existence of nongenetic cases or phenocopies), was consigned to a complex multifactorial etiology, with no firmly established biological correlates (Baron 1986a and 1986b; Risch 1990b; Kendler and Diehl 1993). A single major locus is unlikely as a common mode of inheritance. Oligogenic or polygenic models are plausible alternatives. The advent of molecular genetics was a turning point in schizophrenia research, enabling the systematic application of both reverse genetics (studying random, anonymous DNA markers spanning the genome) and forward-genetics (testing candidate-gene polymorphisms with presumed functional relevance for the disease) (Martin 1987; Baron and Rainer 1988; Owen and Craddock 1996). In this article I review molecular genetic findings about schizophrenia, with an eye toward methodological issues and future research.