Examining the diagnoses which occur in relatives of probands with a given disorder may throw light on the classification of psychiatric illness. For example, in general manic depression and schizophrenia tend to "breed true", supporting the Kraepelinian distinction between these disorders. Relatives of manic depressive probands are also at increased risk of unipolar depression, and relatives of schizophrenic probands have increased rates of schizoid and schizotypal personality disorder, suggesting that the diagnoses may sometimes represent less severe forms of the same underlying disease process. Although it can be difficult to classify puerperal psychosis clinically, the fact that relatives tend to suffer increased rates of affective disorder suggests that in most cases puerperal psychoses are essentially atypical forms of affective psychosis.
The pattern of transmission of manic depression in some families is compatible with X-linkage, and linkage was originally claimed to colour blindness, G6PD deficiency and DNA markers which are all localised to chromosome Xq. More modern studies using DNA markers have reduced the evidence for Xq linkage. If there is an X-linked form of manic depression then it may account for no more than 10-20% of all cases.
At least some other cases may be due to an autosomal dominant gene, although it is not possible to draw any definite conclusions regarding the mode of transmission.
There have been a number of encouraging linkage results in different chromosomal regions, notably on 12 and 21, which await fine-mapping to identify the genes involved.
Association studies have possibly been positive for the gene for BDNF (brain-derived neurotrophic factor), DISC1, CACNA1C and ANK3.
Although there appears to be some genetic contribution to the susceptibility to unipolar depression, it is less marked than for bipolar disease. The pattern of transmission is unclear, and there is no strong evidence from linkage or association studies to demonstrate which loci might be involved.
Twin and adoption studies have demonstrated a genetic influence on predisposition. Also, children of the normal monozygotic cotwins of schizophrenics have a similar risk of schizophrenia as do the children of the schizophrenic parents (supporting a genetic aetiology). However the fact that monozygotic concordance is less than 100% means that environmental factors must also be involved. The mode of transmission of schizophrenia is unclear and is likely to involve the interaction of more than one gene (as may well be the case also for bipolar disorder).
A number of regions have generated positive linkage results, although with little consistency, and fine-mapping studies are in progress.
A large Scottish pedigree has been described in which many subjects have a translocation between chromosomes 1 and 11 and suffer from schizophrenia or other psychiatric illness. The breakpoint on chromosome 1 goes through a gene named DISC1 ("Disrupted in schizophrenia 1"), and association studies of DISC1 have been positive in other samples. Abnormalities of DISC1 may interfere with neuronal development.
A deletion of part of chromosome 22 causes velo-cardio-facial syndrome (VCFS) and some patients with this also suffer from a psychosis indistinguishable from schizophrenia. Indeed in some cases the psychosis is the only abnormality which comes to attention and in a cohort of unselected schizophrenics approximately 1% will turn out to have VCFS. VCFS thus represents a rare genetic cause of schizophrenia. It is possible that genes in this region may influence susceptibility to psychosis in other cases. COMT lies in this region and was originally claimed to be associated with schizophrenia but is now thought to influence prefrontal cognitive function.
Positive association studies were replicated for the genes for neuregulin and DAOA. Neuregulin interacts with DISC1 and is also involved in neuronal development. DAOA (d-amino acid oxidase activator, previously called G72) may be involved in the metabolism of d-serine, an NMDA glutamate receptor agonist, and has also been claimed to be associated with bipolar disorder. PCM1 shows association with schizophrenia and interacts with DISC1 to control neuronal migration. Some other genes are shwoing promising results.
Studies of copy number variants (CNVs - deletions and duplications) show that in addition to the VCFS deletion CNVs are generally more common in subjects with schizophrenia than in controls. CNVs affecting NRXN1 (neurexin 1) are associated with schizophrenia. Deletions at 15q11.2 and duplications at 16p11.2 increase risk.
Family, twin and adoption studies have demonstrated a genetic influence on the predisposition to alcoholism. The mode of transmission is unknown and it is not clear whether single gene effects or polygenic effects occur.
A number of associations have been reported with the dopamine D2 receptor gene (DRD2), but the status of these findings remains uncertain. Linkage studies are underway and have implicated a number of other regions. Note the following example of the influence of genetic polymorphism on the development of psychiatric illness:
About 50% of orientals do not have mitochondrial aldehyde dehydrogenase 2 isoenzyme, which is involved in the normal metabolism of ethanol. In such individuals the consumption of small amounts of alcohol causes unpleasant symptoms (facial flushing, etc.) and this causes them to avoid alcohol. So the mutation which deactivates ALDH2 indirectly protects against the development of alcoholism.
Some association studies suggest involvement of alcohol dehydrogenase 4 (ADH4).
This is a rare syndrome characterised by motor and vocal tics and sometimes involving coprolalia. Some cases are probably due to an autosomal dominant gene. Even though the mode of transmission appears simple, linkage studies investigating a large proportion of the genome have to date been negative.
There is reasonable evidence for a genetic contribution, and association studies have suggested that variation of the dopamine D4 receptor (DRD4) and dopamine transporter (DAT) genes may affect susceptibility.
In addition to attempts to identify genes which contribute aetiologically to disease, there is increasing interest in trying to find common polymorphisms which may affect response to treatment in terms of efficacy or side effects. For example, it is claimed that variation of the gene for the serotonin transporter, which is responsible for the reuptake of serotonin into nerve endings, may affect response to SSRIs. Likewise, variations of genes for serotonin type 2 receptors, in particular HTR2C, may influence not only treatment response to clozapine and other antipsychotics but also the severe weight gain which can occur with clozapine and olanzapine. One study showed that the response of alcoholics treated with bromocriptine was influenced by the genotype of the gene coding for the dopamine D2 receptor.
There is clear evidence that genetic influences contribute to the aetiology of mental illness, and gene-mapping efforts may now be starting to identify some of those involved in schizophrenia at least. Identifying such genes would help in the understanding of the pathogenesis of these illnesses.
In addition, pharmacogenetic studies are in progress which seek to relate response to treatment to underlying genetic polymorphism. These may lead to the ability to use genetic information as an aid to deciding on optimal treatment strategies for individual patients.
January 2012
http://www.mds.qmw.ac.uk/statgen/dcurtis/lectures/pgenfunc.htm
Dave Curtis (david.curtis@qmul.ac.uk)