Meta-analysis of association between the T102C polymorphism of the 5HT2a receptor gene and schizophrenia
Introduction
Since atypical antipsychotic and antidepressant drugs act on serotonin (5HT) receptors, and because LSD, which resembles serotonin, can produce psychosis, 5HT receptors have come under consideration in psychiatric disorders. 5HT receptors may have a role in schizophrenia Inayama et al., 1996, Williams et al., 1997, seasonal depression Arias et al., 2001a, Arias et al., 2001b, suicidality Arias et al., 2001a, Arias et al., 2001b, Du et al., 2001, Tourette's syndrome comorbid with obsessive compulsive disorder (Huang et al., 2001), eating disorders (Nacmias et al., 1999), Alzheimer's disease (Holmes et al., 1998), tardive dyskinesia Segman et al., 2001, Tan et al., 2001, alcoholism (Hwu and Chen, 2000), and essential hypertension (Liolitsa et al., 2001). Considering that all of these disorders have a familial pattern of transmission (Saddock and Saddock, 2000), 5HT receptor genes have been the subject of numerous genetic studies during the past decade. 5HT2 receptors have received special attention due to their role in the therapeutic actions of clozapine.
A meta-analysis of whole-genome linkage scans confirmed linkage between schizophrenia and markers on the long arm of chromosome 13 (Badner and Gershon, 2002). The gene HTR2A, which codes for the 5HT2a receptor, is located on the long arm of chromosome 13 (Williams et al., 1996), and has many known polymorphisms in the population, including the T102C single nucleotide polymorphism, which has been the subject of most research (Spurlock et al., 1998).
In the T102C polymorphism, the base in nucleotide position 102 of HTR2A may be thymine (T) or cytosine (C), with possible genotypes TT, TC, or CC. This mutation does not result in any change in the amino-acid sequence of the 5HT2a receptor, as both alleles encode for a serine in codon 34 (Warren et al., 1993). Yet, in human postmortem studies, the production of 5HT2a receptors in temporal cortex was about 20% less for the C allele than for the T allele (Polesskaya and Sokolov, 2002). The T102C polymorphism is located in exon 1 (Williams et al., 1996) near the gene's promoter, and so may have some role in gene regulation. Also, it has been proposed that a C in position 102 must be methylated Clifford and Nunez, 1996, Petronis, 2000, and C methylation has been known to prevent gene expression Attwood et al., 2002, Bird, 2002, Watson and Goodman, 2002.
The T allele has been considered as the wild type; however, because the chimpanzee's genotype is CC at this site (Cargill et al., 1999) and a methylated C in a CG dinucleotide has a high probability (42 times more than any other nucleotide) for mutation to T (Cooper and Youssoufian, 1988), the C allele may actually be the wild type Clifford and Nunez, 1996, Petronis, 2000. In fact, the “dinucleotide CpG has been progressively eliminated from the genome and is present at only 5–10% of its predicted frequency” (Singal and Ginder, 1999).
From a functional point of view, not only is the activity of the C-allele form of HTR2A significantly less than that of the T allele in normal controls and schizophrenic patients, this difference also is more prominent in schizophrenic patients than in normal controls with the same alleles. Moreover, HTR2A mRNA levels are inversely correlated with the duration of neuroleptic-free intervals (Polesskaya and Sokolov, 2002). Similarly, in electrophysiologic studies, the T and C alleles also differ in activity in schizophrenic patients, such that patients with the 102CC genotype had higher N100 amplitudes than patients with other genotypes after clozapine treatment (Yu et al., 2001).
There have been numerous studies of the association of alleles of the T102C polymorphism with various aspects of schizophrenia, including a formal diagnosis (Williams et al., 1996), earlier onset and poorer outcome (Joober et al., 1999), and susceptibility to tardive dyskinesia (Segman et al., 2001). Although initial case-control studies showed an association with the disorder Inayama et al., 1996, Williams et al., 1996, and the association with the C allele of HTR2A was also confirmed by meta-analysis [odds ratio (OR) of 1.18, 95% CI 1.07–1.31, p=0.0009] (Williams et al., 1997), there was a continuous debate because negative findings were also considerable Chen et al., 2001, Hawi et al., 1997, Ishigaki et al., 1996, Shinkai et al., 1998.
Moreover, we must consider that schizophrenia is a polygenic and multifactorial disorder. Such disorders usually have several responsible genes, of which co-inheritance of a few is necessary to reach the disease threshold. If we suppose that the frequency of each responsible allele of a risk gene in the general population is 20%, at least three risk alleles are necessary to produce the observed population prevalence of schizophrenia (0.2×0.2×0.2=0.008). Determining the effect size of each allele likely is not accurate in association studies with a limited sample size; in these situations, a large sample size is needed. For this reason, we decided to perform another meta-analysis on the association of the T102C polymorphism of HTR2A and schizophrenia since, after 6 years, the number of available studies has doubled. Family-based studies are also now available, and can help to more accurately evaluate the effect size of risk alleles. Thus, we also performed a meta-analysis of family-based studies, although the number of available studies is not as large as the number of case-control studies.
Section snippets
Literature search
To identify studies eligible for meta-analysis, MEDLINE citations (January 1966–August 2002) were surveyed using the National Library of Medicine's PubMed online search engine with combinations of “schizophrenia”, “T102C”, “T/C102”, “HTR2A”, and “5HT2a” as keywords. The retrieved abstracts were read to identify studies that examined the allelic association between a polymorphism within the HTR2A gene and schizophrenia. Studies of this type were then read in their entirety to assess their
Case-control studies
In the meta-analysis of 31 case-control association studies comprised of 4632 cases and 4410 controls, we found a significant association between the C allele of the T102C polymorphism and schizophrenia (Table 1), with a pooled OR equal to 1.1 (95% CI=1.0–1.2, z=2.42, p=0.015). When we calculated the pooled OR for CC homozygosity relative to TT homozygosity (Table 1), the OR increased to 1.3 (95% CI=1.0–1.6), but was only marginally significant (z=1.91, p=0.056). Heterozygosity (CT) was not a
Discussion
Similar to the previous meta-analysis of HTR2A, which yielded an OR of 1.18, we found a significant association between the C allele of the T102C polymorphism and schizophrenia (OR=1.1), especially in European samples (OR=1.2); however, we also found significant heterogeneity between European and East Asian population, which was not recognized in the prior meta-analysis. This heterogeneity, along with the documented differences in allele frequency between the two ethnic groups, strongly
Conclusion
Since the C allele of the T102C polymorphism of HTR2A has less activity, it may have some role in psychiatric disorders. According to this meta-analysis in a large sample size, we found an association of both the C allele and CC homozygosity with schizophrenia overall, especially in European patients. In East Asian countries, there was not a significant association with the C allele or CC homozygosity, and there was a strong difference in allele frequency between samples from East Asian and
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