Functional Genomics and Schizophrenia: Endophenotypes and Mutant Models

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This article summarizes the rationale, methods, and results of gene discovery programs in schizophrenia research and describes functional methods of investigating potential candidate genes. It focuses next on the most prominent current candidate genes and describes (1) evidence for their association with schizophrenia and research into the function of each gene; (2) investigation of the clinical phenotypes and endophenotypes associated with each gene, at the levels of psychopathologic, neurocognitive, electrophysiologic, neuroimaging, and neuropathologic findings; and (3) research into the ethologic, cognitive, social, and psychopharmacologic phenotype of mutants with targeted deletion of each gene. It examines gene–gene and gene–environment interactions. Finally, it looks at future directions for research.

Section snippets

Gene Discovery

The heritability of schizophrenia is substantial, but the etiology of the disorder is poorly understood [7]. With the emergence of molecular genetic and genomic methodologies, identifying the genes involved became a research priority, primarily as a prerequisite for understanding both cellular pathogenesis and gene–environment interaction. Positional cloning methods (linkage studies, cytogenetics, and association analyses) offered powerful tools for gene identification. Rather than depending on

Endophenotypic Approaches

One element in understanding how susceptibility genes may increase the risk for disease has been the endophenotypes approach. Endophenotypes, or intermediate phenotypes, have been described as “measurable components unseen by the unaided eye along the pathway between disease and distal genotype” [25]. The rationale for this approach is that if an endophenotype associated with a disorder is specific and represents a straightforward phenomenon, the number of genes required to produce variation in

Relationship to Schizophrenia

Evidence for the involvement of the dystrobrevin binding protein 1 (DTNBP1; dysbindin) gene came from a dense fine-mapping study of the chromosome 6p susceptibility locus in affected Irish families. The DTNBP1 association now has been reported by many studies [55], but no functional variant has been identified, and studies have differed in the alleles/haplotypes reported. The expectation that single-risk variants and functional mutations would be identified at susceptibility genes

Relationship to Schizophrenia

In 1970, a translocation was reported in an individual who had adolescent conduct disorder and in other members of the extended family; follow-up of this family identified many additional members as having major psychiatric disorders and a (1;11)(q42;q14.3) translocation [75]. Detailed clinical investigation of the family and a linkage analysis generated a logarithm of odds score of 3.6 with schizophrenia as the phenotype, increasing to 7.1 when relatives who had bipolar disorder and recurrent

Relationship to Schizophrenia

In a study of 33 Icelandic families, the deCODE group reported suggestive evidence of linkage to a chromosome 8p locus that previously had been implicated in schizophrenia susceptibility by several studies and in a linkage meta-analysis [9]. Following up this finding in a larger case-control sample, the authors identified several risk haplotypes that mapped to a region containing the neuregulin 1 (NRG1) gene [113]. The core risk haplotype (HAPBICE) at the 5′ end of the gene was replicated in

Relationship to Schizophrenia

Following up a chromosome 13q32-34 susceptibility locus in French-Canadian and Russian schizophrenia samples, an association with markers in a region containing two overlapping genes, DAOA (previously G72) and G30, was reported [131]. Functional experiments indicated that only the DAOA gene is actively translated and that the resultant protein activates the enzyme D-amino acid oxidase (DAO; OMIM 124050). Based on evidence that oxidation of D-serine by DAO attenuates NMDA receptor function

Relationship to Schizophrenia

D-amino acid oxidase (DAO) is a peroxisomal enzyme involved in oxidizing D-serine, an activator of the NMDA receptor. Using yeast-2-hybrid methods, a protein interaction between the schizophrenia susceptibility gene G72 (subsequently DAOA; see previous discussion) and DAO was identified, with in vitro evidence that G72 was an activator of DAO [131]. The authors also presented evidence of association between DAO and schizophrenia in a French-Canadian population and evidence of statistical

Relationship to Schizophrenia

The regulator of G-protein signaling-4 (RGS4) gene is involved in the regulation and timing of duration of G-protein–mediated receptor signaling. This action may be important in the adrenergic modulation of prefrontal NMDA receptor function [157]. RGS4 maps to chromosome 1q23.3 and was investigated for linkage and association in United States and Indian schizophrenia family and case-control samples [158]. This gene, which was selected for investigation based on position and also because of the

Relationship to Schizophrenia

The gene encoding the enzyme catechol-O-methyltransferase (COMT) has been scrutinized intensively as a positional and functional candidate gene for schizophrenia. COMT maps to a chromosomal 22q11 susceptibility locus identified from several linkage studies and by the strong association between the chromosomal microdeletion syndrome involving this locus (VCFS; as discussed previously) and schizophrenia [12], [13]. COMT has a key role in dopamine catabolism, and a functional polymorphism that

AKT1

The AKT signaling pathway was targeted for candidate gene analysis based on evidence for decreases in phosphorylation of components of the pathway and in levels of the AKT1 protein in schizophrenia [173]. These authors reported evidence for association with a single SNP and several haplotypes at the V-AKT Murine Tymoma Viral Oncogene Homolog 1 (AKT1) locus, one of which was significant when corrected for the number of tests performed. AKT1 is a protein kinase that may be involved in many

Other Candidate Genes

Convergent functional genomics, using bottom-up as well as top-down approaches, is now leading to the identification of a number of other putative schizophrenia candidate genes. Two genes involved in the regulation of oligodendrocyte function, oligodendrocyte lineage transcription factor 2 (OLIG2) and 2′3′-cyclic nucleotide 3′-phosphodiesterase (CNP), have been implicated in schizophrenia [175], [176]. Each of these findings requires further genetic investigation in independent samples. Many

Gene–Gene Interactions

Identifying that specific genes contribute to disease risk is important, but understanding the relationships between risk-inducing (or protective) genes is probably more so. The effects of some genes may depend on their interactions with others (ie, epistasis; gene–gene interactions), and statistical evidence of interaction may guide researchers to investigate specific molecular pathways contributing to complex disorders. For example, although COMT variation may not contribute directly to the

Gene–Environment Interactions

Although the previous analysis indicates the need for investigating interactions between genes, it is essential to recognize that the effects of some genes also may depend on their interaction with environmental factors (gene–environment interactions). Although evidence for a genetic contribution to the risk for schizophrenia is overwhelming, it must be juxtaposed with primarily epidemiologic studies that indicate a role for environmental factors, both biologic [196] and psychosocial [197],

Future Directions

The first wave of large-scale whole-genome association studies of schizophrenia will soon be in press, to be followed over the next several years by multiple additional reports. These studies will assay a majority of the genomic variation in the samples investigated but in turn will be superceded by sequencing platforms providing complete sequence information. Carefully investigating and comparing these datasets will be important in identifying novel candidate genes. With such a wealth of data,

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    This work was supported by grants 02-IN1-B227 (JLW), 01-F1-B006 (KJM) and 02-IN1-B113 (MG) from Science Foundation Ireland. KJM is an EMBO Young Investigator.

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