The discovery of susceptibility genes for mental disorders.

R on the genetic basis of mental disorders crossed a major watershed this summer. For the first time, specific genes have been discovered that influence susceptibility to schizophrenia, a psychosis that affects nearly 1% of people throughout the world and accounts for about 2.5% of health-care costs (1). In this issue of PNAS, Chumakov and colleagues (2) describe a new human gene, G72, on chromosome 13q34 that interacts with the gene for Damino acid oxidase (DAAO) on 12q24 to regulate glutaminergic signaling through the N-methyl-D-aspartate (NMDA) receptor pathway. Using traditional positional cloning techniques of linkage and linkage disequilibrium, they show that both of these genes are associated with increased susceptibility to schizophrenia. Therefore, this is the first discovery of a specific gene that also provides a pathogenic molecular mechanism that can account for the major symptoms of a psychiatric disorder. Similarly, two other groups reported this summer that the gene dysbindin on 6p22.3 (3) and the gene neuregulin 1 on 8p (4) also influence susceptibility to schizophrenia and may operate via the same NMDA mechanism. Each of these gene discoveries came from association analysis targeting chromosomal regions first identified by linkage analysis. The success of groups working on three different chromosomal regions of interest confirms the effectiveness of traditional positional cloning techniques in complex mental disorders. Consequently, these results justify optimism for future progress in unraveling complex disorders in which there is interaction among multiple genetic and environmental variables. However, it is important to recognize both the strengths and the limitations of the genetic and functional strategies used by Chumakov and colleagues (2). It is also important to recognize the continuing significance of the prior work that laid the foundation for these particular experiments. Twin and adoption studies demonstrated that susceptibility to schizophrenia is strongly heritable even if children are reared apart from their biological parents. When one twin has schizophrenia, the risk of schizophrenia in the co-twin is greater in monozygotic twins (45%) than in dizygotic twins (15%). However, 40% of the monozygotic co-twins of a person with schizophrenia are clinically normal (5). Furthermore, the risk of illness decreases with degree of genetic relationship more rapidly than can be explained by a single gene or the sum of effects of several such genes. Thus, the inheritance pattern of schizophrenia suggested that multiple genes, each of small effect, interacted nonlinearly with one another and with environmental factors to influence susceptibility (6, 7). This prediction has now been confirmed by more than 20 genomewide linkage scans in more than 1,200 families of schizophrenics. These studies found evidence for several genes of small effect; that is, genes that modify susceptibility but are neither necessary nor sufficient to cause the disorder. However, no evidence was found for any genes with a large individual effect, such as a Mendelian subtype of schizophrenia. By 1997 there were replications in some, but not all, linkage studies for susceptibility genes in regions of chromosomes 6p, 8p, and 22q (7). Now another 5 years of work by many groups has expanded the list of regions of interest to include target regions on 1q21–q22, 6q21–q22.3, and 13q34, as well as less consistent evidence for broad regions of 2q, 3p, 5q, 10p, and 11q (8). The chromosomal locations of the four recently discovered susceptibility genes for schizophrenia are illustrated schematically in Fig. 1. The linkage of schizophrenia to the 15q14 locus of the -7 nicotinic receptor has also been replicated, but does not provide a pathogenic mechanism producing the major symptoms of schizophrenia (9). Until this summer, there was no success in the positional cloning of a susceptibility gene that could explain the major symptoms of schizophrenia or any other nondementing psychiatric disorder. When there are contributions to susceptibility from several genetic and environmental factors, as in schizophrenia, linkage analysis has much less sensitivity for detection of specific genes than does association analysis (10). The most efficient design for detection of specific genes in a complex disorder is the comparison of cases and controls (11). However, association studies in the past often have yielded false positive results because of population stratification and the low prior probability of true association. Consequently, the robustness of findings is improved by working in ethnically homogeneous samples and by targeting chromosomal regions with a high probability of true association based on prior evidence of linkage in the region. This is exactly what was done by Chumakov and colleagues (2). They carried out an association study in the region of 13q34 where they had found prior evidence of linkage. This linkage had been replicated in some other studies (12), but not all (8). Such variability in linkage in different populations is expected for a disorder that depends on the interaction of multiple factors. No particular gene is necessary or sufficient to cause disease, so different genes and environmental factors influence susceptibility in different families. Accordingly, Chumakov and colleagues carried out their initial association study in the sample of the French-Canadian population in which the initial linkage finding had been observed. In addition, they were able to replicate their discovery of a novel human gene they call G72 in an independent Russian sample. The replication of the association findings, following the replication of linkage in the targeted region, provides sound statistical support for G72 being a true susceptibility gene for schizophrenia. What are even more persuasive, however, are the functional studies that were carried out. The functional studies identify a specific pharmacological mechanism that is already known to induce the symptoms of schizophrenia. G72 was found to interact with the gene for DAAO, which oxidizes D-serine. In turn, the binding of D-serine to the glycine modulatory site on the NMDA receptor is needed for glutamate to activate the receptor. Certain combinations of alleles of G72 and DAAO increased the risk of schizophrenia significantly more than the sum of their individual effects, which is evidence of what is called epistasis, or nonadditive