Effects of DRD2/ANKK1 gene variations and clinical factors on aripiprazole efficacy in schizophrenic patients

OBJECTIVES: Aripiprazole, a novel antipsychotic agent, acts as a partial agonist at dopamine D2 receptors (DRD2). We investigate whether its efficacy is predictable by DRD2/ANKK1 gene polymorphisms and clinical factors in Han Chinese hospitalized patients with acutely exacerbated schizophrenia. METHOD: After hospitalization, the patients (n=128) were given aripiprazole for up to 4 weeks. They were genotyped for four functional DRD2/ANKK1 polymorphisms: -141 Ins/Del, Ser311Cys, C957T, and TaqIA. Clinical factors such as gender, age, illness duration, education level, diagnostic subtype, and medication dosage were also recorded. Psychopathology was measured biweekly with the positive and negative syndrome scale (PANSS). The effects of genetic and clinical factors on PANSS performance upon aripiprazole treatment were analyzed by a mixed modeling approach (SAS Proc MIXED). RESULTS: Compared to the patients with TaqI A2/A2 genotype, A1 carriers are associated with superior therapeutic response on positive symptoms after 4-week aripiprazole treatment. Regarding the C957T polymorphism, patients with C/C genotype were associated with poor aripiprazole response for excitement symptoms when compared with T/T patients. The other two polymorphisms, -141 Ins/Del, and Ser311Cys, have no significant effects on PANSS performance. The clinical factors including medication dosage, illness duration, and diagnostic subtype could influence PANSS performance upon aripiprazole treatment. CONCLUSION: This study suggests that DRD2/ANKK1 gene variations and some clinical factors may predict individual response to aripiprazole.     

Genetic polymorphisms in the dopamine-2 receptor (DRD2), dopamine-3 receptor (DRD3), and dopamine transporter (SLC6A3) genes in schizophrenia: Data from an association study

Objective

To investigate the association between dopaminergic polymorphisms [DRD2 −141C Ins/Del, DRD3 Ser9Gly, and SLC6A3 VNTR] and schizophrenia.

Methods

Two hundred and eighty-eight outpatients with schizophrenia (DSM-IV criteria) [mean age (SD) = 36.4 (12.4), 60.1% males] and 421 unrelated healthy controls [mean age (SD) = 40.6 (11.3), 51.3% males] from a homogeneous Spanish Caucasian population were genotyped using standard methods.

Results

There was a significant difference in genotype distribution for the DRD2 −141C Ins/Del polymorphism [(χ² (2) = 12.35, corrected p = 0.012]. The − 141C Del allele was more common in patients than in controls [0.19 vs. 0.13; χ² (1) = 9.14, corrected p = 0.018, OR (95% CI) = 1.57 (1.17–2.10)]. Genotype and allele distributions for DRD3 Ser9Gly and SLC6A3 VNTR polymorphisms were similar in both groups. However, there was tentative evidence of an interaction effect between DRD3 Ser9Gly and SLC6A3 VNTR [Wald = 9.56 (4), p = 0.049]. Compared to the SLC6A3 10/10 genotype category, the risk of schizophrenia was halved among those with 9/10 [OR = 0.51 (95% CI = 0.30–0.89), p = 0.017]. This protective effect was only present in combination with DRD3 Ser/Ser genotype because of the significant interaction between 9/10 and both Ser/Gly [OR = 2.45 (95% CI = 1.16–5.17), p = 0.019] and Gly/Gly [OR = 3.80 (95% CI = 1.24–11.63), p = 0.019].

Conclusions

This study provides evidence that a genetic variant in the DRD2 gene and possible interaction between DRD3 and SLC6A3 genes are associated with schizophrenia. These findings warrant examination in replication studies.     

Influence of DRD2 and ANKK1 genotypes on apomorphine-induced growth hormone (GH) response in alcohol-dependent patients

Background

D₂ receptor function can be assessed by growth hormone (GH) response to apomorphine. Several association studies between dopamine receptor polymorphisms and results of the apomorphine challenge test with normal and alcohol-dependent subjects yielded inconsistent results. In this pilot study, we tested polymorphisms from the DRD2 region for GH response to apomorphine challenge in more detail.

Methods

Apomorphine challenge tests measuring GH responses on 5 time points were performed on day 1 of alcohol detoxification in 43 patients with alcohol dependence; patients were genotyped for 11 polymorphisms including DRD2, ANKK1, NCAM1 and TTC12.

Results

Associations (p < 0.05) were found for ANKK1 (rs11604671, rs1800497) and DRD2 (rs6276, rs1076560), which are located on adjacent chromosomal positions. Consistent with PET studies suggesting a reduced D₂ receptor availability in patients carrying the ANKK1 rs1800497 T polymorphism (formerly known as DRD2 TaqI A1) we found a reduced GH response to apomorphine in those subjects.

Conclusion

This has been the first study showing significant associations between apomorphine-induced GH response and SNPs in DRD2 and ANKK1 in alcohol-dependent patients. In this respect, our preliminary results are in line with other reports which suggested that DRD2 and ANKK1 polymorphisms influence D₂ receptor availability and signal transduction in the dopaminergic pathways. Small sample size in our study limits the generalizability of our results.     

Association between TNF-α promoter -308A/G polymorphism and tardive dyskinesiain Chinese Han patients with schizophrenia

Objective

Previous studies have indicated that the immune may be involved in the pathogenesis of tardive dyskinesia (TD). Some genetic polymorphisms in the human leukocyte antigen (HLA) I and II regions have been associated with TD, and the tumor necrosis factor-α (TNF-α) gene is located in the HLA III region. TNF-α levels in the striatum significantly increased in haloperidol-induced TD in rats. The TNF-α gene −308A/G single nucleotide polymorphism (SNP) has been shown to directly influence TNF-α expression. The genetic association between the TNF-α gene −308A/G SNP and TD is unclear. The present study investigated whether this variation is associated with clinical phenotypes and TD in schizophrenia in a genetically homogeneous northern Chinese Han population.

Methods

We genotyped the TNF-α gene −308A/G SNP in patients with schizophrenia with TD (n = 350) and without TD (n = 410). The Abnormal Involuntary Movement Scale (AIMS) and Positive and Negative Syndrome Scale (PANSS) were used to assess the severity of TD and psychopathology of schizophrenia, respectively.

Results

The allele and genotype frequencies did not significantly differ between patients with schizophrenia with and without TD (p > 0.05). No significant difference was found in the total AIMS score between the genotypes (p > 0.05). However, the PANSS negative symptom subscore was associated with risk for TD (p = 0.004), and a significant difference was found in total AIMS score between the genotypes in TD patients (p = 0.013).

Conclusion

The TNF-α gene −308A/G polymorphism does not appear to play a major role in the susceptibility to TD in patients with schizophrenia in a northern Chinese Han population. However this polymorphism may play a role in the TD severity.     

Association of genetic polymorphisms with personality profile in individuals without psychiatric disorders

Objective

Population-based twin studies demonstrate that approximately 40–50% of the variability in personality dimensions results from genetic factors.This study assessed selected polymorphisms in the COMT Val158Met, MAOA 3′VNTR, 5HTTLPR, 102T/C 5-HT2A, DAT 3′VNTR and DRD2 exon 8 genes and evaluated their association with personality profiles, anxiety levels, and depressiveness in healthy subjects.

Methods

This study included 406 unrelated (mean age 38.51 years), mentally and somatically healthy Caucasian subjects of Polish origin. The prevalence of the gene variants mentioned above and their association with personality profiles, anxiety levels, and depressiveness was assessed using the Temperament and Character Inventory, NEO Five-Factor Inventory, Spielberger's State-Trait Anxiety Inventory and Beck's Depression Inventory.

Results

The effects of the 5HTTLPR gene on the s/s genotype and empathy (C2) were lowest in the entire group. The effects of gender, age and the HT2A gene for the T/T genotype and attachment (RD3) were highest in women.The effects of gender, age and the DAT gene on the 9/9 DAT genotype, compassion (C4) and cooperativeness (C) were lowest in women. The effects of gender, age and the COMT gene on the Met/Met genotype and neuroticism (NEU) NEO-FFI were also lowest in women.

Conclusions

Our results suggest considerable influence of individual genes on the formation of personality traits.     

A genetic schizophrenia-susceptibility region located between the ANKK1 and DRD2 genes

Background

The gene coding for the D2 dopamine receptor (DRD2) is considered to be one of the most pertinent candidate genes in schizophrenia. However, genetic studies have yielded conflicting results whereas the promising TaqIA variant/rs1800497 has been mapped in a novel gene, ANKK1.

Methods

We investigated eleven single nucleotide polymorphisms (SNPs) spanning the DRD2 and ANKK1 genes, using both a case–control association study comparing 144 independent patients to 142 matched healthy subjects, and a transmission disequilibrium test in 108 trios. This classical genetic study was coupled with a cladistic phylogeny-based association test of human variants, and with an interspecies evolution study of ANKK1.

Results

Case–control study, followed by a 108 trios family-based association analysis for replication, revealed an association between schizophrenia and the ANKK1 rs1800497 (p = 0.01, Odds Ratio = 1.5, 95% Confidence Interval = 1.1–2.2), and the intergenic rs2242592 (p = 2 · 10^− 4, OR = 1.8, 95%CI = 1.3–2.5). A significant SNP–SNP interaction was also found (p < 10^− 5, OR = 2.0, 95%CI = 1.6–2.5). The phylogeny-based association test also identified an association between both these polymorphisms and schizophrenia. Finally, interspecies comparison of the sequences from chimpanzee, orangutan, rhesus macaque and human species suggested specific involvement of ANKK1 in the human lineage.

Conclusions

Intergenic rs2242592 appears to be involved in the genetic vulnerability to schizophrenia, whereas the ANKK1 rs1800497 appears to have a modifying rather than causative effect. Finally, ANKK1 may be a specific human lineage-trait involved in a specific human disease, schizophrenia.     

Genetic variants of D2 but not D3 or D4 dopamine receptor gene are associated with rapid onset and poor prognosis of methamphetamine psychosis

D2-like receptors are key targets for methamphetamine in the CNS, and their activation is an initial and indispensable effect in the induction of dependence and psychosis. It is possible that genetic variants of D2-like receptors may affect individual susceptibility to methamphetamine dependence and psychosis. To test this hypothesis, 6 putatively functional polymorphisms of D2-like receptors, −141C Ins/Del, Ser311Cys and TaqIA of the DRD2 gene, Ser9Gly of the DRD3 gene, and −521C>T and a variable number of tandem repeats in exon 3 of the DRD4 gene, were analyzed in 202 patients with methamphetamine dependence and/or psychosis and 243 healthy controls in a Japanese population. No polymorphism examined showed significant association with methamphetamine dependence, but two polymorphisms of DRD2 were associated with the clinical course and prognosis of methamphetamine psychosis. The A1/A1 homozygote of DRD2 was a negative risk factor for a poorer prognosis of psychosis that continues for more than 1 month after the discontinuance of methamphetamine abuse and the beginning of treatment with neuroleptics (p = 0.04, odds ratio (OR) = 0.42, 95% CI; 0.27–0.65) and the complication of spontaneous relapse of methamphetamine psychosis after remission (p = 0.014, OR = 0.34, 95% CI; 0.22–0.54). The genotype of −141C Del positive (Del/Del and Del/Ins) was at risk for rapid onset of methamphetamine psychosis that develops into a psychotic state within 3 years after initiation of methamphetamine abuse (p = 0.00037, OR = 3.62, 95% CI 2.48–5.28). These findings revealed that genetic variants of DRD2, but not DRD3 or DRD4, confer individual risks for rapid onset, prolonged duration, and spontaneous relapse of methamphetamine psychosis.     

No relationship between--141C Ins/Del polymorphism in the promoter region of dopamine D2 receptor and extrapyramidal adverse effects of selective dopamine D2 antagonists in schizophrenic patients: a preliminary study

Previous studies have shown that subjects without Del alleles of the--141C Ins/Del polymorphism in the promoter region of the dopamine D2 receptor (DRD2) gene have lower DRD2 density that those with one or two Del alleles. The present study aims to investigate the relationship between the -141C Ins/Del polymorphism and extrapyramidal adverse effects of bromperidol and nemonapride, antipsychotic drugs with a selective and potent DRD2 antagonistic property, in schizophrenic inpatients. Twenty-seven patients were treated with bromperidol at a fixed-dose of 6, 12 or 18 mg/day, and 25 patients were treated with nemonapride at a fixed-dose of 18 mg/day. The duration of treatment with these drugs was 3 weeks. The Ins and Del alleles were determined by PCR. Extrapyramidal adverse effects were assessed by the Udvalg for Kliniske Unders?gelser side effects rating scale. The subjects consisted of 38 homozygotes of the Ins allele and 14 heterozygotes of the Ins and Del alleles. There were no significant differences in the incidence or severity of extrapyramidal adverse effects between patients with and without the Del allele. It is possible that this result was due to a lack of statistical power. However, the present study suggests that the--141C Ins/Del polymorphism is not related to the development of extrapyramidal adverse effects during acute-phase treatment with antidopaminergic agents.     

Neuropsychological functions in bipolar disorders I and II with and without comorbid alcohol dependence

Objective

Bipolar disorder (BP) is a mental disorder most likely to co-occur with substance dependence and abuse, especially alcohol dependence (ALD). Whether the effect of comorbid alcoholism is different between the BP-I and BP-II subtypes remains unclear. We aimed to identify the neuropsychological performance of BP patients with and without comorbid ALD in partial remission from depression or mania, and compare it with that of healthy controls (HCs).

Methods

We recruited 29 HCs and 94 BP patients, whom we categorized into four groups: (1) BP-I without a history of alcohol abuse or dependence (BP-I^− ALD; n = 22), (2) BP-II without a history of alcohol abuse and dependence (BP-II^− ALD; n = 38), (3) BP-I with comorbid ALD (BP-I^+ ALD; n = 16), and (4) BP-II with comorbid ALD (BP-II^+ ALD; n = 18). Only males were recruited in this study.

Results

When patients comorbid with ALD were not excluded, there were no significant differences on neuropsychological tests between the BP-I and BP-II groups. However, when patients with comorbid ALD were excluded, there were significant differences between the two BP^− ALD groups. The BP-I^− ALD group had lower scores on memory subtests (p ≤ 0.01) than the HC and BP-II^− ALD groups, but the BP-II^− ALD and HC groups had similar scores.

Conclusion

We found it important to exclude ALD comorbidity when evaluating neuropsychological functions due to our finding that ALD affected the cognitive performance in BP-I more severely than in the BP-II group. ALD not only impairs neuropsychological function, but also worsen the clinical course and leads to a more pernicious status and negative cycle.     

C957T polymorphism of the human dopamine D2 receptor gene predicts extrastriatal dopamine receptor availability in vivo

The C957T (rs6277) single nucleotide polymorphism (SNP) of the human dopamine D2 receptor (DRD2) gene (DRD2) affects DRD2 mRNA stability and has been shown to predict striatal DRD2 availability (B_max/K_D) in vivo in man. Specifically, the C/C genotype is associated with low striatal DRD2 availability (C/C<C/T<T/T). It is not known, however, whether this pattern of genetic regulation of DRD2 expression also applies to low density DRD2 populations in extrastriatal regions. We analyzed extrastriatal DRD2 availability (indexed by binding potential, BP_ND) measured in 38 healthy male volunteers with 3D-PET and the high-affinity DRD2 radioligand [¹¹C]FLB457. The subjects were genotyped for the C957T as well as for two other widely studied DRD2 SNPs, the TaqIA (rs1800497) and the −141C Ins/Del (rs1799732). Statistical analyses showed that the C957T C/C genotype was associated with high extrastriatal DRD2 BP_ND throughout the cortex and the thalamus (C/C>C/T>T/T). Also the TaqIA A1 allele carriers (p = 0.101) tended to have higher extrastriatal DRD2 BP_ND compared to non-carriers whereas the −141C Ins/Del genotype did not influence extrastriatal DRD2 BP_ND. Our findings indicate that the DRD2 SNPs regulate DRD2 availability in the human cortex and in the thalamus in vivo. However, the regulation pattern is different from that observed previously for striatal DRD2 availability in vivo, which may reflect distinct functional roles of dopamine and DRD2 in the cortex versus the striatum. The results provide useful information for the interpretation of genetic studies exploring the role of the DRD2 in normal physiology as well as in psychiatric and neurological diseases.     

Association study of polymorphisms in leptin and leptin receptor genes with antipsychotic-induced body weight gain

Background

Antipsychotic-induced weight gain (AIWG) is a serious side-effect of antipsychotic medication leading to metabolic syndrome and increased cardiovascular morbidity. Unfortunately, there are still no valid predictors to assess an individual's risk to gain weight. Previous studies have indicated an impact of genetic variation in the genes encoding leptin, LEP, and leptin receptor, LEPR, on AIWG, but results have not been conclusive. Thus, we investigated polymorphisms in both genes for an association with AIWG.

Methods

A total of 181 schizophrenic and schizoaffective patients treated with various antipsychotics were included. In a small subset of patients, leptin plasma levels were additionally obtained. Five polymorphisms in LEP and LEPR (LEP: rs7799039 (-2548G/A polymorphism), rs10954173, rs3828942; LEPR: rs1327120, rs1137101 (Q223R polymorphism) were genotyped using TaqMan assays. Statistical association with % weight change from baseline weight was performed using ANCOVA with baseline weight as covariate.

Results

ANCOVA showed a non-significant trend for genotype association of the rs7799039 marker (p = .068). No significant association of the other LEP and LEPR SNPs with AIWG was detected. However, we found a significant association between a haplotype of LEP rs7799039G–rs10954173G–rs3828942G (p = .035) and AIWG. The rs7799039 G-allele (p = .042) and G-allele of rs3828942 (p = .032) were associated with higher weight gain.

Conclusion

Our study supports the hypothesis of an impact of LEP gene variation on AIWG. Limitations of our study include heterogeneous samples, short treatment duration and multiple comparisons. Our findings were compared to previous studies in detail in order to provide the readers with a more conclusive picture. However, further studies are warranted including more gene variants and interaction analyses with other genes of the leptin–melanocortin pathway.     

Verbal but not performance IQ is highly correlated to externalizing behavior in boys with ADHD carrying both DRD4 and DAT1 risk genotypes

Objective

Attention-deficit/hyperactivity disorder (ADHD) is often associated with reduced IQ and high levels of externalizing behavior (EB). This study tested if DRD4 7-repeat allele and DAT1 10-repeat allele homzygosity interact in modulating correlations between IQ and EB in affected boys.

Methods

Boys (n = 130) between 6 and 12 years of age diagnosed with ADHD were included in the study. IQ and EB were assessed by WISC-III and Child Behavioral Checklist, respectively. The 40 bp variable number tandem repeat (VNTR) of the DAT1 gene and the 48 bp VNTR of the DRD4 gene polymorphisms were genotyped and 4 subgroups were defined by the presence/absence of the DRD4 7-repeat allele and by the presence/absence of the DAT1 10/10 genotype. Correlation coefficients were compared using the Fisher's Z transformation and regression lines by a Potthoff analysis.

Results

In the total sample, all correlation coefficients between EB score and IQ were non significant. Also, no differences in IQ were observed between the 4 genotype groups. However, different pattern of correlations between IQ and EB score appeared. In boys carrying no or only one genetic risk, IQ and EB score were uncorrelated while in children carrying both risk factors, negative and significant correlations emerged. Notably, correlation of EB to verbal IQ was strong (r = − 0.71) and highly significant (P < 0.01) in boys carrying both risk alleles. All pair-wise comparisons of correlation coefficients were significant for EB–verbal IQ correlation. Test of coincidence of regression lines did not show significant differences.

Conclusions

A specific domain of IQ, namely the verbal quotient is highly correlated to the level of EB in boys with ADHD carrying both dopaminergic risk genotypes. Further investigations are required to replicate these results and determine specificity to ADHD.     

Tobacco smoking produces greater striatal dopamine release in G-allele carriers with mu opioid receptor A118G polymorphism

Objective

To determine if carriers of the allelic expression of the G variant of the human mu opioid receptor (OPRM1) A118G polymorphism have greater increases in striatal dopamine (DA) release after tobacco smoking.

Methods

Nineteen of 20 genotyped male tobacco smokers, after overnight abstinence, smoked denicotinized (denic) and average nicotine (nic) containing tobacco cigarettes in a PET brain imaging study using [¹¹C]raclopride.

Results

The right striatum had more free D₂ receptors than the left striatum pre- and post-tobacco smoking. After smoking the nic cigarettes, mean decreased DA binding was observed in the left dorsal caudate (− 14 6 11; t = 3.77), left and right ventral putamen (− 26 3–8; t = 4.27; 28 2 1; t = 4.25, respectively), and right caudate (17 18 1; t = 3.92). The effects of A118G genotype on the binding potentials for these four regions were then analyzed. Carriers of the G allele had larger magnitudes of DA release in response to nic smoking than those homozygous for the more prevalent AA allele in the right caudate and right ventral pallidum (t = 3.03; p = 0.008 and t = 3.91; p = 0.001). A voxel by voxel whole brain SPM analysis using an independent samples t test did not reveal any other differences between genotype groups. In addition, the venous plasma cortisol levels of the volunteers from 8:30 a.m. to 12:40 p.m. were lower in the AG/GG allele carriers. Nic smoking increased plasma cortisol in both groups, but they were higher in the AA group.

Conclusion

This preliminary study indicates a difference in both brain striatal DA release and plasma cortisol in A118G polymorphic male tobacco smokers.     

The influence on the schizophrenic symptoms by the DRD2Ser/Cys311 and -141C Ins/Del polymorphisms

The hyperactivity of dopaminergic systems is one of the major etiological hypotheses of schizophrenia. The major support for this hypothesis is that effective antipsychotic drugs bind to dopamine receptors and improve acute schizophrenic symptoms. For this reason, we investigated the allelic association between schizophrenia and polymorphisms of the DRD2 genes for the Ser/Cys311 and -141C Ins/Del. The subjects were 190 schizophrenics (120 males and 70 females) and 103 normal controls (53 males and 50 females). There were no significant differences between the patients and controls in the allele frequencies and the frequencies of the genotypes. We found no statistical association between schizophrenia and polymorphisms of the DRD2 genes for the Ser/Cys311 and -141C Ins/Del. These results indicate that the DRD2 gene may not develop schizophrenia. Next, we examined whether the genotypes influence the symptoms of schizophrenia the using Positive and Negative Symptom Scale scores. The Ser/Cys patients exhibited significantly lower positive and negative symptom scores than Ser/Ser patients. Patients with Del/Del, Ins/Del, or Ins/Ins showed higher positive symptom scores in descending order. This result suggested that the Del allele worsens the positive symptoms. We concluded that the DRD2 receptor gene may not influence the onset of schizophrenia, but there is a strong possibility that the Cys311 and -141C Del have a significant influence on the symptoms of schizophrenia.     

Interaction of the DRD3 and BDNF gene variants in subtyped bipolar disorder

Objectives

Bipolar disorder is a severe mental disorder with prominent genetic etiologic factors. Dopaminergic dysfunction has been implicated in the pathogenesis of bipolar disorder, which suggests that the dopamine D3 receptor gene (DRD3) is a strong candidate gene. The brain-derived neurotrophic factor (BDNF) gene has been implicated in the etiology of bipolar disorder. We examined the association between the BDNF Val66Met and DRD3 Ser9Gly polymorphisms with two subtypes of bipolar disorder: bipolar-I and -II. Because BDNF regulates DRD3 expression (1), we also examined possible interactions between these genes.

Methods

We recruited 964 participants: 268 with bipolar-I, 436 with bipolar-II, and 260 healthy controls. The genotypes of the BDNF Val66Met and DRD3 Ser9Gly polymorphisms were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis.

Results

Logistic regression analysis showed a significant main effect for the Val/Val genotype of the BDNF Val66Met polymorphism (P = 0.020), which predicted bipolar-II patients. Significant interaction effects for the BDNF Val66Met Val/Val genotype and both DRD3 Ser9Gly Ser/Ser and Ser/Gly genotypes were found only in bipolar-II patients (P = 0.027 and 0.006, respectively).

Conclusion

We provide initial evidence that the BDNF Val66Met and DRD3 Ser9Gly genotypes interact only in bipolar-II disorder and that bipolar-I and bipolar-II may be genetically distinct.     

Association in Japanese patients between neuroleptic malignant syndrome and functional polymorphisms of the dopamine D(2) receptor gene

A genetic predisposition to the development of neuroleptic malignant syndrome (NMS) has been suggested by clinical studies. Although the molecular basis of NMS is unclear, a dopaminergic blockade mechanism has been considered the main cause. We therefore investigated the association between NMS and three functional polymorphisms of the dopamine D(2) receptor (DRD(2)) gene: TaqI A, -141C Ins/Del, and Ser311Cys. Subjects included 32 Japanese patients, previously diagnosed with NMS, and 132 schizophrenic patients treated with neuroleptics without occurrence of NMS. Polymerase chain reaction and restriction fragment length polymorphism analyses were performed to determine each genotype. We found significant differences in genotypic and allelic frequencies of the -141C Ins/Del polymorphism between patients with and without NMS. The -141C Del allele was significantly more frequent in the NMS group (23.4 vs 11.7%, P=0.026). Similarly, the proportion of -141C Del allele carriers was significantly higher in the NMS group (40.6 vs 20.5%, P=0.022). No significant differences between the two groups were seen for allelic and genotypic frequencies of the TaqI A and Ser311Cys polymorphisms. This result suggests that the -141C Ins/Del polymorphism is likely to predispose toward the development of NMS, probably together with other unidentified factors.     

P2RX7 Gln460Arg polymorphism is associated with depression among diabetic patients

Aims

Both diabetes mellitus and major depression are public health concerns, and the co-occurrence of these illnesses is highly frequent. Acting as a potential risk factor, hyperglycemia might facilitate the manifestation of depression in patients genetically predisposed to affective disorders. In the present study, candidate polymorphisms of the serotonin transporter, the tryptophan hydroxylase 2 (TPH2) genes, as well as of the brain-derived neurotrophic factor BDNF, and the P2RX7 purinergic receptor genes were analyzed in Hungarian diabetic population. We assumed that genetic influence would be stronger on depressive symptoms in the “poor glycemic control” group (PC: HbA_1C > 7%) compared to the “good glycemic control” group (GC: HbA_1C ≤ 7%).

Methods

After excluding patients with current antidepressant medication, 218 diabetic patients' Hospital Anxiety and Depression Scale (HADS) scores were used in multivariate analysis of variance. Based on the HbA_1C levels, 81 patients were in the GC group, and 137 belonged to the PC group.

Results

After correcting for multiple testing, only the association of the P2RX7 Gln460Arg (rs2230912) polymorphism with depressive symptoms remained significant. Patients with the G-allele (Arg-variant) had higher scores on the HADS depression scales (p = 0.007). A gene x glycemic control interaction (p = 0.032) was observed on the anxiety scale at the TPH2 promoter polymorphism: the -703T-allele decreased anxiety scores only in the GC group (p = 0.008).

Conclusions

Our results support the role of the P2RX7 rs2230912 G-allele in the development of depression and emphasize the importance of good glycemic control, acting as a potential protective factor in diabetic patients.     

−141C insertion/deletion polymorphism of the dopamine D2 receptor gene is associated with schizophrenia in Chinese Han population: Evidence from an ethnic group‐specific meta‐analysis

Accumulate evidence has implicated dopamine D2 receptor gene polymorphisms in the etiology of schizophrenia. A single nucleotide polymorphism, ?141C insertion/deletion (Ins/Del) (rs1799732), in the promoter region of the dopamine D2 receptor gene has been linked to schizophrenia; however, the data are inconclusive. This study investigated whether the ?141C polymorphism is associated with the risk of schizophrenia in different ethnic groups by performing a meta‐analysis. A total of 24 case–control studies examining the association between ?141C Ins/Del polymorphism and schizophrenia were identified according to established inclusion criteria. Significant association was revealed between ?141C Ins/Del polymorphism and schizophrenia risk in dominant genetic model (Ins/Ins + Ins/Del versus Del/Del) (odds ratio = 0.33, 95% confidence interval = 0.14–0.81, z = 2.41, P = 0.02) in Chinese Han but not in Caucasian, Japanese or India populations. Our results indicate that ?141C Ins/Del polymorphism might be a susceptibility factor for schizophrenia in Chinese Han population.     

Genetic epistasis between the brain-derived neurotrophic factor Val66Met polymorphism and the 5-HTT promoter polymorphism moderates the susceptibility to depressive disorders after childhood abuse

Background

Based on biological interactions between the serotonergic system and the brain-derived neurotrophic factor (BDNF), BDNF is a plausible candidate for a gene–gene–environment interaction moderating the interaction between the s/l- promoter polymorphism of the serotonin transporter (5-HTTLPR) and childhood abuse. We tested the hypothesis of a three-way interaction with respect to depressive symptoms.

Methods

2035 Caucasian subjects from the Study of Health in Pomerania (German general population) completed the Beck Depression Inventory (BDI-II) and the Childhood Trauma Questionnaire. All subjects were genotyped for the BDNF Val66Met (rs6265) and the s/l 5-HTTLPR polymorphisms.

Results

Tobit regression analyses revealed a three-way-interaction between the three genotypes of 5-HTTLPR and the BDNF genotypes and overall childhood abuse for the BDI-II score (p = 0.02). Emotional abuse carried the main effect of the interaction (p = 0.008). The s/s genotype of the 5-HTTLPR exerted its negative impact on mental health after childhood abuse only in the presence of the BDNF Val/Val genotype but not in the presence of the BDNF Met allele. In contrast, the l allele of the 5-HTTLPR also emerged as a genetic risk factor for depression in carriers of one or two Met alleles.

Conclusions

Our results point to a gene–gene–environment interaction that relevantly impacts on the role of the s/s genotype of the 5-HTTLPR in childhood abuse: Depending on the BDNF background (Val/Val versus Met allele) the s/s genotype showed either protective or risk properties with regard to depressive symptoms.