Serotonergic system and attention deficit hyperactivity disorder (ADHD): a potential susceptibility locus at the 5-HT(1B) receptor gene in 273 nuclear families from a multi-centre sample

Attention deficit hyperactivity disorder (ADHD) is a highly heritable and heterogeneous disorder, which usually becomes apparent during the first few years of childhood. Imbalance in dopamine neurotransmission has been suggested as a factor predisposing to ADHD. However, evidence has suggested an interaction between dopamine and serotonin systems in the pathophysiology of the disorder. Studies using selective agonists of the different 5-HT receptors microinjected into selected brain structures have shown a positive modulating effect on the functional activities of the mesotelencephalic dopaminergic system. This suggests that some of the genetic predisposition to ADHD might be due to DNA variation at serotonin system genes. In this study, we investigated polymorphisms in HTR(1B) and HTR(2A) (which encode the serotonin receptors 5-HT(1B) and 5-HT(2A) respectively) in a European ADHD sample. Using haplotype based haplotype relative risk (HHRR) and transmission disequilibrium test (TDT) analyses, we observed significant preferential transmission of the allele 861G of the HTR(1B) in the total sample (for HHRR; chi(2) = 7.4, P = 0.0065 and TDT; (chi(2) = 6.4, P = 0.014). Analysis of HTR(2A) failed to reveal evidence of association or linkage between the His452Tyr polymorphism and ADHD in the total sample. However, a significantly increased transmission of the allele 452His was observed in the Irish sample alone (chi(2) = 4.9, P = 0.026). These preliminary data suggest an important role for the serotonin system in the development of ADHD. Further studies, preferentially including different ethnic groups are required to substantiate these findings.     

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.     

Linkage of the dopamine receptor D1 gene to attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) has a strong genetic basis, and evidence from human and animal studies suggests the dopamine receptor D1 gene, DRD1, to be a good candidate for involvement. Here, we tested for linkage of DRD1 to ADHD by examining the inheritance of four biallelic DRD1 polymorphisms [D1P.5 (-1251HaeIII), D1P.6 (-800HaeIII), D1.1 (-48DdeI) and D1.7 (+1403Bsp1286I)] in a sample of 156 ADHD families. Owing to linkage disequilibrium between alleles at the four markers, only three haplotypes are common in our sample. Using the transmission/disequilibrium test (TDT), we observed a strong bias for transmission of Haplotype 3 (1.1.1.2) from heterozygous parents to their affected children (P=0.008). Furthermore, using quantitative trait TDT analyses, we found significant and positive relationships between Haplotype 3 transmission and the inattentive symptoms, but not the hyperactive/impulsive symptoms, of ADHD. These findings support the proposed involvement of DRD1 in ADHD, and implicate Haplotype 3, in particular, as containing a potential risk factor for the inattentive symptom dimension of the disorder. Since none of the four marker alleles comprising Haplotype 3 is predicted to alter DRD1 function, we hypothesize that a functional DRD1 variant, conferring susceptibility to ADHD, is on this haplotype. To search for such a variant we screened the DRD1 coding region, by sequencing, focusing on the children who showed preferential transmission of Haplotype 3. DNA from 41 children was analysed, and no sequence variations were identified, indicating that the putative DRD1 risk variant for ADHD resides outside of the coding region of the gene.     

Early onset of treatment effects with oral risperidone

Background

Attention deficit hyperactivity disorder (ADHD) is a common and highly heritable disorder of childhood characterized by inattention, hyperactivity and impulsivity. Molecular genetic and pharmacological studies suggest the involvement of the dopaminergic, serotonergic and noradrenergic neurotransmitter systems in the pathogenesis of ADHD. Monoamine oxidase A (MAO-A) encodes an enzyme that degrades biogenic amines, including neurotransmitters such as norepinephrine, dopamine and serotonin. In this study we examined a 30 bp promoter variable number tandem repeat (VNTR) and a functional G/T single nucleotide polymorphism (SNP) at position 941 in exon 8 (941G/T) of MAO-A for association with ADHD in a Taiwanese sample of 212 ADHD probands.

Methods

Within-family transmission disequilibrium test (TDT) was used to analyse association of MAO-A polymorphisms with ADHD in a Taiwanese population.

Results

A nominally significant association was found between the G-allele of 941G/T in MAO-A and ADHD (TDT:P = 0.034. OR = 1.57). Haplotype analysis identified increased transmission of a haplotype consisting of the 3-repeat allele of the promoter VNTR and the G-allele of the 941G/T SNP (P = 0.045) to ADHD cases which the strong association with the G-allele drove.

Conclusion

These findings suggest the importance of the 941G/T MAO-A polymorphism in the development of ADHD in the Taiwanese population. These results replicate previously published findings in a Caucasian sample.     

Family-based association study of the serotonin-2A receptor gene (5-HT2A) and bipolar disorder

Objectives: The serotonin 2A receptor gene (5-HT2A) is of great interest for research in neuropsychiatric disorders based on the observation that various neuroleptic agents and antidepressants bind with relatively high affinity at 5-HT2A receptors, and the fact that the receptor density in platelets tends to increase in depression. To test for the presence of association between 5-HT2A and bipolar disorder (BP), we studied a large number of triad families having probands affected with DSM-IV bipolar I (BPI), bipolar II (BPII) or schizoaffective disorder, bipolar type. Methods: Two polymorphisms of 5-HT2A, 102T/C, and His452Tyr were analyzed in the 274 bipolar triad families. Both the transmission disequilibrium test (TDT) and haplotype TDT were performed on the genotype data. We also calculated the maternal transmission and paternal transmission for each allele and compared the mean ages of onset across probands grouped by genotype at each of the two markers. Results: No significant transmission disequilibrium between the alleles of 5-HT2A and BP was found. Separate studies of the sub-phenotypes also failed to demonstrate significant association. However, we found a trend towards transmission disequilibrium with the haplotype 102C.His452 (p=0.0504). This trend may become more significant with a larger sample size. Significance: At present, results of this study suggest that the 5-HT2A is unlikely to play a major role in the genetic susceptibility to BP. Future studies will be directed towards increasing sample size, focusing on subtypes of BP or biochemical measures as phenotypes, and investigating other polymorphisms of 5-HT2A to provide more information at the DNA level.     

Association between serotonin 4 receptor gene polymorphisms and bipolar disorder in Japanese case-control samples and the NIMH Genetics Initiative Bipolar Pedigrees

Possible irregularities in serotonergic neurotransmission have been suggested as causes of a variety of neuropsychiatric diseases. We performed mutation and association analyses of the HTR4 gene, on 5q32, encoding the serotonin 4 receptor in mood disorders and schizophrenia. Mutation analysis was performed on the HTR4 exons and exon/intron boundaries in 48 Japanese patients with mood disorders and 48 patients with schizophrenia. Eight polymorphisms and four rare variants were identified. Of these, four polymorphisms at or in close proximity to exon d, g.83097C/T (HTR4-SVR (splice variant region) SNP1), g.83159G/A (HTR4-SVRSNP2), g.83164 (T)9-10 (HTR4-SVRSNP3), and g.83198A/G (HTR4-SVRSNP4), showed significant association with bipolar disorder with odds ratios of 1.5 to 2. These polymorphisms were in linkage disequilibrium, and only three common haplotypes were observed. One of the haplotypes showed significant association with bipolar disorder (P = 0.002). The genotypic and haplotypic associations with bipolar disorder were confirmed by transmission disequilibrium test in the NIMH Genetics Initiative Bipolar Pedigrees with ratios of transmitted to not transmitted alleles of 1.5 to 2.0 (P = 0.01). The same haplotype that showed association with bipolar disorder was suggested to be associated with schizophrenia in the case-control analysis (P = 0.003) but was not confirmed when Japanese schizophrenia families were tested. The polymorphisms associated with mood disorder were located within the region that encodes the divergent C-terminal tails of the 5-HT(4) receptor. These findings suggest that genomic variations in the HTR4 gene may confer susceptibility to mood disorder.     

Linkage disequilibrium between dopamine D1 receptor gene (DRD1) and bipolar disorder.

BACKGROUND: Based on the dopamine hypothesis, the dopamine D1 receptor gene (DRD1) is considered to be a good candidate gene for bipolar disorder (BP). METHODS: In our study, three polymorphisms of the DRD1 gene, -800T/C, -48A/G, and 1403T/C, were analyzed in 286 BP trios. Both the transmission disequilibrium test (TDT) and haplotype TDT were performed on the genotype data to test for the presence of linkage disequilibrium between DRD1 and bipolar disorder. With the extended transmission disequilibrium test (ETDT), we also calculated the maternal transmission and paternal transmission for each allele. RESULTS: Although no association was found for each individual polymorphism, there is a significant association between DRD1 and BP for haplotype TDT analysis (chi(2) = 16.068, df = 3, p =.0011). CONCLUSIONS: These results indicate that DRD1 may play a role in the etiology of bipolar disorder.     

The serotonin 5-HT1B receptor gene and attention deficit hyperactivity disorder

Recent research has suggested that serotonin, in addition to dopamine, may be involved in the development of attention deficit hyperactivity disorder (ADHD). Serotonin regulates dopaminergic neurotransmission in some areas of the brain via several 5-HT receptors including 5-HT1B. Animal studies have suggested the involvement of the 5-HT1B receptors in locomotor behaviour. For these reasons, we hypothesized that the 5-HT1B receptor gene may be a good candidate for genetic studies of ADHD. We tested for linkage disequilibrium between the 5-HT1B G861C polymorphism and ADHD in 115 families using the transmission disequilibrium test (TDT). We found evidence for a trend towards excess transmission of the 861G allele (chi(2) = 2.91, P = 0.09) that when further analysed for parental allele transmissions exhibited significantly greater paternal transmission of the G allele (chi(2) = 4.80, P = 0.03) to the affected child. Although preliminary, results from this study provide additional evidence that serotonin genes may be important risk factors for the development of ADHD.     

Linkage and association of the glutamate receptor 6 gene with autism

A genome scan was previously performed and pointed to chromosome 6q21 as a candidate region for autism. This region contains the glutamate receptor 6 (GluR6 or GRIK2) gene, a functional candidate for the syndrome. Glutamate is the principal excitatory neurotransmitter in the brain and is directly involved in cognitive functions such as memory and learning. We used two different approaches, the affected sib-pair (ASP) method and the transmission disequilibrium test (TDT), to investigate the linkage and association between GluR6 and autism. The ASP method, conducted with additional markers on the 51 original families and in eight new sibling pairs, showed a significant excess of allele sharing, generating an elevated multipoint maximum LOD score (ASPEX MLS = 3.28). TDT analysis, performed in the ASP families and in an independent data set of 107 parent-offspring trios, indicated a significant maternal transmission disequilibrium (TDTall P = 0.0004). Furthermore, TDT analysis (with only one affected proband per family) showed significant association between GluR6 and autism (TDT association P = 0.008). In contrast to maternal transmission, paternal transmission of GluR6 alleles was as expected in the absence of linkage, suggesting a maternal effect such as imprinting. Mutation screening was performed in 33 affected individuals, revealing several nucleotide polymorphisms (SNPs), including one amino acid change (M867I) in a highly conserved domain of the intracytoplasmic C-terminal region of the protein. This change is found in 8% of the autistic subjects and in 4% of the control population and seems to be more maternally transmitted than expected to autistic males (P = 0.007). Taken together, these data suggest that GluR6 is in linkage disequilibrium with autism.     

Synaptosomal-associated protein 25 (SNAP-25) and attention deficit hyperactivity disorder (ADHD): evidence of linkage and association in the Irish population

Several lines of evidence have suggested that ADHD is a polygenic disorder produced by the interaction of several genes each of a minor effect. Synaptosomal-associated protein 25 (SNAP-25) is a presynaptic plasma membrane protein which is expressed highly and specifically in the nerve cells. The gene encodes a protein essential for synaptic vesicle fusion and neurotransmitter release. Animal model studies showed that the coloboma mouse mutant has a hyperactive phenotype similar to that of ADHD. The hyperactive phenotype of this model has been shown to be the result of a deletion of the SNAP-25 gene. DNA variations within or closely mapped to the SNAP-25 gene may alter the level of expression and hence may have an effect on the function of synaptic vesicle fusion and neurotransmitter release. Using HHRR and TDT we analysed 93 ADHD nuclear families from Ireland and found increased preferential transmission of SNAP-25/DdeI allelel to ADHD cases; HHRR (chi(2) = 6.55, P = 0.01) and linkage (TDT) (chi(2) = 6.5, P = 0.015). In contrast to our findings, Barr et al(1) reported an increased transmission of allele 2 of the DdeI polymorphism though this was not statistically significant. However, they also reported a significantly increased transmission of a haplotype (made of allele 1 of MnlI and allele 2 of the DdeI) in their Canadian ADHD sample. It is not clear what the role of SNAP-25 in ADHD is until these findings are either confirmed or refuted in other ADHD samples.     

精神分裂症和心境障碍混合家系5-HTR 6基因多态性的关联分析

目的 在中国汉族人群精神分裂症和心境障碍混合家系中探讨五羟色胺6受体（5-HTR6）基因267C／T多态性与精神分裂症、心境障碍的关联性。方法 采用聚合酶链反应一限制性片断长度多态（PCR—RFLP）技术对67例精神病混合家系患者及其父母进行5-HTR6基因267C／T多态性检测,并予以传递不平衡检验（TDT）。结果 患者组与父母组之间,5-HTR6基因267C／T多态性等位基因分布（χ^2=2．70,v=1,P〉0．05）和基因型分布（χ^2=2．97,v=2,P〉0．05）无明显差异,5-HTR6基因267C／T多态性与精神分裂症（χ^2=5．16,P〈0．05）存在关联,但与心境障碍（χ^2=2．17,P〉0．05）无关联。结论 在中国汉族人群中5-HTR6基因或邻近基因可能是精神分裂症易患基因之一,但可能不是心境障碍的易患基因。     

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.     

Candidate genes for anorexia nervosa in the 1p33-36 linkage region: serotonin 1D and delta opioid receptor loci exhibit significant association to anorexia nervosa

Serotonergic and opioidergic neurotransmitter system alterations have been observed in people with eating disorders; the genes for the serotonin 1D receptor (HTR1D) and the opioid delta receptor (OPRD1) are found on chr1p36.3-34.3, a region identified by our group in a linkage analysis of anorexia nervosa (AN). These candidate genes were evaluated for sequence variation and for linkage and association of this sequence variation to AN in family and case : control data sets. Resequencing of the HTR1D locus and a portion of the OPRD1 locus identified novel SNPs and confirmed existing SNPs. Genotype assay development and genotyping of nine SNPs (four at HTR1D and five at OPRD1) was performed on 191 unrelated individuals fulfilling DSM-IV criteria (w/o amenorrhea criterion) for AN, 442 relatives of AN probands and 98 psychiatrically screened controls. Linkage analysis of these candidate gene SNPs with 33 microsatellite markers in families including relative pairs concordantly affected with restricting AN (N=37) substantially increased the evidence for linkage of this region to restricting AN to an NPL score of 3.91. Statistically significant genotypic, allelic, and haplotypic association to AN in the case : control design was observed at HTR1D and OPRD1 with effect sizes for individual SNPs of 2.63 (95% CI=1.21-5.75) for HTR1D and 1.61 (95% CI=1.11-2.44) for OPRD1. Using genotype data on parents and AN probands, three SNPs at HTR1D were found to exhibit significant transmission disequilibrium (P&<0.05). The combined statistical genetic evidence suggests that HTR1D and OPRD1 or linked genes may be involved in the etiology of AN.     

5-羟色胺转运体基因多态与共患学习困难的儿童注意缺陷多动障碍的相关性

目的探讨共患学习困难(LD)的注意缺陷多动障碍(ADHD)患儿与5-羟色胺转运体(5-HTT)基因连锁多态区(5-HTTLPR)和第2内含子17 bp数目可变的顺向重复(stin2.VNTR)的关联关系。方法对126例共患LD的ADHD患儿和198例不共患LD的ADHD患儿的5-HTTLPR和stin2.VNTR两种多态进行检测,并采用传递不平衡检测(TDT)和单体型分析方法进行关联分析。结果(1)TDT检测:5-HTTLPR多态的S等位基因在共患LD的ADHD和ADHD混合型(ADHD-C)核心家系中优先传递(X2=5.831和5.281,P=0.015和0.020);所有家系均未观察到stin2.VNTR多态中的任何等位基因有传递不平衡现象(均P>0.05);(2)单体型分析:5-HTT基因与共患LD的ADHD和ADHD-C相关联(X2=11.391和13.343,v=3,P=0.010和P=0.004);单体型L／12在共患LD的ADHD和ADHD-C核心家系中传递较少(X2=10.317和8.948,v=1,P=0.001和0.003),而单体型L／10在共患LD的ADHD核心家系中传递较多(X2=4.065,v=1,P=0.044)。结论5-HTT基因可能与共患LD的ADHD相关联,其中主要为共患LD的ADHD-C亚型。     

Physiogenomic association of statin-related myalgia to serotonin receptors

We employed physiogenomic analyses to investigate the relationship between myalgia and selected polymorphisms in serotonergic genes, based on their involvement with pain perception and transduction of nociceptive stimuli. We screened 195 hypercholesterolemic, statin-treated patients, all of whom received either atorvastatin, simvastatin, or pravastatin. Patients were classified as having no myalgia, probable myalgia, or definite myalgia, and assigned a myalgia score of 0, 0.5, or 1, respectively. Fourteen single nucleotide polymorphisms (SNPs) were selected from candidates within the 5-HT receptor gene families [5a-hydroxytryptamine receptor genes (HTR) 1D, 2A, 2C, 3A, 3B, 5A, 6, 7] and the serotonin transporter gene (SLC6A4). SNPs in the HTR3B and HTR7 genes, rs2276307 and rs1935349, respectively, were significantly associated with the myalgia score. Individual differences in pain perception and nociception related to specific serotonergic gene variants may affect the development of myalgia in statin-treated patients.     

Serotonin transporter gene polymorphisms and hyperserotonemia in autistic disorder.

Previous studies have provided conflicting evidence regarding the association of the serotonin transporter (5-HTT) gene with autism. Two polymorphisms have been identified in the human 5-HTT gene, a VNTR in intron 2 and a functional deletion/insertion in the promoter region (5-HTTLPR) with short and long variants. Positive associations of the 5-HTTLPR polymorphism with autism have been reported by two family-based studies, but one found preferential transmission of the short allele and the other of the long allele. Two subsequent studies failed to find evidence of transmission disequilibrium at the 5-HTTLPR locus. These conflicting results could be due to heterogeneity of clinical samples with regard to serotonin (5-HT) blood levels, which have been found to be elevated in some autistic subjects. Thus, we examined the association of the 5-HTTLPR and VNTR polymorphisms of the 5-HTT gene with autism, and we investigated the relationship between 5-HTT variants and whole-blood 5-HT. The transmission/disequilibrium test (TDT) revealed no linkage disequilibrium at either loci in a sample of 96 families comprising 43 trios and 53 sib pairs. Furthermore, no significant relationship between 5-HT blood levels and 5-HTT gene polymorphisms was found. Our results suggest that the 5-HTT gene is unlikely to play a major role as a susceptibility factor in autism.     

Allelic variants of the tryptophan hydroxylase (A218C) and serotonin 1B receptor (A-161T) and personality traits

Human personality traits have a considerable hereditary component, and central serotonergic activity is implicated in the personality factors of the Tridimensional Personality Questionnaire (TPQ). Our population-based association study tested the hypothesis that the tryptophan hydroxylase (TPH) A218C and serotonin 1B receptor (HTR1B) A-161T polymorphisms were associated with TPQ personality trait scores in a sample population of 209 young healthy Chinese. No significant differences were demonstrated comparing scores of subjects bearing different TPH or HTR1B genotypes; however, a trend for difference in the novelty seeking score comparing TPH genotype groups was determined for the male population. Our negative findings suggest that the TPH A218C and HTR1B polymorphisms do not play major roles in the determination of TPQ personality traits.     

Association and linkage of alpha-2A adrenergic receptor gene polymorphisms with childhood ADHD

Attention-deficit hyperactivity disorder (ADHD) is a heritable disorder, prevalent from childhood through adulthood. Although the noradrenergic (NA) system is thought to mediate a portion of the pathophysiology of ADHD, genes in this pathway have not been investigated as frequently as those in the dopaminergic system. Previous association studies of one candidate gene in the NA system, ADRA2A, showed inconsistent results with regard to an MspI polymorphism. In the current study, two nearby single-nucleotide polymorphisms, which define HhaI and DraI restriction fragment length polymorphisms, were also genotyped and were in significant linkage disequilibrium with the MspI RFLP. Transmission disequilibrium tests (TDTs) in a sample of 177 nuclear families showed significant association and linkage of the DraI polymorphism with the ADHD combined subtype (P=0.03), and the quantitative TDT showed association of this polymorphism with the inattentive (P=0.003) and hyperactive-impulsive (P=0.015) symptom dimensions. The haplotype that contained the less common allele of the DraI polymorphism likewise showed a strong relationship with the inattentive (P=0.001) and hyperactive-impulsive (P=0.004) symptom dimensions. This study supports the hypothesis that an allele of the ADRA2A gene is associated and linked with the ADHD combined subtype and suggests that the DraI polymorphism of ADRA2A is linked to a causative polymorphism.     

Association of unipolar major depressive disorder with genes of the serotonergic and dopaminergic pathways.

Major depressive disorder (MDD) is a severe psychiatric disorder with a lifetime prevalence of about 15%.1 The importance of the genetic component is well accepted,2 but the mode of inheritance is complex and non-Mendelian. A line of evidence suggests the involvement of serotonin and dopamine neurotransmitters in the pathophysiology of depression. In the present study, 102 unipolar MDD patients and 172 healthy controls were genotyped for polymorphisms in four serotonergic and three dopaminergic candidate genes [tryptophan hydroxylase (TPH), serotonin receptor 2A (HTR2A), serotonin receptor 2C (HTR2C), serotonin transporter promoter region (5-HTTLPR), dopamine receptor D4 (DRD4), dopamine transporter (DAT1) and catechol-O-methyl transferase (COMT)]. There were no statistical differences between MDD patients and healthy controls in the genotypic and allelic distribution of all polymorphisms investigated. Thus, our study does not support a major role for these polymorphisms in contributing to susceptibility to MDD, although it does not preclude minor effects.