Association of functional DBH genetic variants with alcohol dependence risk and related depression and suicide attempt phenotypes: results from a large multicenter association study.

OBJECTIVE: Dopamine-beta-hydroxylase (DBH) metabolizes the conversion of dopamine to noradrenaline. DBH, located on chromosome 9q34.2 has variants with potential functional consequences which may be related to alterations of neurotransmitter function and several psychiatric phenotypes, including alcohol dependence (AD), depression (MD) and suicidal behavior (SA). The aim of this association study in a large multicenter sample of alcohol-dependent individuals and controls is to investigate the role of DBH SNPs and haplotypes in AD risk and associated phenotypes (AD with MD or SA). METHOD: 1606 inpatient subjects with DSM-IV AD from four addiction treatment centers and 1866 control subjects were included. Characteristics of AD, MD and SA were obtained using standardized structured interviews. After subjects were genotyped for 4 DBH polymorphisms, single SNP case-control and haplotype analyses were conducted. RESULTS: rs1611115 (near 5') C-allele and related haplotypes were significantly associated with alcohol dependence in females. This association with female alcohol dependence also accounts for the significant relationship between this variant and comorbid conditions and traits. CONCLUSIONS: This study presents evidence for a potentially functional DBH variant influencing the risk for alcohol dependence while other comorbid conditions are not independently influenced by this SNP. However, the study also supports the possible role of the dopamine system in the etiology of female alcohol dependence.

The serotonin transporter promoter polymorphism (5-HTTLPR) affects the relation between antidepressant serum concentrations and effectiveness in major depression.

INTRODUCTION: Both the serotonin transporter promotor polymorphism (5-HTTLPR) and serum concentrations of SSRIs have been shown to affect response to SSRIs. Results, however, are inconsistent. The aim of this study was to investigate whether remission or response to SSRIs is influenced by an interaction of 5-HTTLPR and SSRI serum concentrations. METHODS: 49 patients with major depression and SSRI treatment were genotyped for the 5-HTTLPR locus including the rs25531. Drug serum concentrations and depression severity were measured weekly. RESULTS: Logistic regression analysis revealed a significant association between 5-HTTLPR, SSRI serum concentrations and response to treatment. A favourable treatment outcome correlated with SSRI serum concentration in 5-HTTLPR-L(A) allele carriers (r² = 34.3 %; p = 0.001), but not in S/L(G)-allele carriers (p = 0.31). DISCUSSION: In the group of L(A) allele carriers, those MDD patients with a high antidepressant serum concentrations responded better to treatment than patients with a low serum concentration. We conclude that the 5-HTTLPR might affect reponse to SRRI subject to serum concentrations. If replicated this might be a starting point for prospective clinical trials.

Postmortem proteomic analysis in human amygdala of drug addicts: possible impact of tubulin on drug-abusing behavior.

Besides the ventral tegmental area and the nucleus accumbens as the most investigated brain reward structures, several reports about the relation between volume and activity of the amygdala and drug-seeking behavior have emphasized the central role of the amygdala in the etiology of addiction. Considering its proposed important role and the limited number of human protein expression studies with amygdala in drug addiction, we performed a human postmortem proteomic analysis of amygdala tissue obtained from 8 opiate addicts and 7 control individuals. Results were validated by Western blot in an independent postmortem replication sample from 12 opiate addicts compared to 12 controls and 12 suicide victims, as a second "control sample". Applying 2D-electrophoresis and MALDI-TOF-MS analysis, we detected alterations of beta-tubulin expression and decreased levels of the heat-shock protein HSP60 in drug addicts. Western blot analysis in the additional sample demonstrated significantly increased alpha- and beta-tubulin concentrations in the amygdala of drug abusers versus controls (P = 0.021, 0.029) and to suicide victims (P = 0.006, 0.002). Our results suggest that cytoskeletal alterations in the amygdala determined by tubulin seem to be involved in the pathophysiology of drug addiction, probably via a relation to neurotransmission and cellular signaling. Moreover, the loss of neuroprotection against stressors by chaperons as HSP60 might also contribute to structural alteration in the brain of drug addicts. Although further studies have to confirm our results, this might be a possible pathway that may increase our understanding of drug addiction.

No association of alcohol dependence with HOMER 1 and 2 genetic variants.

Several lines of evidence indicate that alterations of the central cortico-accumbens glutamate pathway are involved in the development and maintenance of alcohol- and substance-use disorders. The HOMER protein family is encoded by 3 genes HOMER (1-3) which are components of the excitatory postsynaptic density complex and function to modulate synaptic activity by the regulation of glutamate signaling. HOMER 1 and 2 have been reported to contribute to chronic alcohol-induced long-term neurochemical changes in the endogenous reward system. Data from animal models suggest a potential role of the Homer protein family in the development of alcohol and substance use. The aim of this study is to assess potential associations between HOMER 1 and 2 genetic variants in a larger sample of alcohol-dependent individuals and unrelated controls. Five genetic variants of HOMER 1 and 3 of HOMER 2 were genotyped in a multi-site sample of 1,923 German healthy controls and 2,039 alcohol-dependent subjects. Neither single SNP nor haplotype analysis could detect significant associations with alcohol dependence (AD) and related phenotypes. While most of the HOMER 1 and 2 SNPs are in low-to-moderate linkage disequilibrium, three major haplotypes of HOMER 1 and 4 haplotypes of HOMER 2 are present in the majority of alcohol-dependent and control subjects. In conclusion, our results suggest that single SNPs, respectively, haplotypes of the HOMER 1 and 2 genes are unlikely to play a major role in the pathophysiology of AD.

Predominant expression of tryptophan hydroxylase 1 mRNA in the pituitary: a postmortem study in human brain.

Although the predominant role of tryptophan hydroxylase 2 (TPH2) in the CNS and its influence on the vulnerability to psychiatric disorders have clearly been demonstrated in several studies, the role of TPH1 on neuronal mechanisms, respectively on behavioral traits is still poorly understood. In a previous study of tryptophan hydroxylase 1 (TPH1) and TPH2 mRNA expression in different human brain regions we observed significantly higher TPH1 than TPH2 mRNA concentrations in the pituitary (unpublished observations). Considering the importance of the pituitary in the functional circuits between brain and body, we investigated the TPH1 and TPH2 mRNA expression in more detail, using human postmortem samples of the posterior and anterior pituitary compared to cortex, hippocampus and raphe nuclei. Specimens were available from different psychiatric patients (drug abusers, n=12; suicide victims, n=11; schizophrenics, n=9) and controls (n=15). Additionally we performed immunohistochemical analysis applying monospecific antibodies for both TPH isoforms to verify that the mRNA is of cellular and not just vascular or other origin. Highest TPH2 mRNA levels were observed in the raphe nuclei in patients and controls. By contrast, in the anterior and posterior pituitary TPH1 was found to be the predominantly expressed isoform in all subgroups. TPH1 and TPH2 mRNA expression in the further brain regions was only marginal and nearly identical except in the hypothalamus where higher TPH1 than TPH2 mRNA levels could be measured. Interindividual differences between the subgroups were not detectable. The results of the present study extended our previous findings by the additional immunohistochemical determination of the neuronal TPH1 and TPH2 protein expression in the anterior pituitary and provide evidence against a strictly separated duality of the serotonergic system. It seems that TPH1 might also have an impact on neuronal mechanisms via hypothalamic-pituitary-adrenal axis regulation by its predominant localization in the pituitary. These observations may open up new research strategies not only for several psychiatric disorders, but also for the relationship between psychiatric and somatic diseases.

Impact of gene-gender effects of adrenergic polymorphisms on hypothalamic-pituitary-adrenal axis activity in depressed patients.

OBJECTIVE: There is overwhelming evidence that activation of the hypothalamic-pituitary-adrenal (HPA) system plays a major role in depression and cardiovascular disease in genetically susceptible individuals. We hypothesized that due to the multiple interactions between the sympathetic and the HPA systems via adrenoceptors, polymorphisms in these genes could have an impact on HPA axis activity in major depression. METHODS: Using the dexamethasone/corticotrophin-releasing hormone (DEX/CRH) test, we investigated the association of alpha(2)-adrenoceptor (ADRA2A -1291C-->G) and the beta(2)-adrenoceptor gene (ADRB2 Arg16Gly) in 189 patients with major depression during the acute state of the disease and after remission. RESULTS: Male ADRA2A -1291G allele homozygotes showed significant pretreatment HPA axis hyperactivity, with increased adrenocorticotropin (ACTH; F = 4.9, d.f. = 2, p = 0.009) and cortisol responses (F = 6.4, d.f. = 2, p = 0.003). In contrast, female ADRB2 Arg/Arg homozygotes had increased pretreatment ACTH (F = 7.17, d.f. = 2, p = 0.001) and cortisol (F = 8.95, d.f. = 2, p = 0.000) levels. Interestingly, in the respective genotypes, the stress hormones remained elevated in the second DEX/CRH test, despite a reduction in depressive symptoms. CONCLUSIONS: This study provides evidence that, depending on gender and polymorphisms, there is continuous HPA axis overdrive in a proportion of patients irrespective of the status of depression. Considering the importance of stress hormones for cardiovascular disorders, our data might suggest that these patients are at high risk of comorbidity between depression and cardiovascular disorders.

Reduced gray matter brain volumes are associated with variants of the serotonin transporter gene in major depression.

The serotonergic system is involved in the pathophysiology of major depression as well as in the early central nervous system development and adult neuroplasticity. The aim of the study was to examine in 77 patients with major depression and 77 healthy controls the association between the triallelic polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) and gray matter (GM) brain volumes measured with 1.5 T magnetic resonance imaging. Voxel-based morphometry were estimated on magnetic resonance images and genotyping was performed. We found that healthy controls have a strong association between the 5-HTTLPR and GM volumes of the dorsolateral prefrontal cortex, left anterior gyrus cinguli, left amygdala as well as right hippocampus, whereas there is no such association in patients with major depression. Healthy subjects carrying the S- or L(G)-allele have smaller GM volumes than those with the L(A)-allele, indicating that 5-HTTLPR contributes to the development of brain structures. Patients with depression show reduced GM volumes, particularly when they are homozygous for the L(A)-allele, suggesting that these patients are more vulnerable for morphological changes during depressive episodes.

5-HT1A receptor gene C -1019 G polymorphism and amygdala volume in borderline personality disorder.

Alterations of amygdala structure and function have been repeatedly described in patients with borderline personality disorder (BPD). The aim of our study was to determine whether a functional polymorphism of the 5-hydroxytryptamine(1A) receptor (5-HTR(1A)) gene C -1019 G (identity number: rs6295 G/C) is associated with structural changes of the amygdala in patients with BPD. Twenty-five right-handed female inpatients with BPD according to DSM IV and 25 healthy controls matched for age, sex, handedness and educational status were enrolled. Brain volumetry of the amygdala was performed with a 1.5-T Magnetom Vision apparatus (Siemens, Erlangen, Germany) and analyzed by the software program 'BRAINS'. Patients who have the 5-HTR(1A) gene G allele had significantly smaller amygdala volumes than C/C genotype carriers (P = 0.02). While no difference of allelic distribution between patients and controls was detected, the described effect of 5-HTR(1A) genotype on amygdala volume was found for the whole group of patients, as well as in the subgroup of patients with comorbid major depression (P = 0.004) but not in controls. In contrast to these subgroups of BPD patients who had significant amygdala volume differences, the mean amygdala volume of the whole group of BPD patients was not significantly different from that of controls. In summary, our study provides first evidence that 5-HTR(1A) gene C -1019 G polymorphism is associated with structural changes in the limbic system of BPD patients, a finding that might be disease related and might contribute to explanation of previous discrepant results regarding amygdala volume changes in BPD. Future research is recommended to clarify possible interactions between this functional polymorphism and symptoms, course and treatment responses in this disorder.

GABA-A2 receptor subunit gene (GABRA2) polymorphisms and risk for alcohol dependence.

Gamma-aminobutyric acid (GABA) A receptors are believed to mediate some of the physiological and behavioral actions of ethanol. Recent studies have suggested that genetic variants of the GABA-A receptor alpha2 subunit gene (GABRA2) are associated with alcohol dependence. The aim of this study is to confirm and extend the role of GABRA2 haplotypes in the liability to alcohol dependence. 291 (231 male) treatment-seeking alcohol-dependent individuals and 295 (153 male) control subjects were enrolled into the study. Characteristics of alcohol dependence were obtained using the SSAGA (semi-structured assessment of the genetics of alcoholism, German Version). Genotyping of 10 SNPs across the GABRA2 gene was performed following previous reports and using PCR. One genetic variant was detected to significantly differ between alcohol-dependent subjects and controls. Two common 8 SNP haplotypes and their complementary alleles were identified containing this SNP and were present in 89.9% of controls and 93.4% of the alcohol-dependent individuals. One of the haplotypes (T-C-A-C-A-T-T-C) was significantly associated with alcohol dependence and characteristics of alcohol withdrawal and severity of alcohol dependence (delirium tremens, withdrawal seizures). These findings support and extend the three previous studies implicating a GABA-A receptor subunit as contributing to the genetic risk for alcohol dependence. Possible implications of these findings are discussed.

Is MAO-B activity in platelets associated with the occurrence of suicidality and behavioural personality traits in depressed patients?

OBJECTIVE: Low platelet monoaminoxidase B (MAO-B) activity has been associated with various forms of impulsive behaviour and suicidality. The present study investigated the relationship between MAO-B activity in platelets and aspects of suicidality in depressed patients and controls. METHOD: In 87 patients with affective spectrum disorders (58% suffering from a major depressive episode - MDE) the potential association between platelet MAO-B activity and suicidality was examined. Fifty-nine of the patients had committed suicide attempt recently (SA -'suicide attempters'), 28 patients were acutely depressed without having shown suicidal thoughts or suicidal behaviour in the past (NA -'non-suicide attempters'). RESULTS: The SA and NA were comparable as to their diagnoses and general demographic and psychopathological parameters. MAO-B activity did not differ between SA and NA. No systematic correlations existed between MAO-B activity and any dimensions of suicidal behaviour or psychopathology. As a single finding only a weak positive association of higher MAO-B activity in SA with a fatal intention of the SA was observed. CONCLUSION: Our findings do not support a consistent association of platelet MAO-B activity and suicidal behaviour in general, but specific facts of suicidality might be associated.

D2 dopamine receptor gene haplotypes and their influence on alcohol and tobacco consumption magnitude in alcohol-dependent individuals.

INTRODUCTION: Alcohol dependence and habitual smoking frequently co-occur and possibly mutually influence each other. Both have been related to alterations of dopaminergic neurotransmission. The aim of this analysis of the Munich Gene Data Bank for Alcoholism(MGBA) was to re-evaluate the potential relation between D2 receptor and dopamine transporter gene haplotypes and quantity-related phenotypes of alcohol consumption (average daily alcohol intake before admission for treatment) and smoking (average units smoked per day). METHODS: A total of 333 inpatients (265 males) were enrolled in the study, all of who met the ICD10 diagnosis of alcohol dependence. Mild and strong quantity drinkers and smokers were separated into groups by median split. A number of genetic markers were chosen across D2 dopamine receptor gene (-141 Ins/Del, Taq1B, Taq1D, Ser311Cys; rs1079594 (intron 7); Taq1A) and dopamine transporter (40bp variable number of tandem repeat; rs2617605 (intron 2); rs37022 (intron 7); rs40184 (intron 14)). Genotyping was performed using PCR. RESULTS: Strong drinkers reported significantly higher amounts of smoking and vice versa. While no association was detected for dopamine transporter genetic variants, a number of D2 receptor gene single nucleotide polymorphisms were related to both smoking- and drinking-related behaviours. Subsequent analysis of D2 receptor gene haplotypes revealed that two common haplotypes had a significant association with quantitative phenotypes of regular drinking (Ins-C-G-C-A1) and smoking (Ins-T-G-A-A2). DISCUSSION: The finding of an association between common D2 dopamine receptor gene haplotypes with the quantity of drinking and smoking corroborates with results from previous studies suggesting a relationship between the dopamine system and alcohol and substance use disorders. Furthermore, it makes D2 dopamine receptor a candidate gene significantly influencing both alcohol and nicotine dependence.

Polymorphisms in the angiotensin-converting enzyme gene are associated with unipolar depression, ACE activity and hypercortisolism.

Angiotensin-converting enzyme (ACE) is assumed to influence the activity of the hypothalamic-pituitary-adrenocortical (HPA) system, which shows hyperactivity in the majority of patients with major depression. The ACE gene, known to be associated with cardiovascular disorders, which in turn are accompanied with an increased susceptibility for depression, is therefore a promising candidate gene for affective disorders. We investigated the genetic association between 35 single-nucleotide polymorphisms (SNPs) and an insertion/deletion (I/D)-polymorphism in the ACE gene and the susceptibility for unipolar major depression together with the genetic association with ACE serum activity and functional parameters of the HPA system. Two independent case/control samples with a total of 843 unrelated unipolar depressed patients and 1479 healthy controls were investigated. A case/control sample was screened to detect genetic associations with unipolar major depression. In addition, a replication sample was used to confirm the detected associations and to further investigate functional consequences of the genetic variants associated with depression. In the screening sample, two SNPs within the ACE gene were significantly associated with unipolar major depression. The association with unipolar major depression of one SNP (rs4291) located in the promoter region of the ACE gene was confirmed in our replication sample. The T-allele of this SNP was associated with depression and depressed T-allele carriers showed higher ACE serum activity and HPA-axis hyperactivity. Variants of the ACE gene such as SNP rs4291 are suggested susceptibility factors for unipolar major depression. We could show that SNP rs4291 influences ACE activity and HPA-axis hyperactivity and might therefore represent a common pathophysiologic link for unipolar depression and cardiovascular disease.

The C(-1019)G 5-HT1A promoter polymorphism and personality traits: no evidence for significant association in alcoholic patients.

The 5HT1A receptor is one of at least 14 different receptors for serotonin which has a role in moderating several brain functions and may be involved in the aetiology of several psychiatric disorders. The C(-1019)G 5-HT1A promoter polymorphism was reported to be associated with major depression, depression-related personality traits and suicidal behavior in various samples. The G(-1019) allele carriers are prone to depressive personality traits and suicidal behavior, because serotonergic neurotransmission is reduced. The aim of this study is to replicate previous findings in a sample of 185 Alcohol-dependent individuals. Personality traits were evaluated using the NEO FFI and TCI. History of suicidal behavior was assessed by a standardized semistructured interview (SSAGA). No significant differences across C(-1019)G 5-HT1A genotype groups were found for TCI temperament and character traits and for NEO FFI personality scales. No association was detected between this genetic variant and history of suicide attempts. These results neither support a role of C(-1019)G 5-HT1A promoter polymorphism in the disposition of personality traits like harm avoidance or neuroticism, nor confirm previous research reporting an involvement of the G allele in suicidal behavior in alcoholics. Significant associations, however, were detected between Babor's Type B with number of suicide attempts in history, high neuroticism and harm avoidance scores in alcoholics.

Genetics of suicide.

The concept that genetic factors contribute to the complex trait of suicidal behaviour has stimulated much work aimed at identifying susceptibility genes. So far molecular genetic studies focused on the serotonergic pathway as the intent to die and the lethality of suicide acts were related to the serotonergic system. Two genes have so far emerged as being involved in the vulnerability for suicidality: first, the intronic polymorphisms (A218C or A779C) of the tryptophan hydroxylase 1 (TPH1) gene, which was suggested as a quantitative risk factor for suicidal behaviour; second, the insertion/deletion polymorphism of the serotonin transporter gene (5-HTTLPR), which does not seem to be involved in general suicidal behaviour, but in violent and repeated suicide attempts. The data have further shown that the MAOA gene, which is consistently associated with impulsive-aggressive personality traits, is not related to suicide but might induce violent methods in subjects with other suicide risk factors. Predominantly negative were the findings with any type of the serotonin receptors and inconsistent with catecholamine-synthesizing and -metabolizing enzymes or with the dopaminergic receptors. This paper reviews the status of current knowledge in this area, points to the weakness of the investigations and presents new approaches beyond the serotonergic system.

Ionotropic glutamate receptor gene GRIK3 SER310ALA functional polymorphism is related to delirium tremens in alcoholics.

Upregulation of glutamatergic neurotransmission resulting from chronic ethanol intoxication may cause a hyperexcitable state during alcohol withdrawal, which may lead to seizures and delirium tremens. The aim of our study was to evaluate the association between a history of alcohol withdrawal-induced seizures and delirium tremens, and a functional polymorphism (Ser310Ala) of the GRIK3 gene coding for the glutamatergic kainate receptor subunit GlurR7 in a sample of well-characterized alcoholics compared to controls. In total, 233 patients meeting DSM-IV alcohol dependence criteria and 309 controls, all of German descent, were investigated. GRIK3 functional polymorphism was determined using PCR (polymerase chain reaction) of lymphocyte DNA. History of alcohol withdrawal-induced delirium tremens and seizures were obtained using the SSAGA (Semi-Structured Assessment for the Genetics of Alcoholism). Data were cross-checked with in-patients' clinical files. While a significant relationship between history of delirium tremens and the Ser310 allele was detected, no significant results were obtained for alcohol withdrawal-related seizures. Although this result is suggestive for a significant role of this polymorphism in the pathogenesis of delirium tremens in alcohol-dependent individuals, further investigation and confirmation are warranted.

Tryptophan hydroxylase gene 1 polymorphisms are not associated with suicide attempts in alcohol-dependent individuals.

A serotonergic dysfunction was suggested to be involved into the biological susceptibility of suicidal behaviour. Tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin biosynthesis, is a significant regulating factor in the serotonergic system. Recently the A-6526G, and G-5806T and A-779C polymorphisms of the TPH 1 gene were identified and suggested to be associated with suicidal behaviour, but study results are conflicting. We examined a possible association of the A-6526G, and G-5806T and A-779C polymorphisms with suicide attempts in a sample of 80 alcohol-dependent individuals with a history of at least one suicide attempt. This group was analysed in comparison with 241 alcohol-dependent subjects without such a history. No significant relationship between haplotype and genotype distribution and allele frequencies of these polymorphisms with suicide attempts were detected. Furthermore, no association with number of suicide attempts and TPH haplotypes were found. Our data do not support the hypothesis of A-6526G, G-5806T or A-779C polymorphisms to be associated with suicide attempts in alcohol-dependent individuals.

GRIN1 locus may modify the susceptibility to seizures during alcohol withdrawal.

N-Methyl-D-aspartate (NMDA) receptors, members of the glutamate receptor channel superfamily, are generally inhibited by alcohol. The expression and alternative splicing of the obligatory NR1 subunit is altered by alcohol exposure, emphasizing the involvement of the NR1 subunit, which is coded by the GRIN1 gene, in alcohol-mediated effects. We performed an association study in patients with alcohol dependence with the GRIN1 locus. Two independent case control samples consisting of a total of 442 alcohol-dependent patients and 442 unrelated controls were included. There was no overall difference in allele or genotype frequency between patients and controls. However, the 2108A allele and A-containing genotypes were over-represented in the patients with a history of withdrawal-induced seizures when compared to healthy volunteers (allele: chi(2) = 5.412, df = 1, P = 0.020) or an independent sample of patients without a history of seizures (allele: chi(2) = 4.185, df = 1, P = 0.041). Age at onset, years of alcohol dependence, and a history of delirium tremens did not differ between genotype or allele groups. These findings support the hypothesis that the GRIN1 locus may modify the susceptibility to seizures during alcohol withdrawal. This novel finding warrants replication.

No association of CRH1 receptor polymorphism haplotypes, harm avoidance and other personality dimensions in alcohol dependence: results from the Munich gene bank project for alcoholism.

Because corticotrophin-releasing hormone (CRH) plays a central role in stress regulation, the possible role of CRH1 polymorphism for anxiety-related personality variables such as harm avoidance possibly associated with alcoholism was studied. The research instruments used to phenotype patients were adopted partly from the US collaborative study of the genetics of alcoholism and include a number of personality inventories such as the temperament and character inventory (TCI). Based on the examination of 170 alcoholic subjects no association was found between CRH1 receptor haplotypes of four single nuclotid polymorphisms (SNPs) and low and high temperament traits of harm avoidance, novelty seeking and reward dependence. The possible implications of these findings are discussed.

SNP and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association with major depression.

Tryptophan hydroxylase (TPH), being the rate-limiting enzyme in the biosynthesis of serotonin plays a major role as candidate gene in several psychiatric disorders. Recently, a second TPH isoform (TPH2) was identified in mice, which was exclusively present in the brain. In a previous post-mortem study of our own group, we could demonstrate that TPH2 is also expressed in the human brain, but not in peripheral tissues. This is the first report of an association study between polymorphisms in the TPH2 gene and major depression (MD). We performed single-nucleotide polymorphism (SNP), haplotype and linkage disequlibrium studies on 300 depressed patients and 265 healthy controls with 10 SNPs in the TPH2 gene. Significant association was detected between one SNP (P=0.0012, global P=0.0051) and MD. Haplotype analysis produced additional support for association (P<0.0001, global P=0.0001). Our findings provide evidence for an involvement of genetic variants of the TPH2 gene in the pathogenesis of MD and might be a hint on the repeatedly discussed duality of the serotonergic system. These results may open up new research strategies for the analysis of the observed disturbances in the serotonergic system in patients suffering from several other psychiatric disorders.