- Email: [email protected]
Meta-analysis of association studies between schizophrenia and polymorphisms of the 5-hydroxytryptamine type 2A receptor gene
91
We have investigated an amino acid substitution of cysteine for serine at position 231 in the N-terminal extracellular domain of the 5-HT 2C receptor (G68C in HTR2C at the chromosomal locus Xq24) for possible allelic association with schizophrenia, bipolar affective disorder and unipolar depression. We have previously found association between the HTR2Cser allele and response to the atypical ant ipsychotic drug, clozapine.2 We subsequently genotyped samples of patients with schizophrenia (191), unipolar depression (76), bipolar affective disorder (193) and controls (228) for this polymorphism. All were Western Europeans and the patients were diagnosed according to DSMIllR or DSMIV criteria . The frequencies of the HTR2Cser allele in schizophrenics (14.2%) unipolars (25%) and bipolars (18.1%) compared with the control sample (19.3%) showed no statistically significant difference. However, the presence of the 5-HT2C serine mutation, especially in the homozygous form, may indicate a reduced chance of long remissions in bipolar patients and an increased severity in their symptoms(n = 184, P = 0.04), but more patients are being stud ied to confirm these initial findings. These results indicate that the aetiologies of schizophrenia, unipolar depression and bipolar affective disorder are not associated with the cysteine to serine substitution in the 5·HT2C receptor protein, although presence of the serine variant may indicate increased severity of symptoms experienced by bipolar patients.
I. Lappalainen J., et al. (1995) Genomics 27 274-279. 2. Sodhi M.S. et al. (1995) NeuroReport 7169-172.
~11
META-ANALYSIS OF ASSOCIATION STUDIES BETWEEN SCHIZOPHRENIA AND POLYMORPHISMS OF THE 5_HYDROXYTRYPTAMINE TYPE 2A RECEPTOR GENE Gillian Spurlock", Julie Williams', Peter McGuffin!, Jacques Mallet2, Markus Nothen", Michael Gi114, Harald Aschauer", Rolf Adolfsson", Fabio Macciardi", Michael J. Owen! for the European Multicentre Association Study of Schizophrenia (EMASS)
DepartmentofPsychological Medicine. UWCM. Heath Park. Cardiff, UK. 2Hopital de la Pitie Salpetrie. Paris. France. 3 Institute ofHuman Genetics. University of Bonn, Bonn. Germany. 4Department ofPsychiatry, Trinity Centrefor Health Sciences. St James' Hospital. Dublin. Ireland. 3 Departmentof General Psychiatry. University Hospitalfor Psychiatry. Vienna. Austria. "Depanmem of Psychiatry. University of Umea, Sweden. "InstitutoScientifico H San Raffaele, University of Milano-School of Medicine. Milan. Italy 1
A reported" association between schizophrenia and the Tl02C polymorphism within the gene encoding the 5-hydroxytryptamine type 2A (5HT2A) receptor was further
investigated using the European Multi Centre Association Study (EMASS) sample: Seven countries recruited 1210participants: 571 white schizophrenic patients with a diagnosis of schizophrenia or schizoaffective disorder and 639 ethnically matched controls. A significant overall association between schizophrenia and allele 2 was found with an odds ratio of 1.3 (95% CI 1.1-1.53, p=O.003 corrected)". A meta-analysis of published and unpublished association studies shows increasing evidence of an allelic association with the 2 allele (p=0 .OOO8, OR = 1.19, 95% CI 1.07-1.32) with no evidence of heterogeneity between studies (p=0.7) . This consensus of results provides further evidence that this polymorphism in the gene for 5HT2A receptor, or a locus in linkage disequilibrium with it confers susceptibility to schizophrenia. To investigate this further , studies were carried out in the EMASS sample genotyping additional polymorphisms in the 5HT2A gene (2 in the coding and 2 in the promoter region of the gene) and haplotype analysis was carried out.
I. 8. Inayama et al. (1994) Neuropharm 10, 56s. 2. 9. Williams et al. (1996) The Lancet, 347, 1294.
'2.40 LACK OF ASSOCIATION BETWEEN 5HT2A, 5HT2C, AND D4 RECEPTOR GENE POLYMORPHISMS AND THE DEFICIT SYNDROME OF SCHIZOPHRENIA Robert W. Buchanan, Anil Malhotra, Brian Kirkpatrick, David Goldman, Alan Breier, David Pickar
MarylandPsychiatricResearch Center. Departmentof Psychiatry. University of Maryland. BaltimoreMaryland21228 Serotonergic and dopaminergic neurotransmitter systems have been implicated in the pathophysiology of negative symptoms. The primary evidence for the involvement of these systems is the putative efficacy of serotonergic and dopaminergic pharmacological agents for ameliorating negative symptoms. Further support for the role of D4 polymorphisms is provided by the recent demonstration of an association between novelty seeking, a personality characteristic that is diminished in patients with negative symptoms, and specific forms of the D4 receptor . Sixty-five patients were genotyped for 5HT2A (452 Hist/Tyr; 102 TyrjCyst), SHT2C (CYS23 vs Sern) and D4 (4 vs 7) polymorphisms. The Schedule for the Deficit Syndrome was used to categorize patients into deficit (n = 18), characterized by the presence of primary, enduring negative symptoms, and nondeficit (n = 47) subgroups. There were no significant associations between either genotype or allele frequency for any of the receptor types and deficit syndrome categorization. These results suggest that these receptor polymorphisms are not related to negative symptoms.
We have investigated an amino acid substitution of cysteine for serine at position 231 in the N-terminal extracellular domain of the 5-HT 2C receptor (G68C in HTR2C at the chromosomal locus Xq24) for possible allelic association with schizophrenia, bipolar affective disorder and unipolar depression. We have previously found association between the HTR2Cser allele and response to the atypical ant ipsychotic drug, clozapine.2 We subsequently genotyped samples of patients with schizophrenia (191), unipolar depression (76), bipolar affective disorder (193) and controls (228) for this polymorphism. All were Western Europeans and the patients were diagnosed according to DSMIllR or DSMIV criteria . The frequencies of the HTR2Cser allele in schizophrenics (14.2%) unipolars (25%) and bipolars (18.1%) compared with the control sample (19.3%) showed no statistically significant difference. However, the presence of the 5-HT2C serine mutation, especially in the homozygous form, may indicate a reduced chance of long remissions in bipolar patients and an increased severity in their symptoms(n = 184, P = 0.04), but more patients are being stud ied to confirm these initial findings. These results indicate that the aetiologies of schizophrenia, unipolar depression and bipolar affective disorder are not associated with the cysteine to serine substitution in the 5·HT2C receptor protein, although presence of the serine variant may indicate increased severity of symptoms experienced by bipolar patients.
I. Lappalainen J., et al. (1995) Genomics 27 274-279. 2. Sodhi M.S. et al. (1995) NeuroReport 7169-172.
~11
META-ANALYSIS OF ASSOCIATION STUDIES BETWEEN SCHIZOPHRENIA AND POLYMORPHISMS OF THE 5_HYDROXYTRYPTAMINE TYPE 2A RECEPTOR GENE Gillian Spurlock", Julie Williams', Peter McGuffin!, Jacques Mallet2, Markus Nothen", Michael Gi114, Harald Aschauer", Rolf Adolfsson", Fabio Macciardi", Michael J. Owen! for the European Multicentre Association Study of Schizophrenia (EMASS)
DepartmentofPsychological Medicine. UWCM. Heath Park. Cardiff, UK. 2Hopital de la Pitie Salpetrie. Paris. France. 3 Institute ofHuman Genetics. University of Bonn, Bonn. Germany. 4Department ofPsychiatry, Trinity Centrefor Health Sciences. St James' Hospital. Dublin. Ireland. 3 Departmentof General Psychiatry. University Hospitalfor Psychiatry. Vienna. Austria. "Depanmem of Psychiatry. University of Umea, Sweden. "InstitutoScientifico H San Raffaele, University of Milano-School of Medicine. Milan. Italy 1
A reported" association between schizophrenia and the Tl02C polymorphism within the gene encoding the 5-hydroxytryptamine type 2A (5HT2A) receptor was further
investigated using the European Multi Centre Association Study (EMASS) sample: Seven countries recruited 1210participants: 571 white schizophrenic patients with a diagnosis of schizophrenia or schizoaffective disorder and 639 ethnically matched controls. A significant overall association between schizophrenia and allele 2 was found with an odds ratio of 1.3 (95% CI 1.1-1.53, p=O.003 corrected)". A meta-analysis of published and unpublished association studies shows increasing evidence of an allelic association with the 2 allele (p=0 .OOO8, OR = 1.19, 95% CI 1.07-1.32) with no evidence of heterogeneity between studies (p=0.7) . This consensus of results provides further evidence that this polymorphism in the gene for 5HT2A receptor, or a locus in linkage disequilibrium with it confers susceptibility to schizophrenia. To investigate this further , studies were carried out in the EMASS sample genotyping additional polymorphisms in the 5HT2A gene (2 in the coding and 2 in the promoter region of the gene) and haplotype analysis was carried out.
I. 8. Inayama et al. (1994) Neuropharm 10, 56s. 2. 9. Williams et al. (1996) The Lancet, 347, 1294.
'2.40 LACK OF ASSOCIATION BETWEEN 5HT2A, 5HT2C, AND D4 RECEPTOR GENE POLYMORPHISMS AND THE DEFICIT SYNDROME OF SCHIZOPHRENIA Robert W. Buchanan, Anil Malhotra, Brian Kirkpatrick, David Goldman, Alan Breier, David Pickar
MarylandPsychiatricResearch Center. Departmentof Psychiatry. University of Maryland. BaltimoreMaryland21228 Serotonergic and dopaminergic neurotransmitter systems have been implicated in the pathophysiology of negative symptoms. The primary evidence for the involvement of these systems is the putative efficacy of serotonergic and dopaminergic pharmacological agents for ameliorating negative symptoms. Further support for the role of D4 polymorphisms is provided by the recent demonstration of an association between novelty seeking, a personality characteristic that is diminished in patients with negative symptoms, and specific forms of the D4 receptor . Sixty-five patients were genotyped for 5HT2A (452 Hist/Tyr; 102 TyrjCyst), SHT2C (CYS23 vs Sern) and D4 (4 vs 7) polymorphisms. The Schedule for the Deficit Syndrome was used to categorize patients into deficit (n = 18), characterized by the presence of primary, enduring negative symptoms, and nondeficit (n = 47) subgroups. There were no significant associations between either genotype or allele frequency for any of the receptor types and deficit syndrome categorization. These results suggest that these receptor polymorphisms are not related to negative symptoms.