No association between the -3081A/T polymorphism in the norepinephrine transporter gene promoter and personality traits in healthy subjects

There have been several data suggesting that norepinephrine neurotransmission is involved in the characterization of personality traits. Recently, the -3081A/T polymorphism in the promoter region of the norepinephrine transporter (NET) gene affecting promoter activity has been reported. In the present study, we studied the association between this NET polymorphism and personality traits in 553 Japanese healthy subjects. Personality traits were assessed by the Temperament and Character Inventory (TCI), and the NET genotypes were identified by a PCR-RFLP method. Multivariate two-factor analysis of covariance with genotype and gender as factors and with age as a covariate showed no association between the NET genotypes and the TCI dimension scores. The present study thus suggests that the -3081A/T polymorphism in the NET gene promoter is not involved in the characterization of personality traits in healthy subjects.     

Association study between a functional polymorphism of FK506-binding protein 51 (FKBP5) gene and personality traits in healthy subjects

Previous studies have shown that the function of hypothalamic-pituitary-adrenal (HPA) axis is involved in the characterization of personality traits. FK506-binding protein 51 (FKBP51 or FKBP5) is a co-chaperone of heat-shock protein 90, and plays an important role in the negative feedback regulation of HPA axis function. It has been reported that a C/T single nucleotide polymorphism in the intron 2 of FKBP5 gene (rs1360780) affects FKBP5 protein levels and cortisol response to dexamethasone and psychological stress tests. Therefore, it is hypothesized that the FKBP5 polymorphism affects personality traits. In the present study, we studied the association between this polymorphism and personality traits in 826 Japanese healthy subjects. Personality traits were assessed by the Temperament and Character Inventory (TCI), and the FKBP5 genotype was detected by a real-time PCR and cycling probe technology for SNP typing. In total subjects, the group with the T allele predictive of impaired negative feedback regulation of the HPA axis had higher scores of harm avoidance (HA) (p = 0.043) and lower scores of cooperativeness (CO) (p = 0.019) compared to that without the T allele. The T allele was associated with higher scores of HA in females (p = 0.020) and lower scores of CO in males (p = 0.015). The present study thus suggests that the FKBP5 polymorphism affects HA and CO in healthy subjects, with gender specificity.     

No association between 5-HTTLPR and harm avoidance in Korean college students

There have been numerous studies on the association between 5-HTTLPR (polymorphisms in the promoter region of the serotonin transporter gene) and anxiety-related personality traits, with conflicting results. In this study, we administered Korean version of the Temperament and Character Inventory (K-TCI) to a sample of 158 Korean college students and genotyped for the 5-HTTLPR in order to compare the TCI dimensional scores including harm avoidance according to the 5-HTTLPR genotype and sex. We could not find the association between 5-HTTLPR and harm avoidance and other TCI measures. Considering known allele frequencies differences of 5-HTTLPR among different ethnic groups, further cross-cultural studies with a larger sample would be needed.     

CYP2C19 polymorphism affects personality traits of Japanese females

It has been suggested that personality traits are heritable. The polymorphic cytochrome P450 (CYP) 2C19 metabolizes sex hormones and 5-hydroxytryptamine, which are involved in multiple brain functions. In the present study, the relationship between the CYP2C19 polymorphism and personality traits was examined in 487 Japanese healthy volunteers. Personality traits were assessed by the Temperament and Character Inventory (TCI), and the two mutated alleles causing absent CYP2C19 activity were identified by a PCR-RFLP method. In females, the scores of reward dependence (p=0.026), cooperativeness (p=0.001), and self-transcendence (ST) (p=0.049) were significantly lower in poor metabolizers (PMs) than in extensive metabolizers (EMs). In males, none of the seven TCI dimensions was significantly different between EMs and PMs. The present study thus suggests that the CYP2C19 polymorphism affects personality traits of Japanese females.     

No association of COMT val158met polymorphism and psychotic symptoms in Lewy body dementias

We sought to determine whether the COMT val158met polymorphism (rs4680) is associated with delusions and hallucinations in people with dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). A total of 218 individuals, recruited from centres in Norway, Sweden and the UK were included in this study; 121 with clinically or neuropathologically diagnosed DLB/PDD and 97 age-matched, cognitively normal controls. All participants with dementia underwent serial evaluation of neuropsychiatric symptoms to assess the presence of persistent delusions and hallucinations using the Columbia University Scale for Psychopathology in Alzheimer's disease, the Neuropsychiatric Inventory or the Present Behavioural Examination. Severity of cognitive impairment was measured using the Mini Mental State Examination (MMSE). Both controls and participants with dementia were genotyped for rs4680. In contrast to previous findings, analysis by logistic regression failed to find any associations between rs4680 and psychotic symptoms. Larger studies in well characterised cohorts are warranted in order to investigate this relationship further.     

Combination of the serotonin transporter and norepinephrine transporter gene promoter polymorphisms might influence harm avoidance and novelty seeking in healthy females

It has been demonstrated that the interaction between serotonin transporter (5HTT) and norepinephrine transporter (NET) functions affects each transporter function and behavior in studies using knockout mice model. In the present study, we examined the effects of the 5HTT and NET gene promoter polymorphisms on personality traits in 575 Japanese healthy subjects. The 5HTT (long/short, L/S) and NET (-3081 A/T) genotypes were identified by PCR methods, and personality traits were assessed by the Temperament and Character Inventory (TCI). Neither of the two polymorphisms affected any TCI dimension, but the interaction between them had significant effects on harm avoidance and novelty seeking in females. Subsequent analyses showed that the females with the combination of the SS genotype reducing 5HTT function and the TT genotype reducing NET function had higher harm avoidance and lower novelty seeking. The present study suggests that the combination of 5HTT and NET polymorphisms influences harm avoidance and novelty seeking in females.     

Impact of the COMT Val(108/158)Met polymorphism on the mu-opioid receptor system in the human brain: mu-opioid receptor, met-enkephalin and beta-endorphin expression

The Val^108/158Met polymorphism of the catechol-O-methyltransferase gene (COMT) is known to interact with the function of various neuroreceptor systems in the brain. We have recently shown by post-mortem receptor autoradiography that the number of mu-opioid (MOP) receptor binding sites depends on the number of COMT Met^108/158 alleles in distinct human brain regions. We now investigated COMT Val^108/158Met related levels of the MOP receptor protein and its endogenous ligands met-enkephalin and beta-endorphin in the human frontal cortex, thalamus and basal ganglia. Semiquantitative immunostaining and in situ hybridization were applied in a cohort of 17 human brain tissues from healthy donors. MOP receptor protein levels paralleled previous ligand binding results with a significantly higher MOP receptor expression in the mediodorsal nucleus of the thalamus of COMT Met^108/158 allele carriers. Also met-enkephalin peptide levels correlated with the genotype in this structure, with the lowest expression in COMT Met^108/158 homozygous individuals. Beta-endorphin was not detectable in the cortex, basal ganglia or thalamus, and therefore is unlikely to contribute to changes of the MOP receptor system. These results confirm the impact of the COMT Val^108/158Met polymorphism on the MOP receptor system and may support the hypothesis of an enkephalin related turnover of MOP receptors at least in some brain structures.     

Association between A218C polymorphism of the tryptophan-hydroxylase-1 gene,harm avoidance and binge eating behavior in bulimia nervosa

Genes involved in serotonin transmission are likely involved in the biological predisposition to bulimia nervosa. We investigated whether the A218C polymorphism of the tryptophan-hydroxylase-1 gene was associated to bulimia nervosa and/or to some phenotypic aspects of the disorder. One hundred eighty Caucasian women (91 patients with bulimia nervosa and 89 healthy controls) were enrolled into the study. They underwent a blood sample collection for A218C polymorphism of the tryptophan-hydroxylase-1 genotyping and a clinical evaluation assessing comorbidity for Axis I and II psychiatric disorders, harm avoidance personality dimension and bulimic symptoms. The distribution of both tryptophan-hydroxylase-1 A218C genotypes and alleles did not significantly differ between patients and controls. Bulimic women with the AA genotype exhibited a more severe binge eating behavior and higher harm avoidance scores than those with CC genotype. These findings support the idea that tryptophan-hydroxylase-1 A218C polymorphism does not play a part in the genetic susceptibility to bulimia nervosa, but it seems to be involved in predisposing bulimic patients to a more disturbed eating behavior and higher harm avoidance.     

Association study of a functional catechol-O-methyltransferase polymorphism and executive function in elderly males without dementia

Cognitive function in older people is a major factor influencing quality of life. The catechol-O-methyltransferase (COMT) gene, which is essential in the metabolic degradation of prefrontal dopamine, has been considered as a leading candidate gene in the variation in cognitive performance. The aim of this study was to investigate the effect of a functional COMT (Val158Met) polymorphism on several cognition domains in a relatively homogeneous population consisting of elderly Chinese males without dementia. Six neuropsychological measurements, including Spatial Span Forward and Backward, Digit Span Forward and Backward, and Trail Making Test-A and -B, were assessed in 161 aged males. It was found that the Met/Met carriers showed a better performance than the Val/Met and Val/Val subjects on the Digit Span Forward (a measure of general attention; p=0.017, after correction for education level) test, but not on the other cognitive tests. These findings suggest that the COMT Val158Met genotype may contribute to differences in normal cognitive aging, particularly in the area of general attention.     

Meta-analysis of Association Between a Catechol-O-Methyltransferase Gene Polymorphism and Attention Deficit Hyperactivity Disorder

There have been conflicting reports on the association between the Val158/108Met polymorphism of the catechol-O-methyltransferase (COMT) gene and attention deficit hyperactivity disorder (ADHD). Therefore we would like to perform a meta-analysis of previous studies to assess the overall magnitude and significance of the association. Family-based and case–control studies of the association between the COMT gene polymorphism and ADHD were searched systematically and comprehensively. Odds ratios (OR) of association were pooled by the fixed effects model if no significant heterogeneity was present among different studies. Subgroup analysis by gender and ADHD subtypes were also performed. Eleven family-based and two case–control studies were identified. After pooling the results, no significant association between the COMT Val158/108Met polymorphism and ADHD was found (OR 0.99 (95% CI: 0.88–1.12), P = 0.87). There was also no significant association when the results were stratified by gender or ADHD subtype. There was no significant statistical heterogeneity (χ² = 12.27, P = 0.2) although clinical heterogeneity was present in the studies, especially the ethnicity of subjects. Sensitivity analysis demonstrated absence of undue influence of any single study. Standard regression analysis showed no significant publication bias. We concluded that no significant association was present between the most common COMT gene polymorphism and ADHD. Further studies should employ larger sample size in more homogeneous subjects. Further investigations in moderator variables and gene–gene and gene–environment interactions are also warranted.     

Functional polymorphism of the GTP cyclohydrolase 1 gene affects the personality trait of novelty seeking in healthy subjects

GTP cyclohydrolase 1 (GCH1) is the initial and rate-limiting enzyme in the biosynthesis of tetrahydrobiopterin, which is an essential cofactor for biosynthetic enzymes of dopamine, serotonin, and nitric oxide. In the present study, the association of functional polymorphism of the GCH1 gene (C+243T, rs841) with personality traits was examined in 902 healthy Japanese subjects. Personality traits were assessed by the Temperament and Character Inventory (TCI), and the GCH1 genotype was detected by a PCR-RFLP method. There were no significant main effects of the GCH1 genotype on the seven TCI dimension scores, but significant interaction effects between the GCH1 genotype and gender were found on the scores of novelty seeking. Post-hoc analysis revealed that males with the C/C genotype had higher scores of novelty seeking than those with the C/T genotype or those with the T/T genotype, while in females the scores of novelty seeking were not different among the genotype groups. The present study thus suggests that the C+243T polymorphism of the GCH1 gene affects the personality trait of novelty seeking in males.     

The -181 A/C polymorphism in the excitatory amino acid transporter-2 gene promoter affects the personality trait of reward dependence in healthy subjects

There have been some animal and human data suggesting that excitatory amino acid transporter (EAAT)-2, the major subtype of EAAT, is involved in human mental function and behavior. Recently, it has been shown that the -181 A/C polymorphism in the EAAT2 gene promoter affects plasma glutamate concentrations in humans. In the present study, the association of this genetic polymorphism with personality traits was examined in 575 Japanese healthy volunteers. Personality traits were assessed by the Temperament and Character Inventory, and the EAAT2 polymorphism was detected by a PCR-RFLP method. The scores of reward dependence were significantly (p=0.017) lower in the group with the A allele (A/A and A/C) than in that without this allele (C/C). When males and females were analyzed separately, the significant difference between the two genotype groups was observed in females (p=0.021) but not in males. The present study thus suggests that the -181 A/C polymorphism in the EAAT2 gene promoter affects the personality trait of reward dependence in healthy subjects.     

Evidence of association between Val66Met polymorphism at BDNF gene and anxiety disorders in a community sample of children and adolescents

Different lines of evidence support BDNF as a candidate gene in mood and anxiety modulation. More recently, the Met allele of the BDNF Val66Met polymorphism has been implicated in anxiety in animal models and anxiety-traits in humans. The aim of this study is to evaluate the a priori hypothesis that the association between anxiety disorders and Val66Met polymorphism at the BDNF gene would be replicated in a community sample of children and adolescents. 240 subjects from a total sample of 2457 children and adolescents aged 10-17 years from the public schools in the catchment area of the primary care unit of a university hospital participated in this case-control study and were assessed for psychopathology using the K-SADS-PL. A sample of saliva was collected for DNA analysis of Val66Met polymorphism. BDNF was the single gene evaluated in this sample. We found a significant association between carrying one copy of the Met allele and higher chance of anxiety disorders in children and adolescents. The association remained positive even after the adjustment for potential confounders (228 subjects; OR = 3.53 (CI95% 1.77-7.06; p < 0.001)). Our results support the a priori hypothesis of an association between anxiety and the polymorphism Val66Met. To our knowledge, this is the first study documenting a potential role of this polymorphism in a community sample of anxious children and adolescents.     

Preliminary evidence of association between EFHC2, a gene implicated in fear recognition,and harm avoidance

Genetic variation at the EF-hand domain containing 2 gene (EFHC2) locus has been associated with fear recognition in Turner syndrome. The aim of this study was to examine whether EFHC2 variants are associated with non-syndromic anxiety-related traits [harm avoidance (HA) and behavioral inhibition (BI)] and with panic disorder (PD). Our sample comprised 127 PD patients and 132 controls without psychiatric disorder. We genotyped nine SNPs within the EFHC2 locus and used PLINK to perform association analyses. An intronic SNP (rs1562875) was associated with HA (permuted p = 0.031) accounting alone for over 3% of variance in this trait. This same SNP was nominally, but not empirically, associated with BI (r² = 0.022; nominal p = 0.022) and PD (OR = 2.64; nominal p = 0.009). The same association was found in a subsample of only females. In sum, we observed evidence of association between a variant in EFHC2, a gene previously associated with the processing of fear and social threat, and HA. Larger studies are warranted to confirm this association.     

No association between the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and schizophrenia in Asian populations: Evidence from a case-control study and meta-analysis

Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that plays an important role in the development and maintenance of adult neurons and is important regulator of synaptic plasticity in human brain. It has been reported that there are alterations in BDNF levels in the brains of patients with schizophrenia. It has also been reported that transneuronal transfer of BDNF is dependent on neuronal activity, suggesting that BDNF plays an important role in neurotransmission. A single nucleotide polymorphism (SNP) in the BDNF gene that causes a valine to methionine substitution at codon 66 (Val66Met) has been demonstrated to affect human memory and hippocampal function. A possible positive association between the BDNF Val66Met polymorphism and schizophrenia has also been shown in Scottish and Spanish populations. Furthermore, the BDNF Val66Met polymorphism has been implicated in the age of onset of schizophrenia. In the present study, we attempted to replicate these findings in a Japanese case-control sample (211 patients with schizophrenia and 205 controls). We did not find an association between the BDNF Val66Met polymorphism and schizophrenia. An association between the Val66Met polymorphism and age of onset was not observed either. Furthermore, a meta-analysis including the present and previous Asian studies comparing 2059 patients with schizophrenia and 2765 controls also revealed no significant association between the BDNF Val66Met polymorphism and schizophrenia. Our results do not support a significant role for the BDNF Val66Met polymorphism in the development of schizophrenia in Asian populations.     

Lack of association between the unique LMP2 gene polymorphism and the outcome of lung cancer in a population of Chinese Han nationality

Lung cancer is characterized by a widely ranging incidence variation; it is the most common cancer in China. In this study we will assess the association of low-molecular-mass protease 2 (LMP2) gene codon 60 polymorphism with the risk of lung cancer. Genomic DNA of peripheral blood mononuclear cells was isolated from 207 patients with lung cancer and 264 healthy controls. DNA direct sequencing and polymerase chain reaction-restriction fragment length polymorphism were performed to scrutinize LMP2 gene codon 60 polymorphism. The risk of LMP2 gene polymorphism in lung cancer was assessed using an unconditional logistic regression model adjusted by the confounding factors. As a result of DNA direct sequencing, the LMP2 codon 60 polymorphic substitution of the nucleotide was CGC → TGC in Chinese individuals, not CGC → CAC as reported in other ethnic populations. In histology-specific analysis and TNM stages, there was no apparent association between this LMP2 gene polymorphism and any of the histologic types or TNM stages of lung cancer using the Arg/Arg genotypes as the reference group (all p values > 0.05). These results suggest that the polymorphic site is unique in the Chinese population of Han nationality at the LMP2 codon 60 loci (Arg60Cys), but a lack of association with lung cancer exists.     

Association between the brain-derived neurotrophic factor Val66Met polymorphism and brain morphology in a Japanese sample of schizophrenia and healthy comparisons

Magnetic resonance imaging was used to investigate the relation between the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and volumetric measurements for the medial temporal lobe structures (amygdala, hippocampus, and parahippocampal gyrus) and prefrontal sub-regions (the superior frontal gyrus, middle frontal gyrus, inferior frontal gyrus, ventral medial prefrontal cortex, orbitofrontal cortex, and straight gyrus) in a Japanese sample of 33 schizophrenia patients and 29 healthy subjects. For the controls, the Met carriers had significantly smaller parahippocampal and left superior frontal gyri than the Val homozygotes. The schizophrenia patients carrying the Met allele had a significantly smaller right parahippocampal gyrus than those with the Val/Val genotype, but the genotype did not affect the prefrontal regions in schizophrenia patients. These findings might reflect different genotypic effects of BDNF on brain morphology in schizophrenia patients and healthy controls, implicating the possible role of the brain morphology as an endophenotype for future genetic studies in schizophrenia.     

No genetic association between the SLC1A2 gene and Japanese patients with schizophrenia

Glutamatergic dysfunction may be a pathophysiological feature in the brains of schizophrenic patients. In addition to glutamate receptors, excitatory amino acid transporters (EAATs) have received much attention because they directly affect glutamatergic neurotransmission by excluding excessive glutamate from the synaptic cleft. Among these, EAAT2 (also known as solute carrier family 1, member 2; SLC1A2) has been widely studied in schizophrenia pathophysiology. During the last decade, we reported significant decreases in EAAT2 mRNA expression in the prefrontal cortex and parahippocampal gyrus in postmortem schizophrenic brains. Previously, a haplotype association between SLC1A2 and Japanese patients with schizophrenia was reported. In this study, we reinvestigated the association between SLC1A2 and schizophrenia by performing a case–control association study with twice as many subjects (401 cases and 407 controls) as compared to a previous study, and especially focused on the region where a previous association with schizophrenia had been shown. Our current results failed to show any significant association with schizophrenia in individual single nucleotide polymorphisms (SNPs), two- and three-SNP-based haplotypes, or with possible pairwise haplotype analysis. SCL1A2 appears not to be a genetic risk factor for schizophrenia.     

Genetic association between the dopamine D3 gene polymorphism (Ser9Gly) and schizophrenia in Japanese populations: evidence from a case-control study and meta-analysis

Dysregulation in the dopaminergic system has been implicated in the pathophysiology of schizophrenia (SCZ). Dopamine D3 receptors (DRD3) concentrated in limbic regions of the brain (important for cognitive, emotional and endocrine function) may be particularly relevant to SCZ. A recent meta-analysis with mixed ethnicities reported a marginal significant association between the Ser9Gly homozygosity in the first exon of the DRD3 gene and SCZ. To further evaluate the controversial association between this polymorphism and SCZ, a case–control study and meta-analysis was conducted using the homogeneous Japanese population. In our Japanese case–control sample (246 cases/198 controls), we found an association between the DRD3 Ser9Gly polymorphism and SCZ (genotype: χ² = 9.76, d.f. = 2, p = 0.008; Ser allele versus Gly allele: χ² = 7.96, d.f. = 1, p = 0.0048; OR = 0.65; 95% CI = 0.48–0.88). However in a meta-analysis of nine Japanese case–control studies comprising 2056 subjects the association between DRD3 Ser9Gly polymorphism and SCZ did not persisted. The Mantel–Haenszel pooled OR for SCZ among carriers of the DRD3 Ser9Gly homozygosity (Ser/Ser homozygotes and Gly/Gly homozygotes) of the nine Japanese studies was 1.16 (95% CI 0.97–1.39), pointing to a non-significant effect of the DRD3 Ser9Gly homozygosity as a risk factor for SCZ. Overall, our results suggest that the DRD3 Ser9Gly polymorphism may not confer susceptibility to SCZ in the Japanese population. Given that the Ser9Gly variant may play a putative role in DRD3 function, further studies on the DRD3 with linked variants are warranted.