Genetic basis for psychotic disorders

14 October 2008

Schizophrenia is a group of psychiatric conditions manifesting as hallucinations, paranoid delusions, and/or disorders of thought. A genetic basis for schizophrenia has long been suspected with twin studies suggesting a heritability of over 80%, and several candidate genes have subsequently emerged [Ross CA et al. (2006) Neuron. 52(1):139-53]. Current knowledge suggests that each risk allele identified confers a small increase in risk of schizophrenia, with the constellation of alleles producing an individual’s overall genetic risk of developing this complex disorder; environmental influences are also presumed to contribute.

Writing in Nature Genetics, O’Donovan et al. have identified twelve more genetic polymorphisms that may be associated with schizophrenia [O'Donovan MC et al. (2008) Nat Genet. 40, 1053 - 1055]. The group examined the genomes of 479 schizophrenic patients and compared them to 2,937 controls. Twelve single nucleotide polymorphisms (SNPs) were found that were seen in the schizophrenic patients, but not in the control population. When these twelve genetic loci were examined in over 5,000 more schizophrenic patients and compared with over 10,000 more controls, one polymorphism consistently appeared in the schizophrenic patients and not in the controls. This locus, the ZNF804A gene is therefore strongly implicated in the pathophysiology of schizophrenia. When the genome-wide analysis (GWA) was repeated with bipolar-disorder patients plus schizophrenia compared to controls, the ZNF804A polymorphism once again emerged as the leading difference between patients and control subjects. ZNF804A codes for a protein with a zinc binding domain and a DNA binding domain. Although the function of this gene is unknown, its related protein structure suggests a role in DNA transcription regulation.

A second study appearing in Nature Genetics by Ferreira et al. uses a similar GWA technique to look for further candidate genetic polymorphisms for bipolar disorder [Ferreira MA et al. (2008) Nat Genet. 40, 1056-1058]. The authors analysed the genomes of 1,233 bipolar disorder patients and compared these to the genomes from 1,439 controls. 14 polymorphisms emerged, but were all less significant than the main polymorphism observed in the O’Donovan et al. schizophrenia cases. Nevertheless, the most significant polymorphism seen in the bipolar patients mapped to CACNA1C, a gene encoding a calcium ion channel subunit. The GWA was then repeated using additional data from other studies giving a total of 4,387 bipolar disorder genomes which were compared with 6,209 control genomes. This larger analysis produced a further candidate genetic polymorphism situated on the ANK3 gene, which codes for a protein that regulates the assembly of sodium ion channels. Therefore, it appears as though dysfunction of ion channels, coded by genetic mutations, may be related to bipolar disorder.

Writing in PNAS, Pickard et al.  also demonstrated that a genetic polymorphism may be involved in a neurotransmitter system linked to bipolar disorder [Pickard BS et al. (2008) Proc Natl Acad Sci USA 105(39):14940-5]. The authors had previously identified a polymorphism in a gene coding for a glutamatergic receptor that appeared to reduce the risk of developing bipolar disorder. In their latest study they aimed to demonstrate a putative mechanism for how this polymorphism may be protective. They examined the mRNA of the gene in question and discovered that the mRNA from the protective polymorphism had a deletion in a region of the mRNA called the 3’ untranslated region (3’UTR). The 3’UTR component of mRNA is responsible for stabilising mRNA so that it becomes translated to a protein, in this case a GRIK4 glutamate receptor. The polymorphism causes the mRNA to become more stable so that more GRIK4 receptors were expressed, making the glutamatergic neurotransmitter system more active. Underactivity of the glutamatergic system is thought to cause bipolar disorder [Belsham B. (2001) Hum Psychopharmacol.16(2):139-146].

Comment: Together, these three publications strengthen knowledge about the genetic basis of schizophrenia and bipolar disorder. New genetic polymorphisms have been discovered as possible causes of schizophrenia and bipolar disorder. The implicated genes code for ion channels, control the expression of receptors, or otherwise control the expression of other as of yet unidentified genes. Further studies are necessary to elicit more candidate genes and elucidate the mechanisms by which these mutations lead to the symptoms of schizophrenia and bipolar disorder.

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