Rapid ReviewGenes for schizophrenia? Recent findings and their pathophysiological implications
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
References (33)
- et al.
Neuregulin1 and susceptibility to schizophrenia
Am J Hum Genet
(2002) - et al.
Association of neuregulin 1 with schizophrenia confirmed in a Scottish population
Am J Hum Genet
(2003) - et al.
Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia
Am J Hum Genet
(2002) - et al.
Support for an association of schizophrenia with genetic variation in the 6p22.3 gene, dysbindin, in sib-pair families with linkage and in an additional sample of triad families
Am J Hum Genet
(2003) - et al.
Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex
Neuron
(2000) Schizophrenia and velo-cardio-facial syndrome
Lancet
(2002)- et al.
A highly significant association between a COMT haplotype and schizophrenia
Am J Hum Genet
(2002) - et al.
Molecular determinants of metabotropic glutamate receptor signalling
Trends Pharmacol Sci
(2001) - et al.
Dysbindin, a novel coiled-coil-containing protein that interacts with the dystrobrevins in muscle and brain
J Biol Chem
(2001) Phasic versus tonic dopamine release and modulation of glutamate system responsivity: a hypothesis for the etiology of schizophrenia
Neuroscience
(1991)
Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia
Mol Psychiatry
Meta-analysis of genome scans for schizophrenia
Am J Med Genet
The discovery of susceptibility genes for mental disorders
Proc Natl Acad Sci USA
Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia
Proc Natl Acad Sci USA
Association and linkage analyses of RGS4 polymorphisms in schizophrenia
Hum Mol Genet
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