Association study of serotonin 2A receptor (5-HT2A) and serotonin transporter (5-HTT) gene polymorphisms with schizophrenia

OBJECTIVE: To investigate (i) the association between four serotonergic polymorphisms (A-1438G and T102C of the 5-HT2A receptor gene, and 5-HTT VNTR and 5-HTTLPR of the 5-HT transporter gene) and schizophrenia and (ii) the potential interaction of those polymorphisms in the development of schizophrenia. SUBJECTS AND METHODS: 227 outpatients with schizophrenia (DSM-IV criteria) and 420 unrelated healthy controls from Asturias (Northern Spain) were genotyped using standard methods. RESULTS: Both groups showed Hardy-Weinberg equilibrium for the analyzed genetic variability. A-1438G and T102C polymorphisms are in complete linkage disequilibrium in our population. There was an apparent difference in the distribution of genotypes for the A-1438G (or T102C) polymorphisms (p=0.018, not significant after a Bonferroni correction). The 5-HT2A -1438A (or 102T) allele was significantly more frequent in patients than controls (0.53 and 0.45, respectively; corrected p=0.028, OR=1.39 (95% CI=1.11-1.75)). Genotype and allele distributions for 5-HTT polymorphisms were similar in both groups. However, assessment of the combined influence of 5-HT2A A-1438G and 5-HTTLPR polymorphisms demonstrated a significant effect (chi(2) (3)=11.51, p=0.009), whereby the combination of -1438A and 5-HTTLPR S alleles was associated with schizophrenia. CONCLUSIONS: Our findings support a possible synergistic effect of genetic factors influencing serotonergic neurotransmission on susceptibility to schizophrenia.     

Association analysis for the C-1019G promoter variant of the 5-HT1A receptor gene with auditory evoked potentials in major depression

Involvement of the serotonergic system in N1 and P2 components of auditory evoked potentials (AEPs) has been implicated. Moreover, studies have indicated the presence of heritability in the genesis of AEP components. The serotonin 1A (5-HT1A) receptor gene is a strong candidate for N1 and P2 components of the AEPs because 5-HT1A receptor regulates the firing of serotonergic neurons. The present study tested the hypothesis that the 5-HT1A promoter genetic polymorphism (C-1019G) is associated with N1 and P2 components of AEPs in unmedicated major depression patients. The sample consisted of 221 Chinese patients (mean age: 44.3 years; male/female: 93/128) diagnosed with major depression. AEPs and 5-HT1A genotyping were done for each patient. Patients with the C/C genotype had a significantly shorter P2 latency when compared with C/G or G/G genotype patients (p = 0.049), and the difference in P2 latency was significant among the 5-HT1A genotype groups in male patients (p = 0.031) but not in female patients (p = 0.398). These findings suggest that this 5-HT1A polymorphism may affect AEP P2 latency in a gender-dependent manner. Further studies with other genetic polymorphisms in the serotonergic system may help to clarify the relation between serotonergic function and AEP components.     

Genetics of the serotonergic system in suicidal behavior

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-HT(1B) receptor (G861C, C129T substitution) and the 5-HT(2A) 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-HT(1B) 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-HT(2A) receptor gene in humans. The results of studies of 5-HT(2A) receptor gene polymorphisms do not indicate significant major associations with suicidal behavior. In contrast, the 5-HT(2A) 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.     

Association of 5-HT2A receptor gene polymorphisms with gastrointestinal disorders in Egyptian children with autistic disorder

Gastrointestinal disturbances (GID) are frequently reported in children with autism spectrum disorders (ASD). Recently, mounting evidence suggests that there may be a genetic link for autism with gastrointestinal disturbances.We aimed to investigate whether there were any association between the -1438A/G, 102T/C and His452Tyr polymorphisms of the serotonin 2A receptor gene (5-HT2A) in Egyptian children with ASD and GID. Eighty children with autistic disorder and 100 healthy control children were examined. -1438A/G, 102T/C and His452Tyr polymorphisms of 5-HT2A were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Significant increase of the G allele and the GG genotype of the -1438A/G polymorphism was observed in children with autism than control, but there were no significant differences in the frequencies either of the 102T/C genotype or His452Tyr genotype between the two groups. There was a significant increase of homozygote A allele of the -1438A/G and CC genotype of the 102T/C polymorphism in ASD children with GID. This study supports the possible involvement of the 5-HT2A receptor in the development of ASD and associated GID.     

Family-based association study of serotonergic candidate genes and attention-deficit/hyperactivity disorder in a German sample

Summary Alterations in the serotonergic pathway have been implicated in the pathogenesis of attention-deficit/hyperactivity disorder (ADHD). The aim of this study was to investigate seven genetic variants in three genes (serotonin transporter (5-HTT), serotonin receptor 1B (5-HTR1B) and serotonin receptor 2A (5-HTR2A)), which have previously been shown to be associated with ADHD. The polymorphisms under investigation were the 5-HTTLPR, the VNTR in intron 2 and the 3′UTR SNP in 5-HTT, the 5-HTR1B variations 861G>C and 102T>C, and the 5-HTR2A variations His452Tyr and 1438G>A. We genotyped these variants in a sample of 102 families with 229 children with ADHD according to DSM-IV criteria. Among the affected children, 69% fulfilled criteria for the combined type, 27% for the predominantly inattentive type, and 4% for the predominantly hyperactive-impulsive type. Associations were tested by the pedigree transmission disequilibrium test (PDT). All investigated polymorphisms in serotonergic candidate genes showed no association to ADHD in our sample. Earlier studies of these polymorphisms had also shown inconsistent results, with some studies reporting significant associations and others demonstrating no association. This discordance between studies may reflect variation in patient ascertainment criteria, genetic heterogeneity, too low statistical power for the expected effects or false positive results in the initial reports. We cannot rule out the possibility that other variations in the investigated genes contribute to the etiology of ADHD.     

Evidence for the serotonin HTR2A receptor gene as a susceptibility factor in attention deficit hyperactivity disorder (ADHD)

A recent study demonstrated that treatment of hyperactive mice with psychostimulants and serotonergic agents produced a calming effect that was dependent on serotonergic neurotransmission and was not associated with any changes in extracellular dopamine levels. The complex interaction between the serotonergic and dopaminergic neurotransmitter systems suggests that a balance between the two systems may be necessary for mediating hyperactive behaviour. Defects in serotonin system genes, therefore, may disrupt normal brain serotonin function causing an imbalance between these neurotransmitter systems leading to the development of attention deficit hyperactivity disorder (ADHD). Using the transmission disequilibrium test (TDT), the current study assesses for linkage disequilibrium between polymorphisms in the serotonin HTR2A receptor gene and ADHD. One hundred and fifteen families with a total of 143 children diagnosed with ADHD (DSM-IV) were genotyped for the His452 Tyr and the T102C polymorphisms in the serotonin HTR2A receptor gene. TDT analysis revealed a preferential transmission of the 452Tyr allele to the affected offspring (P = 0.03), suggesting linkage disequilibrium of this polymorphism with ADHD. This may open a new door in ADHD molecular genetics research, expanding the existing view of a catecholaminergic hypothesis to include a serotonergic hypothesis and should help elucidate the complex interplay among the neurotransmitter systems in the etiology of ADHD.     

Association analysis of the 5-HT5A gene in depression, psychosis and antipsychotic response

The serotonergic system is targeted by both antidepressants and atypical antipsychotic drugs such as clozapine. Genetic variation in the 5-HT5A gene might be involved in susceptibility to depression, the major psychoses or in influencing clinical response to treatment. To examine this hypothesis we genotyped two polymorphisms (-19G/C; 12A/T) in the human 5-HT5A receptor gene in a sample of 269 unrelated schizophrenic patients treated with clozapine, 112 bipolar patients, 75 unipolar patients and 187 controls. After five-fold correction for multiple testing, allelic association was found with the -19G/C polymorphism and bipolar affective disorder, (p = 0.025; OR 0.56), unipolar depression (p = 0.004; OR 0.52) and schizophrenia (p = 0.036; OR 0.67) indicating a potential protective effect of the G19 allele. For the 12A/T polymorphism allelic association was observed with unipolar depression only (p = 0.004). We conclude that allelic variation in the human 5-HT5A receptor gene may be involved in susceptibility to schizophrenia and affective disorders but not in determining response to clozapine.     

T102C and -1438 G/A polymorphisms of the 5-HT2A receptor gene in Turkish patients with obsessive-compulsive disorder.

OBJECTIVE: This study aimed to investigate the possible association between T102C and -1438 G/A polymorphism in the 5-HT2A receptor gene and susceptibility to and clinical features of obsessive-compulsive disorder (OCD). METHOD: Fifty-eight patients with OCD and 83 healthy controls were included in the study. All patients were interviewed and rated by Yale-Brown Obsessive-Compulsive Scale. T102C and -1438 G/A polymorphisms of 5-HT2A receptor gene were determined by PCR technique in DNAs of peripheral leucocytes. RESULTS: OCD patients and healthy controls did not show significant differences in genotype distribution for both polymorphisms investigated. We found that frequencies of the TT genotype for T102C polymorphism and the AA genotype for -1438 G/A polymorphism were significantly higher in patients with severe OCD compared to those with moderate or moderate-severe OCD. CONCLUSION: The -1438 G/A and T102C polymorphisms of the 5-HT2A receptor gene are not associated with an increased risk of OCD. Our data suggest that the TT genotype of T102C and the AA genotype of -1438 G/A polymorphism might be a factor in clinical severity of OCD.     

Exploration of 19 serotoninergic candidate genes in adults and children with attention-deficit/hyperactivity disorder identifies association for 5HT2A, DDC and MAOB

Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder in which different genetic and environmental susceptibility factors are involved. Several lines of evidence support the view that at least 30% of ADHD patients diagnosed in childhood continue to suffer the disorder during adulthood and that genetic risk factors may play an essential role in the persistence of the disorder throughout lifespan. Genetic, biochemical and pharmacological studies support the idea that the serotonin system participates in the etiology of ADHD. Based on these data, we aimed to analyze single nucleotide polymorphisms across 19 genes involved in the serotoninergic neurotransmission in a clinical sample of 451 ADHD patients (188 adults and 263 children) and 400 controls using a population-based association study. Several significant associations were found after correcting for multiple testing: (1) the DDC gene was strongly associated with both adulthood (P=0.00053; odds ratio (OR)=2.17) and childhood ADHD (P=0.0017; OR=1.90); (2) the MAOB gene was found specifically associated in the adult ADHD sample (P=0.0029; OR=1.90) and (3) the 5HT2A gene showed evidence of association only with the combined ADHD subtype both in adults (P=0.0036; OR=1.63) and children (P=0.0084; OR=1.49). Our data support the contribution of the serotoninergic system in the genetic predisposition to ADHD, identifying common childhood and adulthood ADHD susceptibility factors, associations that are specific to ADHD subtypes and one variant potentially involved in the continuity of the disorder throughout lifespan.     

Prefrontal executive function and D1, D3, 5-HT2A and 5-HT6 receptor gene variations in healthy adults

OBJECTIVE: The Val158Met polymorphism of the catechol-O-methyltransferase gene has been demonstrated to be associated with prefrontal executive function explaining 4% of variance in perseverative errors on the Wisconsin Card Sorting Test (WCST). Studies suggest that dopamine D(1) and D(3) and serotonin 5-HT(2A) and 5-HT(6) receptors may also be involved in prefrontal cognitive function and that genetic polymorphisms (D(1) A-48G, D(3) Ser9Gly, 5-HT(2A) T102C, and 5-HT(6) T267C) of these receptors may be associated with brain glucose metabolism or neurophysiological function. The current study's objective was to investigate whether executive function varies with these genetic variations. METHODS: A sample of 216 healthy Han Chinese adults were measured with the WCST and genotyped for the 4 genetic polymorphisms. RESULTS: Kruskal-Wallis tests showed a significant difference in WCST perseverative errors among the genotypes D(3) Ser9Gly (p = 0.009), 5-HT(2A) T102C (p = 0.038) and 5-HT(6) T267C (p = 0.010), but not in the genotype D(1) A-48G. Multiple regression analysis for the WCST natural logarithm values (i.e., for fulfilling the normal distribution requirement) showed that subjects' perseverative errors were significantly influenced by D(1) A-48G, D(3) Ser9Gly, 5-HT(2A) T102C and 5-HT(6) T267C polymorphisms after adjustment of other variables. CONCLUSION: The preliminary data suggest that D(1), D(3), 5-HT(2A) and 5-HT(6) genetic mutations may influence prefrontal executive cognition in healthy adults. Further studies in larger samples with other ethnicities or in mentally ill patients are warranted.     

Association of the 5-HT2A receptor gene polymorphism 102 T/C with ischemic stroke

Serotonin (5-HT) has been implicated in a number of cardiovascular disorders due to its ability to induce vascular contraction and platelet aggregation through activation of the 5-HT2 receptor family. In this study, we investigated the association of stroke in a Scandinavian population with two common polymorphisms in the 5-HT2A receptor gene. The two polymorphisms under investigation, namely the 102T/C and the −1438A/G variations of the 5-HT2A receptor gene, were examined in a case control association study involving 99 stroke patients and a comparable number of controls. Among patients, the prevalence of the homozygous 102T/T genotype was significantly higher than in controls (28.3% vs 13.5%; p<0.01). The allelic frequency of 102T carriers was also significantly higher in stroke patients than in controls (p=0.002, OR=1.88, 95%CI, 1.27–2.80). The association between the 102T allele and stroke was significant in both males and females. There was no association between stroke and the −1438A/G polymorphism. Taken together, this study indicates that the 102T/C polymorphism in the 5-HT2A receptor gene could be an independent risk factor for developing stroke.     

The association between serotonin-related gene polymorphisms and panic disorder

Dysfunction of the serotonergic system has been hypothesized to play an important role in panic disorder. We investigated the 5-HT2A receptor (5HTR2A) and tryptophan hydroxylase (TPH) genes for an association with panic disorder (PD). Patients with PD (n=107) and control subjects (n=161) were genotyped for 5HTR2A 1438A/G, 5HTR2A 102T/C, and TPH218 A/C. The severity of their symptoms was measured using the Spielberger State-Trait Anxiety Inventory (STAI), Panic Disorder Severity Scale (PDSS), Anxiety Sensitivity Index (ASI), Acute Panic Inventory (API), and Hamilton's Rating Scale for Depression (HAMD). There were no significant differences in the genotype distributions or allelic frequencies in the three serotonergic polymorphisms between PD patients and normal controls. However, we found a significant difference in symptom severity among the genotypes of both the 5HTR2A 1438A/G and 102T/C polymorphisms. Although there were no significant differences in the genotype and allele distributions, we found a significant association between panic symptom severity and the serotonin 2A receptor gene. This result suggests that 5HTR2A 1438A/G and 102T/C polymorphic regions can be associated with the phenotype or the pathogenesis of panic disorder.     

Lack of association between serotonin-2A receptor gene (HTR2A) polymorphisms and tardive dyskinesia in schizophrenia

Tardive dyskinesia (TD) is a disabling neurological side effect associated with long-term treatment with typical antipsychotics. Family studies and animal models lend evidence for hereditary predisposition to TD. The newer atypical antipsychotics pose a minimal risk for TD which is in part attributed to their ability to block the serotonin-2A (5-HT(2A)) receptor. 5-HT(2A) receptors were also identified in the basal ganglia; a brain region that plays a critical role in antipsychotic-induced movement disorders. We tested the significance of variation in the 5-HT(2A) receptor gene (HTR2A) in relation to the TD phenotype. Three polymorphisms in HTR2A, one silent (C102T), one that alters the amino acid sequence (his452tyr) and one in the promoter region (A-1437G) were investigated in 136 patients refractory or intolerant to treatment with typical antipsychotics and with a DSM-IIIR diagnosis of schizophrenia. We did not find any significant difference in allele, genotype or haplotype frequencies of polymorphisms in HTR2A among patients with or without TD (P > 0.05). Further analysis using the ANCOVA statistic with a continuous measure of the TD phenotype (Abnormal Involuntary Movement Scale (AIMS) score) found that the AIMS scores were not significantly influenced by HTR2A polymorphisms, despite controlling for potential confounders such as age, gender and ethnicity (P > 0.05). Theoretically, central serotonergic function can be subject to genetic control at various other mechanistic levels including the rate of serotonin synthesis (tryptophane hydroxylase gene), release, reuptake (serotonin transporter gene) and degradation (monoamine oxidase gene). Analyses of these other serotonergic genes are indicated. In summary, polymorphisms in HTR2A do not appear to influence the risk for TD. Further studies evaluating in tandem multiple candidate genes relevant for the serotonergic system are warranted to dissect the genetic basis of the complex TD phenotype.     

5-HT2A受体基因102 T/C多态性与慢性抽动障碍的遗传关联

目的 探讨慢性抽动障碍与5-HT2A受体基因中102 T/C多态性的关系。方法 采用聚合酶链式反应(PCR)与限制性片段长度多态性(RFLPs)方法,对慢性抽动障碍儿童(n=72)与其亲生父母(n=131)的5-HT2A受体102 T/C的多态性分型,数据采用单体型相对风险(GHRR和HHRR)与传递不平衡检验(TDT)方法进行分析。 结果 合并焦虑情绪的慢性抽动障碍与5-HT2A受体102 T/C位点T等位基因存在关联或连锁不平衡(TDT 检验X2=5.45,P<0.05),而总的样本及其他分组与该位点无显著关联。 结论 5-HT2A受体102 T/C位点T等位基因与合并焦虑情绪的慢性抽动障碍相关联。     

5-羟色胺2A受体基因多态性与抑郁症的关联

目的：探讨中国汉族人群难治性抑郁症患者与5-羟色胺2A(5-HT2A)受体基因的T102C多态性之间的关系。方法：抽取79例难治性抑郁症患者作研究，以102名正常人作对照。应用聚合酶链式反应(PCR)扩增技术及限制性片段长度多态性(RFLP)分别测定所有研究对象的5-HT2A受体基因的基因型和等位基因。结果：5-HT2A受体基因的3种基因型(A1／A1，A1／A2和A2／A2)在难治性抑郁症组的分布分别为31．6％、54．4％和13．9％，在对照组分别为29．4％、45．1％和25．5％，两组间差异无显著性。结论：5-HB。受体基因的T102C多态性与难治性抑郁症之间无显著关联。     

No evidence of an association between norepinephrine transporter gene polymorphisms and attention deficit hyperactivity disorder: a family-based and case-control association study in a Korean sample

Neurobiological and pharmacological research has suggested that dysregulation of the central noradrenergic systems might be involved in the pathophysiology of attention deficit hyperactivity disorder (ADHD). Previous studies have demonstrated that the norepinephrine transporter gene (SLC6A2) is associated with ADHD. The aims of this study were to examine the association of the SLC6A2 G1287A and -3081(A/T) polymorphisms with ADHD in Korean children and adolescents, and to determine the relationships of the genotypes of these two polymorphisms with continuous performance test results and the Junior Temperament and Character Inventory profiles of ADHD. In a case-control study, we assessed 186 ADHD probands and 150 normal controls; 109 trios were studied in a family-based association analysis. There were no significant differences in the genotype or allele frequencies of the SLC6A2 G1287A and -3081(A/T) polymorphisms between the ADHD and control groups (p > 0.05). In the transmission disequilibrium test analyses, there was no evidence for biased transmission of any of the alleles of the SLC6A2 G1287A and -3081(A/T) polymorphisms. In the haplotype analyses of these two polymorphisms, the global and individual chi(2) tests showed no significant associations between any of the haplotypes and ADHD. There were no significant differences with respect to the continuous performance test results and the Junior Temperament and Character Inventory profiles in the ADHD probands according to the genotypes of the SLC6A2 G1287A and -3081(A/T) polymorphisms. Our findings do not support SLC6A2 as a major genetic susceptibility factor in ADHD.     

A case-control association study of the polymorphism at the promoter region of the DRD4 gene in Korean boys with attention deficit-hyperactivity disorder: evidence of association with the -521 C/T SNP

Recent genetic studies at the 5' end of the dopamine D4 receptor (DRD4) gene have identified several polymorphisms having a possible relationship with attention deficit-hyperactivity disorder (ADHD). This study examined the association between the -521 and -376 promoter single nucleotide polymorphisms (SNPs) of the DRD4 gene and ADHD through a case-control association study in Korean boys, who constitute a single ethnic population. Ninety-four ADHD and ninety-five control boys were enrolled in this study. All of the ADHD subjects completed a comprehensive and standardized diagnostic and psychological evaluation battery including the ADHD Rating Scale-IV (ARS). Genotyping for the 2 promoter SNPs was performed. There were significant differences in the genotype and allele frequencies of the -521 C/T SNP between the ADHD and control groups (chi2=6.28, p=0.043 and chi2=6.22, p=0.013, respectively). However, the distribution of the -376 C/T genotypes and alleles were similar in the ADHD and control groups. The subtypes of ADHD were not related to either of these two SNPs. In the ADHD subjects, the -521 TT genotype group had a higher score in the inattentive subscale and a lower score in the hyperactive subscale of the parents version of ARS, although these differences did not attain statistical significance (p=0.146, p=0.082). In conclusion, there was a significant association between the -521 C/T SNP and ADHD in Korean boys. These results suggest a role of the -521 C/T SNP in the susceptibility for ADHD.     

No difference between platelet serotonin--5-HT(2A) receptors from children with and without ADHD.

To further investigate the possible function of the serotonergic system in the pathophysiology of attention deficit hyperactivity disorder (ADHD), platelet serotonin 5-HT2A receptors were characterized for 19 ADHD children and 17 age-matched control subjects. Subjects were evaluated using the Diagnostic Interview for Children and Adolescents (DICA-R-C)-DSM IV and the Children's Depression Inventory. An aggressive subgroup was also determined by the presence of two or more positive aggressive symptoms on either subjects' or parents' reports. Platelets were isolated from venous blood and 5-HT2A receptor number, and affinity was determined using 125I-LSD binding. There was no difference in platelet 5-HT2A receptor binding characteristics between the two groups. The results from this pilot study suggest a limited function of 5-HT2A receptors in the pathophysiology of ADHD and extend the findings of other previous negative studies of the peripheral serotonergic system in ADHD.