Trends in Genetics
Volume 21, Issue 9, September 2005, Pages 518-525
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Schizophrenia: genes at last?

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Genetic epidemiological studies suggest that individual variation in susceptibility to schizophrenia is largely genetic, reflecting alleles of moderate to small effect in multiple genes. Molecular genetic studies have identified several potential regions of linkage and two associated chromosomal abnormalities, and evidence is accumulating in favour of several positional candidate genes. Currently, the positional candidate genes for which we consider the evidence to be strong are those encoding dysbindin (DTNBP1) and neuregulin 1 (NRG1). For other genes, disrupted in schizophrenia 1 (DISC1), D-amino-acid oxidase (DAO), D-amino-acid oxidase activator (DAOA, formerly known as G72) and regulator of G-protein signalling 4 (RGS4), the data are promising but not yet compelling. The identification of these, and other susceptibility genes, will open up new avenues for research aimed at understanding the pathogenesis of schizophrenia, and will catalyse a re-appraisal of the classification of psychiatric disorders.

Introduction

Schizophrenia is a severe psychiatric disorder with a lifetime risk of ∼1%. The disorder is characterized by psychotic symptoms in particular delusions and hallucinations, reduced interest and drive, altered emotional reactivity and disorganised behaviour. Often relatively subtle cognitive and behavioural signs are present from early childhood, but the characteristic features generally have their onset in the late teens and early twenties. Although outcomes are variable, even with treatment, the typical course is one of relapses followed by only partial remission, and a marked reduction in social and occupational function such that sufferers are often the most vulnerable, isolated and disadvantaged individuals in society.

Section snippets

Genetic epidemiology

Schizophrenia has been the subject of numerous family, twin and adoption studies that show conclusively that risk of illness is increased among the relatives of affected individuals and that this is largely the result of genetic factors [1]. However, although heritability (Box 1) is high, ∼80%, concordance in mono-zygotic twins is typically ∼50%, pointing to the importance of environmental factors. Genetic epidemiology also tells us that, similar to other common disorders, schizophrenia has a

Defining the phenotype for genetic research

Schizophrenia displays considerable heterogeneity of symptoms, course and outcome. Although it has not yet been possible to distinguish aetiologically distinct sub-groups, it is possible that the disorder, as defined by current diagnostic criteria, includes several different disease processes. However, structured and semi-structured interviews together with explicit operational diagnostic criteria permit the reliable diagnosis of a syndrome with high heritability, which should in principle be

Are there clues for genetics from epidemiology, pathophysiology and neurobiology?

Epidemiological, pharmacological and neurobiological studies have made some progress in our general understanding of schizophrenia (e.g 9, 10). However, it is not possible confidently to implicate specific pathophysiological processes or to nominate compelling candidate genes from the currently rather vague concepts of altered neurodevelopment, synaptic dysfunction and aberrant neuronal connectivity that have been proposed. The more specific hypotheses based on abnormalities in

Linkage

Until recently, the results of linkage studies in schizophrenia were disappointing. Early hopes of finding mendelian forms did not materialize, and most studies neither achieved stringent ‘genome-wide’ levels of significance nor replicated pre-existing findings (reviewed in [11]). These disappointing findings are probably attributable to a combination of small genetic effects, inadequate sample sizes (with typical samples being between 20 and 100 families and only two full genome scans being

Positional candidate genes

The convergence of positive linkage findings has led to several detailed mapping studies of linked regions and some of these have implicated specific genes [19]. The putative susceptibility genes for which the most follow-up data are available are those encoding dysbindin (DTNBP1, also known as dystrobrevin binding-protein 1), neuregulin1 (NRG1), D-amino-acid oxidase (DAO), D-amino-acid oxidase activator (DAOA, formerly known as G72) and regulator of G-protein signalling 4 (RGS4). In our view,

Chromosomal abnormalities associated with schizophrenia

Several associations between schizophrenia and chromosomal abnormalities have been reported [49], but only two provide convincing evidence for the location of a susceptibility gene. Several studies have shown that adults with 22q11 deletion syndrome (also known as DiGeorge syndrome, Velo-cardio-facial syndrome, Sphrintzen syndrome and conotruncal anomaly face syndrome) have an increased risk for schizophrenia (reviewed by [50]), with the largest study of adult patients to date (n=50) estimating

Overlap with findings in bipolar disorder

Bipolar disorder is a genetically complex disorder 64, 65 that is characterized by disturbances in mood ranging from extreme elation (mania) to severe depression often accompanied by hallucinations, delusions and cognitive changes. Traditionally, psychiatric research in general, and the search for predisposing genes in particular, has proceeded under the assumption that schizophrenia and bipolar disorder are separate disease entities. However, a recent twin study [66] has added to previous

Implications of recent findings

In our view, the evidence now strongly implicates DTNBP1 and NRG1 as susceptibility genes for schizophrenia. Data for DISC1, which we have discussed to illustrate the possible utility of cytogenetic abnormalities, and several other genes including DAO, DAOA and RGS4, which we have not discussed, are promising but not yet compelling. However, even in the most convincing cases, the risk haplotypes appear to be associated with small effect sizes [odds ratio (OR)<2.5], and, although this is

Glossary

Odds ratio (OR):
is approximates to the ‘relative-risk’ and is a measure of the increased risk conferred by possession of a risk factor. If possession of a risk factor is associated with a two-fold increased risk of a disorder relative to the population risk, the risk factor is said to have a relative risk of two.
λs:
the risk of illness in siblings relative to the population risk. In schizophrenia, the risk of a sibling of a sufferer developing the disorder is approximately 10% compared with

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