Trends in Molecular Medicine
ReviewSearching for schizophrenia genes
Section snippets
Neurobiological theories of schizophrenia
Attempts to elucidate the biological correlates of schizophrenia have traditionally focused on one of several levels of explanation, including the neuropsychological, the neuropathological and the neurochemical. The view that schizophrenia is caused by disturbances in particular neurotransmitter systems arose during the 1950s and 1960s, given credence by the lack of obvious structural pathology in the schizophrenic brain and the observed anti-psychotic or psychotomimetic effects of certain
Genetic epidemiology of schizophrenia
Evidence for a strong genetic component to the aetiology of schizophrenia can be drawn from family, twin and adoption studies, which have shown that the risk of developing the illness increases exponentially with the level of genetic relatedness to an individual suffering from the disorder 20 (Fig. 1). Thus, in comparison with the 1% risk for schizophrenia in the general population, third-degree relatives (e.g.cousins) carry an approximate 2% chance of developing the illness, and the risk
Molecular genetic approaches
Unlike molecules studied in the brain, the primary genetic sequences that encode them remain fixed, being generally unaffected by environmental or compensatory influences. Attempts to identify the particular genetic variants that contribute to schizophrenia susceptibility thus have enormous potential to elucidate the primary pathological mechanisms. Unfortunately, molecular genetics shares many of the problems encountered by other forms of schizophrenia research, such as the probable
New directions
A relatively recent development in the hunt for schizophrenia susceptibility genes has rested on the identification of traits that might more directly reflect the operation of fundamental processes of potential relevance to schizophrenia. These ‘intermediate’ phenotypes 53 should be measurable in individuals without schizophrenic symptoms, and might have a less complex genetic basis that is more amenable to linkage and association studies. Of particular note are studies showing abnormalities in
Conclusions
Genetic epidemiological studies have provided evidence for a strong genetic component to the aetiology of schizophrenia. However, attempts to identify susceptibility genes face formidable challenges arising from both genetic and phenotypic complexity. Research to date has largely excluded the possibility that genes of major effect exist, even in a subset of families. Linkage studies have yielded some evidence for the location of genes of moderate effect, although, at present, none of these
Glossary
- λs
- The risk to siblings of an affected individual, compared with the general population. It can be used to assess the effect size of an individual genetic variant (i.e. the risk to siblings resulting from possession of the disease allele).
- Epistasis
- Interactions between two or more genetic loci.
- Familiality
- Increased risk of illness in relatives of an affected individual.
- Polymorphisms
- Variation in DNA sequence that produces two or more alleles at a particular locus, existing in significant (>1%)
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