Positive association between a DNA sequence variant in the serotonin 2A receptor gene and schizophrenia

Inayama, Yasuhiro; Yanagawa, Hiroshi; Sakai, Toshiaki; Ishida, Takaaki; Nonomura, Yasuhiro; Kono, Yoshihiro; Takahata, Ryuichi; Koh, Jun Sung; Sakai, Jun; Takai, Akira; Inada, Yasushi; Asaba, H

doi:10.1002/(sici)1096-8628(19960216)67:1<103::aid-ajmg18>3.0.co;2-s

Cited by 132 publications

(57 citation statements)

References 13 publications

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“…For example, DRD2 À141delC 3 and Taq I A 4 polymorphism caused a functional change of the product, and both are reported to have an association with antipsychotic response. 5,6 HTR2A 102T4C polymorphism showed an association with the presence of schizophrenia, 7 and À1438G4A polymorphism with a clozapine response. 8 In addition, HTR2A H452Y polymorphism, which caused a functional change of the expressed gene product, 9 is reported to be involved in clozapine response.…”

Section: Introductionsupporting

confidence: 87%

Effect of DRD2, 5-HT2A, and COMT genes on antipsychotic response to risperidone

et al. 2003

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Risperidone is a widely used atypical antipsychotic with certain advantages over typical antipsychotics. Although variations in the efficacy of treatment with risperidone have been observed, no specific predictable marker has been identified as of yet. In all, 73 Japanese patients with schizophrenia were given risperidone for 8 weeks, and clinical symptoms were evaluated using the Positive and Negative Syndrome Scale (PANSS). Six candidate polymorphisms (HTR2A À1438G4A, 102T4C, H452Y; DRD2 À141delC, Taq I A; COMT V158M) were genotyped. The diplotype configuration for each individual was estimated by the maximum-likelihood method. Multiple linear regressions were used to analyze the effects of these haplotypes/genotype and other prognostic factors on PANSS scale performance. After adjustment for the effects of patient-related variables, HTR2A diplotype and COMT genotype, as well as other potential prognostic factors, did not significantly influence the clinical performance. A DRD2 haplotype tended to correlate with better clinical performance. Compared with patients who had Ins-A2/Ins-A2 diplotype (n¼25), PANSS total scores of patients with Ins-A2/ Del-A1 diplotype (n¼10) showed 40% greater improvement (P¼0.03). The PANSS total scores of patients with HTR2A A-T/A-T diplotype (n¼22) tended to show 15% worse improvement compared with A-T/G-C diplotype (n¼33) (P¼0.06). These results should be treated with caution because of limitations due to small sample size, heterogeneity of patients with respect to past antipsychotic use history, and no correction for multiple corrections. However, the present findings generate important hypotheses in a sample of Japanese schizophrenia patients that may lay the foundation for future pharmacogenomics investigations in other populations.

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Section: Introductionsupporting

confidence: 87%

Effect of DRD2, 5-HT2A, and COMT genes on antipsychotic response to risperidone

et al. 2003

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“…In addition, there was no clear trend of differential distribution between patients and controls. These results could not confirm previous findings of association with schizophrenia [Inayama et al, 1996;Williams et al, 1996;Joober et al, 1999;Araga and Narasu, 2002]. However, it is likely that serotonergic associations are stronger when specific phenotypes such as suicidal behaviour and clinical dimensions are considered [Bonnier et al, 2002;Golimbet et al, 2002] and therefore could not be detected in our sample.…”

Section: Discussioncontrasting

confidence: 88%

“…However, association and linkage genetic studies have failed to produce consistent results supporting the involvement of serotonergic mutations in mental illnesses such as schizophrenia and bipolar disorder. Polymorphisms in the gene coding for 5-HT2A receptors have been related to schizophrenia, bipolar disorder and psychotic symptomatology [Inayama et al, 1996;Williams et al, 1996;Du et al, 1999;Joober et al, 1999;Nacmias et al, 2001;Araga and Narasu, 2002;Bonnier et al, 2002;Golimbet et al, 2002]. Genetic variants of the serotonin transporter (5-HTT) have also been associated with psychotic disorders Malhotra et al, 1998;Hranilovic et al, 2000;Kaiser et al, 2001;Tsai et al, 2002].…”

Section: Introductionmentioning

confidence: 99%

Serotonergic polymorphisms and psychotic disorders in populations from North Spain

Mata¹,

Arranz²,

Patiño

et al. 2003

American J of Med Genetics Pt B

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There is strong biological evidence relating alterations in the serotonergic system with mental disorders. These alterations may be originated at the DNA level by sequence mutations that alter the functioning of serotonin receptors and transporter. To test this hypothesis we investigated three genetic variants of the 5-HT2A receptor (-1438G/A, 102T/C and His452Tyr) and two variants of the serotonin transporter (a VNTR in the second intron and a 44 bp insertion/delition in the promoter region of the gene) in a clinical sample recruited in a human isolate and in surrounding areas in Northern Spain (N = 257) and in ethnically matched controls (N = 334). No clear association was found between 5-HT2A variants and psychosis. However, marginal associations were observed between the 5-HTT LPR and VNTR variants and psychosis (P≤0.05) indicating a minor contribution to psychosis of genetic alterations in this gene.

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“…These workers suggested that this gene, or a locus in linkage disequilibrium with it, conferred susceptibility to schizophrenia because the proportion of allele 2 and genotype 2/2 of the T102C polymorphism was higher than expected in schizophrenic patients and was associated with the pathogenesis of this condition. Although similar results were observed in Japanese patients and controls (Inayama et al, 1996), the findings of Williams et al have been criticized by various authors (Clifford and Nunez, 1996;Malhotra et al, 1996;Arranz et al, 1996;Sasaki et al, 1996;Crow, 1996). The investigations of Williams et al and Inayama et al were repeated in another study by Erdmann et al (1996) who demonstrated that there was structural variability (2 amino-acid substitutions) in the human 5-HT 2a receptor but that receptor variants were encountered at similar frequencies in both schizophrenic individuals and normal controls, indicating that the presence of these variants were not etiologically related to schizophrenia.…”

Section: Reviewmentioning

confidence: 99%

Localization of genes modulating the predisposition to schizophrenia: a revision

Lopes-Machado

Duarte

2000

Genet. Mol. Biol.

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The genetics of schizophrenia or bipolar affective disorder has advanced greatly at the molecular level since the introduction of probes for the localization of specific genes. Research on gene candidates for susceptibility to schizophrenia can broadly be divided into two types, i.e., linkage studies, where a gene is found near a specific DNA marker on a specific chromosome, and association studies, when a condition is associated with a specific allele of a specific gene. This review covers a decade of publications in this area, from the 1988 works of Bassett et al. and Sherrington et al. on a gene localized on the long arm of chromosome 5 at the 5q11-13 loci, to the 1997 work of Lin et al. pointing to the 13q14.1-q32 loci of chromosome 13 and to the 1998 work of Wright et al. on an HLA DRB1 gene locus on chromosome 6 at 6p21-3. The most replicated loci were those in the long arm of chromosome 22 (22q12-q13.1) and on the short arm of chromosome 6 (6p24-22). In this critical review of the molecular genetic studies involved in the localization of genes which modulate the predisposition to schizophrenia the high variability in the results obtained by different workers suggests that multiple loci are involved in the predisposition to this illness.

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Positive association between a DNA sequence variant in the serotonin 2A receptor gene and schizophrenia

Cited by 132 publications

References 13 publications

Effect of DRD2, 5-HT2A, and COMT genes on antipsychotic response to risperidone

Effect of DRD2, 5-HT2A, and COMT genes on antipsychotic response to risperidone

Serotonergic polymorphisms and psychotic disorders in populations from North Spain

Localization of genes modulating the predisposition to schizophrenia: a revision

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