Trends in Genetics
Schizophrenia: genes at last?
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
References (83)
- et al.
Candidate-gene association studies of schizophrenia
Am. J. Hum. Genet.
(1999) Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: schizophrenia
Am. J. Hum. Genet.
(2003)- et al.
Guidelines for genotyping in genomewide linkage studies: single-nucleotide-polymorphism maps versus microsatellite maps
Am. J. Hum. Genet.
(2004) Strong evidence for association between the dystrobrevin binding protein 1 gene (DTNBP1) and schizophrenia in 488 parent-offspring trios from Bulgaria
Biol. Psychiatry
(2004)Linkage disequilibrium mapping of schizophrenia susceptibility to the CAPON region of chromosome 1q22
Am. J. Hum. Genet.
(2004)Polymorphisms in the trace amine receptor 4 (TRAR4) gene on chromosome 6q23.2 are associated with susceptibility to schizophrenia
Am. J. Hum. Genet.
(2004)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)Support for 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)The DTNBP1 (dysbindin) gene contributes to schizophrenia, depending on family history of the disease
Am. J. Hum. Genet.
(2003)Association of the DTNBP1 locus with schizophrenia in a U.S. population
Am. J. Hum. Genet.
(2004)