No evidence for an association of the CTLA4 gene with bipolar I disorder

The purpose of the present paper was to investigate the relationship between the first exon at position +49 (A/G) polymorphism of the cytotoxic T lymphocyte antigen 4 (CTLA4) gene and bipolar disorder. Among the Korean patients diagnosed with bipolar disorder according to Diagnostic and Statistical Manual of Mental Disorders (4th edn; DSM-IV), 90 patients without serious medical illness, neurologic illness, hormonal disorder, or concomitant mental illness were selected. The normal control group consisted of 149 age- and sex-matched subjects without current or past history of autoimmune diseases or mental disorder. DNA was extracted from peripheral blood using proteinase K; and the exon 1 region of the CTLA4 gene was amplified by polymerase chain reaction. Gene typing was performed using single strand conformation polymorphism. There were no significant differences in genotype frequencies of CTLA4*G/G, CTLA4*G/A, and CTLA4*A/A between the patients with bipolar disorder and the control group (48.9% vs 46.3%, 44.4% vs 39.6%, and 6.7% vs 14.1%, respectively). There were no significant differences in allelic frequencies of CTLA4*G and CTLA4*A between the patients with bipolar disorder and the control group (71.1% vs 66.1%; 28.9% vs 33.9%, respectively). In the present study an association was not found of exon 1 (+49) polymorphism of CTLA4 gene with bipolar disorder in the Korean population.     

Investigating the association between neurocognition and psychosis in bipolar disorder: further evidence for the overlap with schizophrenia

Objectives: In schizophrenia, a distinction is made between psychosis with developmental and cognitive impairment on the one hand and psychosis without developmental impairment and positive symptoms on the other. In this study, we investigated whether this model can be extended to bipolar disorder by testing the hypothesis that neurocognitive functioning is inversely related to positive psychotic symptoms in bipolar disorder. Methods: Neurocognitive functioning and psychopathology were assessed in (i) 76 patients with bipolar disorder, (ii) 39 of their healthy first‐degree relatives, and (iii) 61 healthy controls. Cognitive performance of bipolar patients and their first‐degree relatives was investigated, taking into account the possible moderating effect of the level of expression of psychosis in patients and relatives. Results: Bipolar patients showed impaired cognitive performance on multiple cognitive domains, whereas performance of their relatives was comparable to that of controls. A history of psychotic symptoms in patients was suggestive of less likelihood of cognitive alterations in relatives, and the presence of subclinical psychotic symptoms within the group of relatives predicted better cognitive performance. Conclusions: The finding of similar psychosis‐cognition associations in bipolar disorder as implied by the two pathways leading to nonaffective psychotic disorders suggests that this model might be extended to the continuum spanning affective and nonaffective psychosis. This is in line with the idea of a partially overlapping vulnerability to bipolar disorder and schizophrenia and provides an explanation for the apparent differences in cognitive alterations in those at risk for the two disorders.     

Association of promoter variants of human dopamine transporter gene with schizophrenia in Han Chinese

ObjectiveAlthough dopamine was implicated in the etiology of schizophrenia, the human dopamine transporter gene (DAT1; SLC6A3) has not consistently been associated with schizophrenia. The purpose of this study was to examine whether six polymorphisms within the DAT1 gene are associated with schizophrenia.MethodsSix polymorphisms of the DAT1 gene (3 SNPs [rs6413429, rs2652511, and rs2975226] in the promoter region, one SNP [rs6347] in exon 9, and one SNP [rs27072]/one variable number tandem repeat [VNTR] in exon 15) were analyzed in 352 Chinese patients with schizophrenia and in 311 healthy controls. Pretreatment psychopathology was assessed using the Positive and Negative Syndrome Scale in a subset of 160 hospitalized schizophrenia patients who were drug-free or drug-naïve.ResultsA statistically significant difference in two polymorphisms (rs2652511 and rs2975226) and a promoter region haplotype (rs2652511, rs2975226, and rs6413429) was found between patients and healthy controls. No association with schizophrenia was found for other polymorphisms and another haplotype (3′ region). Symptoms severity (PANSS global, positive, negative and general symptoms scores) was similar regardless of DAT1 polymorphism.ConclusionThe promoter region of the DAT1 gene may play a role in increasing susceptibility to schizophrenia, but does not affect the severity of psychotic symptoms in Han Chinese.     

Identification of rare high-risk copy number variants affecting the dopamine transporter gene in mental disorders

Background: The dopamine transporter, also known as solute carrier 6A3 (SLC6A3), plays an important role in synaptic transmission by regulating the reuptake of dopamine in the synapses. In line with this, variations in the gene encoding this transporter have been linked to both schizophrenia and affective disorders. Recently, copy number variants (CNVs) in SLC6A3 have been identified in healthy subjects but so far, the implication of CNVs affecting this gene in psychiatric diseases has not been addressed. Aims: In the present study, we aimed to investigate whether CNVs affecting SLC6A3 represent rare high-risk variants of psychiatric disorders. Methods: We performed a systematic screening for CNVs affecting SLC6A3 in 761 healthy controls, 672 schizophrenia patients, and 194 patients with bipolar disorder in addition to 253 family members from six large pedigrees affected by mental disorders using single nucleotide polymorphism arrays and subsequent verification by real-time polymerase chain reaction. Results: We identified two duplications and one deletion affecting SLC6A3 in the patients, while no such CNVs were identified in any of the controls. The identified CNVs were of different sizes and two affected several genes in addition to SLC6A3. Conclusion: Our findings suggest that rare high-risk CNVs affecting the gene encoding the dopamine transporter contribute to the pathogenesis of schizophrenia and affective disorders.     

Serotonin transporter gene polymorphism and its association with bipolar disorder across different ethnic groups in Malaysia

ObjectivesThe risk variants have been shown to vary substantially across populations and a genetic study in a heterogeneous population might shed a new light in the disease mechanism. This preliminary study aims to determine the frequency of the serotonin transporter gene polymorphism (5-HTTLPR) in the three main ethnic groups in Malaysia and its association with bipolar disorder.MethodsThis is a candidate gene association study of randomly selected forty five unrelated bipolar disorder probands and sixty six controls. Diagnosis was evaluated using the Mini International Neuropsychiatric Interview (M.I.N.I). The control group consisted of healthy volunteers without personal psychiatric history and family history of mood disorder. Patients' whole blood was collected for genotyping.ResultsThis study revealed that the frequency of the short variant of 5-HTTLPR in healthy control group was highest in Indians (42.9%) followed by Malays (23.5%) and was absent in Chinese. The association between the homozygous ss genotype of the 5-HTTLPR polymorphism with bipolar disorder was not found in the pooled subjects (χ² = 1.52, d.f. = 1, p = 0.218, OR = 4.67, 95% C.I. = 0.69–7.58) and after stratification into Malays (p = 0.315, OR = 2.03, 95% CI = 0.50–8.17), Indians (p = 0.310; OR = 0.44, 95% CI = 0.21–0.92) and Chinese.ConclusionThe differences in the frequency of the short allele of 5-HTTLPR across the three main ethnic groups in Malaysia were noteworthy. The present study showed no significant association between the homozygous short variant of the 5-HTTLPR and bipolar disorder in the pooled subject and after stratification into the three main ethnic groups in Malaysia.     

A polymorphism of the norepinephrine transporter gene in bipolar disorder and schizophrenia: lack of association

Norepinephrine is one of the neurotransmitters which has been implicated in the pathogenesis of mood disorders and schizophrenia. The norepinephrine transporter (NET) gene may be a candidate gene for the study of the genetics of these disorders. In this study, 198 patients with schizophrenia and 100 patients with bipolar disorder were analysed for a silent mutation 1287 A/G, located in the coding region (exon 9) of the NET gene, to determine the association between this polymorphism of the NET gene and bipolar disorder or schizophrenia. No association was found between the studied polymorphism of the NET gene and either bipolar disorder or schizophrenia.     

Identification of a novel polymorphism of the human dopamine transporter (DAT1) gene and the significant association with alcoholism

Human dopamine transporter gene (DAT1) has a variable number of tandem repeats (VNTR) in its 3'-untranslated region (UTR). The association between the VNTR polymorphism and neuropsychiatric disorders has been studied, but their relationship is still unclear. Here we identified a novel polymorphism in the 3'-UTR of the DAT1 gene, G2319A, and a significant association between the polymorphism and alcoholism was observed in both genotypic and allelic frequencies (P = 0.040 and 0.019, extended Fisher's exact test, respectively). There was a significant gene dose effect on the risk for alcoholism associated with the 2319-A allele (chi2 = 6.16, df = 2, P = 0.046, linearity tendency test: Cochranq-Armitage analysis). Moreover, in the haplotype analysis with G2319A- and VNTR-polymorphisms, a positive gene dose efffect on the risk with the A10 allele (P = 0.044, linearity tendency test) and a negative gene dose effect with the G10 allele (P = 0.010, linearity tendency test) for alcoholism were significantly detected. Odds ratio for alcoholism with the A10 and G10 alleles were 1.76 (1.12-2.76) and 0.53 (0.32-0.79), respectively. These results indicate that the DAT1 gene may confer vulnerability to alcoholism.     

A dopamine transporter mutation associated with bipolar affective disorder causes inhibition of transporter cell surface expression

The dopamine transporter (DAT) plays a crucial role in dopaminergic neurotransmission as it clears the extracellular space of dopamine (DA) and thus controls the concentration of active neurotransmitter. Genetic association studies have reported a variable number of tandem repeat polymorphisms in the 3'-noncoding region of the DAT gene implicating this protein in the development of various psychiatric disorders. In a sample of bipolar patients, two rare missense substitutions (A559V and E602G) have been identified, one of which (E602G) was inherited by the patient from her affected father. None of these mutations had been identified in any control subjects of this survey. Using a heterologous cellular expression system, we have analysed possible consequences of these mutations on functional properties of the encoded DAT protein. DA transport measurements and antagonist binding revealed that the A559V mutant protein is fully functional, whereas the E602G mutant is not. Further analyses by confocal microscopy showed that the E602G protein is transcribed and translated but not delivered to the cell surface. Taken together, our results suggest that this missense mutation has functional consequences thus supporting the need to screen larger samples of patients and their relatives for this rare but bipolar disorder-associated mutation in the DAT gene.     

A family-based and case-control association study of the dopamine D4 receptor gene and dopamine transporter gene in attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is a highly heritable psychiatric condition of early childhood onset characterised by marked inattention, hyperactivity and impulsiveness. Molecular genetic investigations of ADHD have found positive associations with the 480-bp allele of a VNTR situated in the 3' untranslated region of DAT1 and allele 7 of a VNTR in exon 3 of DRD4. A number of independent studies have attempted to replicate these findings but the results have been inconsistent. We used both family-based and case control approaches to examine these polymorphisms in a sample of 137 children diagnosed with ICD-10, DSM-IV or DSM-III-R ADHD. We found no evidence of association with the DAT1 polymorphism, despite a sample size that has up to 80% power to detect a previously reported effect size. We observed a significant increase in the DRD4 7 repeat allele amongst ADHD probands (21.7%) and their parents (18.9% in mothers, 22.3% in fathers), compared to ethnically matched controls (12.8%). However TDT analysis showed no preferential transmission of allele 7 to ADHD probands.     

No evidence of association from transmission disequilibrium analysis of the hKCa3 gene in bipolar disorder

Objective: A recent case–control study has suggested that modest enlargements of a highly polymorphic CAG repeat in exon 1 of the gene encoding potassium channel hKCa3 may be associated with bipolar disorder (BPD). We have examined this hypothesis by genotyping this locus in a family-based association study.

Method: One hundred and twenty-eight parent–offspring trios of British Caucasian origin were examined where the proband was diagnosed with the American Psychiatric Association's Diagnostic and Statistical Manual (DSM)-IV BPD I (n=123) or II (n=5). An improved assay was used, with redesigned polymerase chain reaction (PCR) primers, permitting quicker and higher resolution genotyping. The resultant genotypes were analysed using the extended transmission/disequilibrium test (ETDT).

Results: The experimental data did not provide evidence for the preferential transmission of large alleles to bipolar cases (χ2=11.12, df=10, p=0.349).

Conclusions: Our data provide no support for the hypothesis that variation at the hKCa3 gene contributes to susceptibility to BPD.     

Stroop performance in bipolar disorder: further evidence for abnormalities in the ventral prefrontal cortex

OBJECTIVES: Bipolar patients are impaired in Stroop task performance, a measure of selective attention. Structural and functional abnormalities in task-associated regions, in particular the prefrontal cortex (PFC), have been reported in this population. We aimed to examine the relationship between functional abnormalities, impaired task performance and the severity of depressive symptoms in bipolar patients. METHODS: Remitted bipolar patients (n = 10; all medicated), either euthymic or with subsyndromal depression, and age-matched control subjects (n = 11) viewed 10 alternating blocks of incongruent Stroop and control stimuli, naming the colour of the ink. Neural response was measured using functional magnetic resonance imaging. We computed between-group differences in neural response and within-group correlations with mood and anxiety. RESULTS: There were no significant between-group differences in task performance. During the Stroop condition, controls demonstrated greater activation of visual and dorsolateral and ventrolateral prefrontal cortical areas; bipolar patients demonstrated relative deactivation within orbital and medial prefrontal cortices. Depression scores showed a trend towards a negative correlation with the magnitude of orbitofrontal cortex deactivation in bipolar patients, whereas state anxiety correlated positively with activation of dorsolateral PFC and precuneus in controls. CONCLUSIONS: Our findings confirm previous reports of decreased ventral prefrontal activity during Stroop task performance in bipolar patients, and suggest a possible negative correlation between this and depression severity in bipolar patients. These findings further highlight the ventromedial PFC as a potential candidate for illness related dysfunction in bipolar disorder.     

Analysis of 10 independent samples provides evidence for association between schizophrenia and a SNP flanking fibroblast growth factor receptor 2

We and others have previously reported linkage to schizophrenia on chromosome 10q25-q26 but, to date, a susceptibility gene in the region has not been identified. We examined data from 3606 single-nucleotide polymorphisms (SNPs) mapping to 10q25-q26 that had been typed in a genome-wide association study (GWAS) of schizophrenia (479 UK cases/2937 controls). SNPs with P<0.01 (n=40) were genotyped in an additional 163 UK cases and those markers that remained nominally significant at P<0.01 (n=22) were genotyped in replication samples from Ireland, Germany and Bulgaria consisting of a total of 1664 cases with schizophrenia and 3541 controls. Only one SNP, rs17101921, was nominally significant after meta-analyses across the replication samples and this was genotyped in an additional six samples from the United States/Australia, Germany, China, Japan, Israel and Sweden (n=5142 cases/6561 controls). Across all replication samples, the allele at rs17101921 that was associated in the GWAS showed evidence for association independent of the original data (OR 1.17 (95% CI 1.06-1.29), P=0.0009). The SNP maps 85 kb from the nearest gene encoding fibroblast growth factor receptor 2 (FGFR2) making this a potential susceptibility gene for schizophrenia.     

Meta-analysis of the association of serotonin transporter gene polymorphism with obsessive-compulsive disorder

Evidence has supported a role for serotonin system dysfunction in the pathogenesis of the obsessive-compulsive disorder (OCD). Many studies examined the association between OCD and a functional polymorphism of the serotonin transporter gene promoter (5-HTTLPR) but yielded inconsistent results. Current study aimed to determine conclusively whether there is an association by using a meta-analytic method. Over 3000 subjects from 13 independent case-control association studies were included in the analysis. By using random effects model, data from these studies were pooled to compare the genotypes and allelic distribution of the 5-HTTLPR polymorphism between OCD patients and control subjects. In the analysis, OCD was found to be associated with the SS homozygous genotype (OR=1.21, p=0.04), but was inversely associated with the LS heterozygous genotype (OR=0.79, p=0.03). No association with the LL homozygous genotype or the allelic distribution was found. These results suggest that variations of the serotonin transporter gene influence the risk of OCD, but their functional roles in the pathogenesis of OCD need to be elucidated.     

Age at onset in bipolar I affective disorder: further evidence for three subgroups

OBJECTIVE: Preliminary data suggested that there are three subgroups of bipolar affective disorder based on age at onset. The authors sought to replicate those findings and determine the cut-off age of each subgroup. METHOD: Admixture analysis was used to determine the best-fitting model for the observed ages at onset of 368 consecutively admitted patients. The results obtained were compared with those of the previously described model. The authors also investigated whether affected siblings are more likely to belong to the same theoretical age-at-onset subgroup as identified by admixture analysis. RESULTS: The existence of three subgroups defined by age at onset was confirmed. The mean ages estimated in this model were 17.4 years (SD=2.3), 25.1 years (SD=6.2), and 40.4 years (SD=11.3). Affected siblings were more likely to belong to the same theoretical subgroup. CONCLUSIONS: There are three age-at-onset subgroups of bipolar patients, and specific familial vulnerability factors might underlie each subgroup.     

A preliminary report of the dopamine receptor D4 and the dopamine transporter 1 gene polymorphism and its association with attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent childhood-onset psychiatric syndromes affecting 5%–10% of school-age children worldwide. Distortions in the catecholaminergic system seem to be responsible for this condition. Within this system there are several candidate genes, the dopamine receptor D₄ (DRD4) and the dopamine transporter 1 (DAT1), with common polymorphism which might be associated with ADHD. We performed a family based association study with 36 trios and 19 parent proband pairs. All diagnoses were confirmed by the “Hypescheme” diagnostic computer program. In this study we did not observe an association of ADHD with DRD4 and DAT1 polymorphism neither by the haplotype relative risk (HRR) method nor by the transmission disequilibrium test (TdT) method. The odds ratio for the DRD4 7-allele was 1.01 and 0.94 for both statistical tests, respectively, and the respective odds ratio for the DAT1 6-allele were 0.91 and 0.88.     

Association and linkage of allelic variants of the dopamine transporter gene in ADHD

Previously, we had reported a genome-wide scan for attention-deficit/hyperactivity disorder (ADHD) in 102 families with affected sibs of German ancestry; the highest multipoint LOD score of 4.75 was obtained on chromosome 5p13 (parametric HLOD analysis under a dominant model) near the dopamine transporter gene (DAT1). We genotyped 30 single nucleotide polymorphisms (SNPs) in this candidate gene and its 5' region in 329 families (including the 102 initial families) with 523 affected offspring. We found that (1) SNP rs463379 was significantly associated with ADHD upon correction for multiple testing (P=0.0046); (2) the global P-value for association of haplotypes was significant for block two upon correction for all (n=3) tested blocks (P=0.0048); (3) within block two we detected a nominal P=0.000034 for one specific marker combination. This CGC haplotype showed relative risks of 1.95 and 2.43 for heterozygous and homozygous carriers, respectively; and (4) finally, our linkage data and the genotype-IBD sharing test (GIST) suggest that genetic variation at the DAT1 locus explains our linkage peak and that rs463379 (P<0.05) is the only SNP of the above haplotype that contributed to the linkage signal. In sum, we have accumulated evidence that genetic variation at the DAT1 locus underlies our ADHD linkage peak on chromosome 5; additionally solid association for a single SNP and a haplotype were shown. Future studies are required to assess if variation at this locus also explains other positive linkage results obtained for chromosome 5p.