5-HT2A Receptor Gene Polymorphism Research Articles

Tardive dyskinesia is not associated with the polymorphisms of 5-HT2A receptor gene, serotonin transporter gene and catechol- o-methyltransferase gene

Background. – The pathophysiology of tardive dyskinesia (TD) is not completely understood. Aim. – To assess the relationship of TD with 5-HT2A receptor gene, serotonin transporter gene (5 HTT), and catechol- o-methyltransferase (COMT) gene polymorphisms. Method. – Our study comprised 111 unrelated subjects who strictly met DSM-IV criteria for schizophrenia and 32 TD, and 79 healthy unrelated controls; all the subjects were of Turkish origin. The analyses of 5-HT2A receptor gene, 5 HTT gene, and COMT gene polymorphisms were performed using polymerase chain reaction (PCR) technique. Results. – The polymorphisms of these genes were not significantly different between the schizophrenic patients, TD and control subjects. Conclusion. – Our findings indicated that 5-HT2A receptor gene, 5 HTT gene, and COMT gene polymorphisms were similar in schizophrenia with non-TD, schizophrenia with TD, and healthy controls. These polymorphisms, though, do not help to evaluate the susceptibility to TD.

No evidence for an association between the 5-hydroxytryptamine 5-HT2a receptor gene and schizophrenia in Kuwaiti Arabs.

The prevalence of T102C polymorphism of the 5-hydroxytryptamine 5-HT2a receptor gene has been investigated using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in 80 Kuwaiti Arabs with schizophrenia and in 109 normal healthy controls with a similar ethnic background. There was no significant difference in the frequency of T102 polymorphism in the Kuwaiti cohort of schizophrenia patients and the controls (P = 0.23). The data from Kuwaiti Arabs (although our sample size is relatively small) support the findings from some other populations (Caucasians, Japanese), in which a lack of association has been found between T102C polymorphism and the onset of schizophrenia.

Association of the T102C polymorphism of 5-HT2A receptor gene with aura in migraine

Objective: To find out the significance of the 5-HT2A receptor gene polymorphism in migraine. Study design: A PCR study in which 61 migraineurs and 44 healthy controls were included. Methods: The T102C polymorphism of the 5-HT2A receptor gene was studied. The results of the migraineurs and controls were compared. The relationship between the gene polymorphism and aura was also assessed. Results: The representations of the 5-HT2A genotypes were similar in migraineurs and controls ( p>0.05) as well as in the male and female migraineurs ( p>0.05). The family history of migraine did not associate with 5-HT2A receptor gene polymorphism ( p>0.05). There was a significant relationship between the presence of C/C genotype and migraine with aura ( p=0.02) while C/T and T/T genotypes were over represented in the patients with migraine without aura ( p<0.01). Conclusion: The T102C polymorphism of the 5-HT2A receptor gene is not directly related to the increased risk of migraine. The associations between the genotypes of this gene and aura may suggest that 5-HT2A receptor gene polymorphism may be involved in determining the subtypes of or accompanying symptoms in the migraine disease.

Serotonergic genes and suicidality.

Several lines of evidence indicate that abnormalities in the functioning of the central serotonergic system are involved in the pathogenesis of depressive illness and suicidal behavior. Studies have shown that the number of brain and platelet serotonin transporter binding sites are reduced in patients with depression and in suicide victims, and that the density of 5-HT2A receptors is increased in brain regions of depressed in suicide victims and in platelets of depressed suicidal patients. Genes that code for proteins, such as tryptophan hydroxylase, 5-HT transporter, and 5-HT2A receptor, involved in regulating serotonergic neurotransmission, have thus been major candidate genes for association studies of suicide and suicidal behavior. Recent studies by our group and by others have shown that genetic variations in the serotonin-system-related genes might be associated with suicidal ideation and completed suicide. We have shown that the 102 C allele in 5-HT2A receptor gene was significantly associated with suicidal ideation (chi2 = 8.5. p < .005) in depressed patients. Patients with a 102 C/C genotype had a significantly higher mean HAMD item #3 score (indication of suicidal ideation) than T/C or T/7 genotype patients. Our results suggest that the 102T/C polymorphism in 5-HT2A receptor gene is primarily associated with suicidal ideation in patients with major depression and not with depression itself. We also found that the 5-HT transporter gene S/L polymorphism was significantly associated with completed suicide. The frequency of the L/L genotype in depressed suicide victims was almost double of that found in control group (48.6% vs. 26.2%). The odds ratio for the L allele was 2.1 (95% CI 1.2-3.7). The association between polymorphism in serotonergic genes and suicidality supports the hypothesis that genetic factors can modulate suicide risk by influencing serotonergic activity.

5-HT2A receptor gene polymorphism is associated with food and alcohol intake in obese people.

To test the association between a polymorphism of the 5-HT2A receptor gene, -1438G/A, and energy and nutrients intake, including alcohol. Two hundred and seventy six unrelated overweight subjects (180 women, 96 men) were recruited from the Nutrition Department of Bichat Hospital in Paris on the basis of 120% of ideal body weight (body mass index, BMI=33.3+/-4.8 kg/m2). A second overweight sample (31 women, 49 men) was drawn from the Stanislas Family Study, composed of volunteers for a free health examination in Nancy (BMI=29.6+/-3.1 kg/m2). Energy and nutrients intake were assessed using the diet history method in Paris and the 3-day record method in Nancy. We analyzed the polymorphism by PCR followed by MspI digestion. Statistical differences between genotypes were assessed by using the non-parametric Kruskal-Wallis test. In the whole overweight population, the A allele was associated with lower energy intake 10. 3+/-2.8, 9.9+/-2.8, 9.3+/-2.9 MJ/day for GG, GA and AA genotypes respectively (P<0.05). This association was significant in the patient sample from Paris and in the overweight male volunteers from Nancy. Allele A-related lowering in energy intake was due to a trend to lower intakes in all the main nutrients. The A allele was also associated with a lower alcohol consumption: 18.4+/-19.7, 15.3+/-21. 2 and 12.3+/-17.5 g/day for GG, GA and AA genotypes, respectively (P<0.05). These data indicate that a gene polymorphism may influence food and alcohol intake in overweight humans. This could be explained by the role of the serotonergic system as a determinant of food intake.

Association of polymorphism of serotonin 2A receptor gene with suicidal ideation in major depressive disorder.

There is evidence indicating that density of 5-HT2A receptors is altered in brain regions of depressed suicide victims and in platelets of suicidal subjects with major depression or schizophrenia. Recent studies have also shown an association between the allele C of 102T/C polymorphism in the 5-HT2A receptor gene and schizophrenia. The present investigation tested the hypothesis that the observed changes in 5-HT2A receptor density in platelets of patients with major depression are a trait rather than state phenomenon and are associated with the 102 C allele in 5-HT2A receptor gene in a sample of 120 patients with major depression and a group of 131 control subjects comparable with respect to age, sex, and ethnic background. The allele and genotype frequencies of 102T/C polymorphism in 5-HT2A receptor gene were compared between patients and control subjects and between suicidal and non-suicidal patient groups. The major finding of this study was a significant association between the 102 C allele in 5-HT2A receptor gene and major depression, chi(2) = 4.5, df = 1, P = 0.03, particularly in patients with suicidal ideation, chi(2) = 8.5, df = 1, P < 0.005. Furthermore, we found that patients with a 102 C/C genotype had a significantly higher mean HAMD item 3 score (indication of suicidal ideation) than T/C or T/T genotype patients. Our results suggest that the 102T/C polymorphism in 5-HT2A receptor gene is primarily associated with suicidal ideation in patients with major depression. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:56-60, 2000.

Association of 5HT2A receptor gene polymorphism and alcohol abuse with behavior problems

This study investigated the association between T/C polymorphism, at position 102, of the 5-hydroxytryptamine 2A receptor gene and alcoholism with and without behavior problems. Eighty-five subjects (45 men, 40 women) with alcohol abuse, 75 subjects (51 men, 24 women) with alcohol dependence, and 70 normal control subjects (21 men, 49 women) participated in the study. The results show that the frequency of the homozygous T102 genotype was significantly lower in the group of male alcohol abuse with behavior problems than in the female group (chi(2) = 4.072, df = 1, P < 0.05) and the allele frequency of T102 was also lower in the male group than in the female group (chi(2) = 4.187, df = 1, P < 0.05). Of the male alcohol abuse subjects, the group with behavior problems was found to have lower frequencies of the T102 allele than the group without behavior problems (chi(2) = 4.328, df = 1, P < 0.05). In conclusion, this study demonstrates that alcoholism is heterogeneous and male alcohol abuse with behavioral problems was associated with T/C 102 polymorphism of the 5HT2A receptor gene. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:797-800, 2000.

Serotonin-2A receptor polymorphism (102T/C) in mood disorders

Serotonergic dysfunction has been implicated in mood disorders and suicidal behaviors. This study examined the association between a serotonin-2A (5HT 2A) receptor gene polymorphism (102T/C) and mood disorders. The genotype and allele frequencies did not differ between patients with mood disorders and control subjects. Furthermore, the 102T/C polymorphism was not found to be associated with suicidal history in mood disorder patients. Our results suggest that this polymorphism is unlikely to play a role in the genetic susceptibility to mood disorders.

Excess TPH 17 779C allele in surviving cotwins of monozygotic twin suicide victims

Genetic factors contribute to the risk of psychopathology in many psychiatric conditions, but the specific genes are yet to be identified. Neurotransmitter alterations are implicated in the etiology of psychopathology based, in part, on studies of neurotransmitter receptors and their biosynthetic or degradative enzymes in postmortem tissue. Identification of the altered receptors and enzymes serves to identify candidate genes of potential etiological significance. Polymorphisms in these genes can contribute to alterations in protein function in vivo that are part of the neurochemical underpinnings of psychopathologies such as major depressive disorder, psychoses, alcoholism, personality disorders, aggressive–impulsive traits, or suicidal behavior. Altered serotonergic function is implicated in the etiology and pathogenesis of several major psychiatric conditions. In particular, there is much evidence for an association of lower serotonergic function and suicidal behavior. Thus genes related to the serotonergic system are candidate genes worthy of study as part of the genetic diathesis for suicidal behavior. This review examines the following polymorphisms in the serotonin biosynthetic enzyme tryptophan hydroxylase (TPH; A779C substitution), the serotonin transporter (5-HTT, 5-HTTLPR allele), the 5-HT1B receptor (G861C, C129T substitution) and the 5-HT2A receptor (T102C) for their relationship to suicidal behavior. For the TPH gene, we found the less common U or A allele variant of the A779C polymorphism was associated with suicide attempt. Other studies have found the U allele to be associated with aggression and lower serotonergic function in vivo. A 44 base pair insertion/deletion in the 5′ flanking promoter region of the 5-HTT gene may result in less 5-HTT expression and 5-HTT binding. We examined 220 cases postmortem and found no association between the promoter genotype and 5-HTT binding. We also found no association with major depressive disorder (MDD), suicide or pathological aggression, despite finding significantly fewer 5-HTT sites in the prefrontal cortex of depressed and/or suicide cases. In genomic DNA samples from 178 unrelated subjects, we detected two polymorphisms for the 5-HT1B receptor at nucleotides 861 and 129. However, no association between either polymorphism and depression, suicide, aggression, or alcoholism was observed. There are two common polymorphisms for the 5-HT2A receptor gene in humans. The results of studies of 5-HT2A receptor gene polymorphisms do not indicate significant major associations with suicidal behavior. In contrast, the 5-HT2A receptor itself is reported to be increased in suicide. Functional polymorphisms involving the promoter region that affect gene expression may explain this finding. Studies of candidate genes related to serotonergic function in brain are increasingly used to establish genetic alterations contributing to psychiatric illness. The most meaningful studies combine the study of candidate genes with direct measures of related proteins as well as psychopathology.

5-HT 2A promoter polymorphism in anorexia nervosa

A study 1 Collier DA Arranz MJ Li T Mupita D Brown N Treasure J Association between the 5-HT2A gene promoter polymorphism and anorexia nervosa. Lancet. 1997; 350: 412 Summary Full Text Full Text PDF PubMed Scopus (200) Google Scholar has shown an association between a polymorphism (−1438G/A) in the promoter region of the 5-HT2A gene and anorexia nervosa: Two independent groups failed to replicate these data. 2 Hinney A Ziegler A Nothen MA Remschmidt H Hebebrand J 5-HT2A receptor gene polymorphism, anorexia nervosa, and obesity. Lancet. 1997; 350: 1324-1325 Summary Full Text Full Text PDF PubMed Scopus (77) Google Scholar , 3 Campbell DA Sundaramurthy D Markham AF Pieri LF Lack of association between 5-HT2A gene promoter polymorphism and susceptibility to anorexia nervosa. Lancet. 1998; 351: 499 Summary Full Text Full Text PDF PubMed Scopus (75) Google Scholar We studied this polymorphism in two clinical subtypes of anorexia nervosa and in controls. We analysed the segregation of this polymorphism in 77 female patients with anorexia nervosa, according to DSM-IV criteria (43 restricting-type, body-mass index [BMI] 14·9 [SD 2·6] kg/m 2 Hinney A Ziegler A Nothen MA Remschmidt H Hebebrand J 5-HT2A receptor gene polymorphism, anorexia nervosa, and obesity. Lancet. 1997; 350: 1324-1325 Summary Full Text Full Text PDF PubMed Scopus (77) Google Scholar , and 34 purging type, BMI 16·0 [1·9· kg/m 2 Hinney A Ziegler A Nothen MA Remschmidt H Hebebrand J 5-HT2A receptor gene polymorphism, anorexia nervosa, and obesity. Lancet. 1997; 350: 1324-1325 Summary Full Text Full Text PDF PubMed Scopus (77) Google Scholar , 15–34 years (mean age 24·58 [5·75] years). All patients or their parents gave their informed written consent. We also studied 107 normal female age-matched controls (age 15–36 years, mean age 25·33 [5·57] years), obtained from the DNA bank of the CNR (National Research Council, Florence, Italy). All controls were carefully assessed to exclude any neurological or psychiatric disorders. DNA from affected and non-affected individuals was extracted from transformed lymphoblasts or peripheral blood samples with the phenol-chloroform procedure. Amplification from 200 ng of genomic DNA was done with a Thermal Cycler 9600 (Perkin Elmer). The − 1438G/A polymorphism was analysed as previously described. 1 Collier DA Arranz MJ Li T Mupita D Brown N Treasure J Association between the 5-HT2A gene promoter polymorphism and anorexia nervosa. Lancet. 1997; 350: 412 Summary Full Text Full Text PDF PubMed Scopus (200) Google Scholar The frequencies of 1438G/A alleles were estimated by gene counting. Statistical analysis was done with the χ2 test.

No association between schizophrenia and the serotonin receptor 5HTR2a in an Italian population.

A major role of the serotonergic system has been hypothesized in the pathogenesis of schizophrenia, mostly based on the evidence of action of new and atypical neuroleptics such as Risperidone or Clozapine. We evaluated the genotypes and alleles of the 5HT2a receptor gene in 67 nuclear families following the Haplotype Relative Risk (HRR) strategy and in a second sample of 100 schizophrenics and 103 controls. The 5HT2a receptor gene polymorphism, following PCR amplification and subsequent Hpa II digestion, reveals a two-alleles system in the coding region of the gene. We did not find statistically significant differences between patients and controls for genotypes, nor for alleles, both in the HRR and in the case-control groups. These results do not confirm the positive association obtained by Inayama et al.: [Neuropsychopharmacology 1(35): 145-219, 1994] and by Williams et al. [Lancet, 397:1294-1296, 1996] in our population.

Migraine association and linkage analyses of the human 5-hydroxytryptamine (5HT2A) receptor gene.

5-Hydroxytryptamine (5HT), commonly known as serotonin, which predominantly serves as an inhibitory neurotransmitter in the brain, has long been implicated in migraine pathophysiology. This study tested an MspI polymorphism in the human 5HT2A receptor gene (HTR2A) and a closely linked microsatellite marker (D13S126), for linkage and association with common migraine. In the association analyses, no significant differences were found between the migraine and control populations for both the MspI polymorphism and the D13S126 microsatellite marker. The linkage studies involving three families comprising 36 affected members were analysed using both parametric (FASTLINK) and non-parametric (MFLINK and APM) techniques. Significant close linkage was indicated between the MspI polymorphism and the D13S126 microsatellite marker at a recombination fraction (theta) of zero (lod score = 7.15). Linkage results for the MspI polymorphism were not very informative in the three families, producing maximum and minimum lod scores of only 0.35 and -0.39 at recombination fractions (theta) of 0.2 and 0.00, respectively. However, linkage analysis between the D13S126 marker and migraine indicated significant non-linkage (lod < -2) up to a recombination fraction (theta) of 0.028. Results from this study exclude the HTR2A gene, which has been localized to chromosome 13q14-q21, for involvement with common migraine.

Aggression, suicide, and serotonin: relationships to CSF amine metabolites.

In an earlier, separate study, the authors found that human aggression and suicide (a specific aggression-related behavior) were associated with lower levels of CSF 5-hydroxyindoleacetic acid (5-HIAA), a serotonin metabolite. That study focused on subjects with personality disorders without affective illness. In the present study they examine the life history of aggression and history of suicidal behavior in 12 subjects with borderline personality disorders without major affective disorder. Histories of aggressive behaviors and of suicide attempts were significantly associated with each other, and each was significantly associated with lower 5-HIAA levels. Altered serotonin metabolism may be a highly significant contributing factor to these behaviors in whatever diagnostic group they occur.