A large proportion of candidate-gene studies have focused on key enzymes and proteins involved in dopamine-norepinephrine- and serotonin-based neurotransmitter systems. Among the first candidates to be studied by association analysis was the gene for tyrosine hydroxylase, a rate-limiting enzyme in the metabolism of catecholamines. The apparent success of linkage to chromosome 11p15 in the large Old Order Amish kindreds with multiple cases of bipolar disorder (Egeland et al., 1987) led to further studies of genes in the area. Initial promising results (Leboyer et al., 1990) were followed by a series of conflicting, but overall negative studies (Furlong et al., 1999; Turecki et al., 1997). This story has been repeated for many of the other candidates subsequently investigated, and, at present, even partly replicated findings have to be approached with some caution.
The enzyme catechol-omethyl transferase (COMT) is also involved in the degradation of monoamines. The gene coding for this enzyme is associated with a common and functional polymorphism that alters the activity of the protein. Alleles associated with low enzyme activity may increase the likelihood of developing bipolar illness and increase the likelihood that the illness will take a rapid cycling form (Kirov et al., 1998). Monoamine oxidase (MAO) is another key enzyme in amine metabolism. There are several forms of the enzyme, and the gene for type A has been quite extensively studied. A modest association has been found between forms of the microsatellite polymorphism and the likelihood of bipolar disorder, especially in females; the gene is on the X chromosome (Furlong et al., 1999; Preisig et al., 2000).
Specific serotonin reuptake inhibitors (SSRIs) are a mainstay of pharmacotherapy in the treatment of depressive phases of bipolar disorder. It is logical that their substrate, the human serotonin reuptake transporter (hSERT), and its gene on the long arm of chromosome 17 have been the focus of intensive study. A polymorphism (a variable number tandem repeat [VNTR]) affects the function of the gene, and there is evidence that the 12-repeat allele modestly increases the susceptibility to bipolar disorder in Caucasian populations (Craddock et al., 2001). The effect is relatively small, but studies have been consistent, and the concept of a secondary "push" on top of another more substantial genetic weighting factor (or factors) could explain some of the variability in the penetrance of the condition. The primary function of aminergic neurotransmitters is to interact with a post-synaptic receptor to achieve their signalling actions. These membrane-bound receptor proteins are key candidates for dysfunction in bipolar illness. The serotonergic receptor system has been examined both at the sequence level (Shimron-Abarbanell et al., 1996) and by association analysis for seven of the 5-HT receptor types, with very mixed results and with both positive and negative findings in abundance (Potash & DePaulo, 2000).
Dopaminergic receptors have perhaps been more extensively studied in patients with schizophrenia than bipolar disorder, and here again the results have been mixed (Potash & DePaulo, 2000). An interesting example is DRD5, the gene encoding the type 5 dopamine receptor, which is found especially in the limbic and frontal cortex in human brain. This is strongly associated with schizophrenia, but not bipolar disorder (Muir et al., 2001), and yet it lies within the region of highest linkage (at 4p16.3) in a large Scottish family with bipolar disorder (Blackwood et al., 1996). The gene for wolframin, the protein involved in Wolfram's syndrome, which is commonly associated with psychiatric disorders, is also in the region, although it is not mutated in the Scottish bipolar pedigree. The DRD3 gene codes for the type 3 dopamine receptor, and its localisation is largely confined to limbic brain regions. Although it is postulated to have a role in the precipitation of mania by dopamine agonists, studies of relevant polymorphisms have not shown convincing evidence for association in bipolar disorder.
The confusing results that emerge from association studies of neurotransmitter systems may arise because the studies are too small to detect genes that are relatively rare in the population as a whole or have a small individual effect in causing disease that has polygenic causation.
There has been a great deal of recent interest in the part played by intracellular signalling cascades in both the genesis of mood disorders and the actions of pharmacotherapeutic agents. Common to these has been the realisation that the adult brain is a much more functionally and anatomically plastic organ than previously thought, and that changes in neuronal intracellular messenger cascades are vitally important in controlling such changes (Manji & Lenox, 2000). Long-term stress has been shown to induce neuronal apoptosis and prevent neurogenesis in the hippocampus, and several studies have suggested that severe mood disorders can induce significant damage (perhaps by glucocorticoid overactivity) in key brain regions thought to be affected in bipolar disorder, such as the hippocampus (Manji etal., 2001).
Antidepressants and mood stabilisers, such as lithium, are known to have important effects on intracellular signalling mechanisms that influence cellular plasticity and apoptosis, in a time-dependent fashion that more closely mimics their clinical activity than direct effects on the extracellular neurotransmitter systems. Of the intracellular mechanisms, the protein cascades that involve cyclic (c) AMP are especially interesting. Long-term antidepressant medication (various classes) increases intracellular levels of cAMP and activates the intranuclear response elements, including cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF), via the protein kinase A system (Vaidya & Duman, 2001). BDNF is thought to play a crucial role in neuronal plasticity and survival, perhaps via the antiapoptotic activities of bcl-2 proteins. The phosphodiesterase PDE4 is involved in the cytoplasmic breakdown of cAMP, and inhibitors such as rolipram have an antidepressant effect, again potentially by the chronic upregulation of the CREB-BDNF system via cAMP.
The intracellular signalling cascades provide many candidates for association studies with bipolar disorder, but few studies have been conducted. The G protein-coupled receptor kinase-3 gene (GRK-3) is located at 22q11 near the velocardiofacial region (see below), and its expression was decreased in a family with bipolar disorder. The gene for inositol monophosphatase type 2 is located at 18p11.2, where there is evidence of linkage in bipolar disorder (Kato, 2001).
Trinucleotide repeats consist of three nucleotides consecutively repeated within a region of DNA. The commonest of these comprise of strings of the nucleotide sequence (CGG), (CAG) or (CTG). Their presence may confer instability on a gene because they are prone to undergo a novel type of mutation known as triplet repeat, expansion, a dynamic mutation that results in an expansion of the length of the repeat, sometimes to hundreds of bases, that ultimately disrupts gene function. Diseases caused by trinucleotide repeat expansion include Huntington's disease and fragile X syndrome, and the mechanism, though not yet fully understood, explains some of the unusual nonmendelian patterns of inheritance found in these disorders. Unstable repeats have the property of extending in length during meiosis, and this leads to the clinical phenomenon of "anticipation", which describes the increase in severity of symptoms of illness and a progressively earlier age at onset in successive generations. Longer expansions cause greater disruption of gene function, leading to greater severity of illness. Analysis of bipolar pedigrees has been consistent with anticipation, showing, on average, a 6-10-year advance in age at onset from one generation to the next (Margolis et al., 1999), although the interpretation of the apparent anticipation is confounded by other population trends in age of onset (Visscher et al., 2001). Several studies have reported association between bipolar disorder and CAG and CTG repeats in the genome, but a role for repeats has not been confirmed by the analysis of any single candidate gene. Repeat expansion remains an interesting but unconfirmed possibility in a subgroup of bipolar disorder.
Genomic imprinting mediated by DNA methylation was proposed as the explanation of an apparent bias towards paternal inheritance in linkage to chromosome 18p in bipolar disorder following the observation that around 20% of families collected for a linkage study appeared to be maternally inherited (McMahonetal., 1995; Stineetal., 1995). Mitochondrial inheritance is another possible explanation of maternal inheritance in a subgroup of families (Kato & Kato, 2000). There are single case reports of patients comorbid with depression and known mitochondrial diseases. In human postmortem brain tissue, an increase in a deletion in mitochondrial (mt)DNA was found, but the frequency of this deletion was not sufficient to have clinical effect. Two mtDNA polymorphisms that caused amino-acid substitutions were significantly associated with bipolar disorder. However, the mitochondrial hypothesis was not supported when the whole mitochondrial genome was sequenced in nine bipolar probands from families showing exclusively maternal transmission (McMahon et al., 2000). There were no differences in the frequency of mtDNA haplotypes between bipolar patients and controls, although a small effect was found with one polymorphism that had previously been associated in a Japanese study.
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