Despite the limitations of the accumulated linkage and association studies, there are good suggestions that these studies have identified plausible candidate genes for schizophrenia. Table 2 summarizes the evidence in support of a set of possible candidate genes for schizophrenia. Reports supporting the role of many of these genes have appeared in top-tier international journals known for rigorous peer review. The evidence for several genes is encouraging but currently insufficient to declare any a clear-cut cause of schizophrenia.
The accumulated data provide particular support for DISC1, DTNBP1, NRG1, and RGS4. Each of these genes has received support from multiple lines of evidence with imperfect consistency: 1) The case for each of these as a candidate gene for schizophrenia is supported by linkage studies; 2) The preponderance of association study findings provides further support; 3) mRNA from each gene is expressed in the prefrontal cortex as well as in other areas of the brain; and 4) Additional neurobiological data link the functions of these genes to biological processes thought to be related to schizophrenia. For example, DISC1 modulates neurite outgrowth, there is an extensive literature on the involvement of NRG1 in the development of the CNS, and RGS4 may modulate intracellular signaling for many G-protein-coupled receptors. Moreover, DTNBP1 and RGS4 have been reported to be differentially expressed in postmortem brain samples of individuals with schizophrenia.
This encouraging summation of work in progress masks a critical issue—the lack or consistent replication for the same markers and haplotypes across studies. The literature supports the contention that genetic variation in these genes is associated with schizophrenia, but it lacks impressive consistency in the precise genetic regions and alleles implicated. In contrast, association studies of other complex human genetic diseases have produced unambiguous, consistent, and clear-cut (“hard”) replication. For example, 1) in Type 1 diabetes mellitus, the bulk of both the linkage and association data implicate the HLA region and INS [22]; 2) for Type 2 diabetes mellitus, there are a number of findings in the literature where the association evidence appears to be consistent and compelling (CAPN10, KCNJ11, and PPARG)—the data indicate that the same marker allele is significantly associated and has an effect size of similar direction and magnitude [22] (the linkage data are less congruent, probably due to power considerations); and 3) for age-related macular degeneration, at least five studies show highly significant association with the same CFH Y402H polymorphism [23–27] in a region strongly implicated by multiple linkage studies. For these findings, the data are highly compelling and consistent and provide a solid foundation for the next generation of studies to investigate the mechanisms of the gene–phenotype connection. Power/type 2 error appears to be a major factor—if the genetic effect is sufficiently large (HLA in Type 1 diabetes mellitus or CFH in age-related macular degeneration)—or, if the sample size is large, then there appears to be a greater chance of “hard” replication.
At present, the data for schizophrenia are confusing, and there are two broad possibilities. The first possibility is that the current findings for some of the best current genes are true. This implies that the genetics of schizophrenia are different from other complex traits in the existence of very high degrees of etiological heterogeneity: schizophrenia is hyper-complex, and we need to invoke more complicated genetic models than other biomedical disorders. The alternative possibility is that the current findings are clouded by Type 1 and Type 2 error. Schizophrenia is similar to other complex traits: it is possible that there are kernels of wheat, but it is highly likely that there is a lot of chaff. At present, the second and more parsimonious possibility has not been rigorously excluded. The impact of Type 1/Type 2 error is likely, and it is not clear why schizophrenia should be inherently more complex. At present, we cannot resolve these possibilities.
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