Elsevier

The Lancet

Volume 361, Issue 9355, 1 February 2003, Pages 417-419
The Lancet

Rapid Review
Genes for schizophrenia? Recent findings and their pathophysiological implications

https://doi.org/10.1016/S0140-6736(03)12379-3Get rights and content

Summary

Context

Schizophrenia is highly heritable, but the genes have remained elusive. Identifying the genes is essential if the pathogenesis and pathophysiology of schizophrenia is finally to be understood, and to give the prospect of more effective treatment.

Starting point

H Stefansson and colleagues (Am J Hum Genet 2002; 71: 877–92) showed association of the neuregulin (NRG1) gene with schizophrenia. Other recent papers describe six additional susceptibility genes. Replications are already being reported for some of them. The genes are biologically plausible, and may have convergent effects on glutamatergic and other synapses. We review the evidence for each gene, the possible pathogenic mechanisms, and the implications of the findings.

Where next?

Given earlier failures to replicate apparent breakthroughs, the results should be viewed with caution. Unequivocal replications remain the top priority. The respective contributions of each gene, epistatic effects, and functional interactions between the gene products, all need investigation. Confirmation that any of the genes is a true susceptibility gene for schizophrenia could trigger the same rapid therapeutic progress as has occurred recently in Alzheimer's disease.

Section snippets

Recent studies

Most of the studies (table) focused on chromosomal regions implicated by earlier data, and used various methods to refine the region of linkage, identify single nucleotide polymorphisms (SNPs) within the area, find the SNPs associated with schizophrenia, and identify the candidate gene(s) containing the associated SNPs and haplotype (a combination of SNPs).

The Icelandic deCODE Genetics group first did a genome-wide scan which replicated findings of linkage of schizophrenia to chromosome 8p.

Interpretation of genetic findings

The genetic findings are potentially very important but should be viewed with caution. First, for each gene, more than one SNP shows association with schizophrenia, but rarely are data from individual SNPs highly significant. The findings rely for their impact on the strength of associations seen with haplotypes inferred from estimations which are extremely sensitive to even low rates of genotyping error. Second, in some cases (DTNBP1 and RGS4) the associations, although well replicated, are

Pathophysiological mechanisms

In the prevailing pathogenic model, schizophrenia is a neurodevelopmental disorder22, 23 leading to abnormal synaptic connectivity.24 Glutamatergic transmission via N-methyl-D-aspartate (NMDA) receptors may be especially involved.25 All the genes relate to one or more of these interlinked processes. G72 and DAAO impact most directly on NMDA receptors, since DAAO metabolises D-serine, an endogenous modulator of the receptor,26 and G72 is probably an activator of DAAO.9 Neuregulin is present in

Conclusions

Salutary past experience requires that stringent criteria are applied when evaluating reports of schizophrenia susceptibility genes. The recent findings are a major step forward in the quality and quantity of evidence. The apparent commonalities and relevance of putative functions, and the fact that the findings for neuregulin, dysbindin, and RGS4 have been replicated, are impressive. However, the case for each gene remains to a greater or lesser extent incomplete, and further independent

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