Brief reportParent-of-origin effect and genomic imprinting of the HTR2A receptor gene T102C polymorphism in psychosis
Introduction
The serotonin (5-HT) neurotransmitter system has been proposed as a potential source of dysfunction in mood disorders (Lucki, 1998) and schizophrenia (Malhotra et al., 2004, Wong and Van Tol, 2003), partly because the 5-HT transporter (5-HTT) and receptors are major targets for antidepressants and atypical antipsychotics, respectively (Leonard, 1994, Meltzer and Nash, 1991). Post-mortem brain tissue studies suggest a possible alteration in 5-HT receptor populations in schizophrenia: decreased HTR2A receptor mRNA and increased 5HT1B mRNA levels in the hippocampal formation have been reported (Lopez-Figueroa et al., 2004). In patients with mood disorders, 5-HTT binding is lower throughout the prefrontal cortex (Mann et al., 2000). Previous genetic association studies on schizophrenia and mood disorders have examined the HTR2A receptor gene, which is located on chromosome 13q14–q21 in humans, and consists of three exons separated by two introns, spanning over 20 kb (Chen et al., 1992).
A commonly studied polymorphism is the silent thymine to cytosine substitution at position 102 in exon 1 (HTR2A T102C). A genetic association between schizophrenia and the “C” allele of this polymorphism has been shown through meta-analysis (Williams et al., 1997), but a recent meta-analysis of association studies in bipolar disorder, showed no significant effect for this polymorphism (Anguelova et al., 2003). The biological function of this polymorphism is unclear because it is synonymous and therefore does not alter amino acid sequence, although it may affect mRNA secondary structure (Arranz et al., 1995). Another polymorphism in the HTR2A promoter region (− 1438A/G) is in complete linkage disequilibrium with T102C and could theoretically influence expression of the HTR2A T102C alleles. However, Sokolov and Polesskaya, 2002, found that this promoter SNP does not affect transcription in vitro. The presence of a cytosine (C) at position 102 and a guanosine (G) at the position − 1438 create two additional CpG islands, which are present in 102C chromosomes, but absent in 102T chromosomes. CpG sites are potential targets for methylation, a mechanism for regulating gene transcription (Jaenisch and Bird, 2003). In a post-mortem study of subjects who committed suicide, subjects with the HRT2A 102T allele had a higher density of 5HT-2A receptors than carriers of the HRT2A C102 allele, (Turecki et al., 1999), however the results of other binding experiments are inconsistent with these findings (Kouzmenko et al., 1997). Analysis of mRNA expression in human post-mortem brain tissue suggests that the expression of the HTR2A C102 allele in the cortex of heterozygous individuals is significantly lower than that of the T allele (Polesskaya and Sokolov, 2002).
The complex inheritance patterns of schizophrenia and bipolar disorder, including monozygotic twin concordance rates of 48% for schizophrenia (Gottesman, 1994), and 43% for bipolar disorder (Kieseppa et al., 2004), suggest that epigenetic mechanisms may be relevant in major psychoses (Wong et al., 2005). Genomic imprinting is one epigenetic mechanism in which a particular allele can influence the level of gene expression (Surani et al., 1986). The existence of genomic imprinting can be inferred by the presence of a parent-of-origin effect (POE) in the transmissions from maternal or paternal meiosis to an affected child. Family-based genetic association studies using the transmission disequilibrium test have examined the T102C polymorphism in major psychoses (schizophrenia and bipolar disorder), but few of these studies analyzed POE, though one study found no evidence of imprinting in bipolar disorder (Murphy et al., 2001).
In light of these findings, our aim was to investigate POE at the HTR2A T102C polymorphism in major psychoses by analyzing paternal and maternal transmission of these alleles in nuclear families with schizophrenia or bipolar probands. We also examine both HRT2A T102C DNA variants to see if they are associated with differences in allele-specific mRNA expression in post-mortem brain samples from patients with schizophrenia or bipolar disorder.
Section snippets
Subject recruitment and sample description
The family-based DNA sample consisted of 81 nuclear families (mother, father and proband = trios) in which probands had a DSM-IV diagnosis of schizophrenia and 314 trios in which probands had diagnosis of bipolar disorder. Trios are used instead of case-control samples to study genomic imprinting because the transmission of specific alleles from each parent to the proband can be detected. The patients were recruited from several psychiatric clinics in Toronto and central Canada. Within the
POE effect in the families
Two family-based tests for allelic association, TDT and ETDT, were applied to genotype data from 314 bipolar and 81 schizophrenia families. The TDT yielded a slight trend for bipolar disorder (P = 0.092) with allele T102 transmitted in 133 (and not in 107) probands with heterozygous parents. In order to test for the presence of association under the assumption of genomic imprinting, we performed the ETDT. In the bipolar sample, the comparison of maternally transmitted vs. non-transmitted alleles
Discussion
We found no significant differences in the levels of the HTR2A C/T mRNA ratio in major psychoses compared with control subjects. However, the marginally lower C/T allele ratio in schizophrenia and bipolar groups suggests that epigenetic mechanisms may be relevant to expression of this gene in major psychoses. Few studies have explored the allele-specific expression of the HTR2A T102C SNP in different diagnostic groups. Previous studies have shown higher levels of the “C” allele, but did not
Acknowledgements
This work was made possible through the support of the Canadian Institutes for Health Research (CIHR), and the National Alliance for Research in Schizophrenia and Depression (NARSAD). AHCW is a CIHR Clinician-Scientist Fellow and NARSAD Young. VDL is supported by a Postdoctoral Research Fellowship and a Pilot Grant from the American Foundation for Suicide Prevention. Post-mortem brain mRNA and DNA was donated by The Stanley Medical Research Institute courtesy of Drs. Michael B. Knable, E.
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2009, Biochimica et Biophysica Acta - General SubjectsCitation Excerpt :Another study has shown that the HTR2A is paternally imprinted in human fibroblasts and transcribed from the maternal allele only [124]. However, Polesskaya and Sokoloff [125] were not able to replicate this ‘on or off’ polymorphic imprinting, and a more recent study also found no evidence of imprinting of HTR2A [126]. Regardless, expression levels of HTR2A C102 have been shown to be reduced in the temporal cortex [125], and ligand binding studies have shown that subjects with the HTR2A C102 allele have reduced receptor binding in postmortem brain [127] and in platelets [128].
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