Lack of association between variations in the melanocortin 5 receptor gene and bipolar disorder

OBJECTIVE: The melanocortin 5 receptor gene maps to the bipolar susceptibility locus on chromosome 18p11.2. Given the biological role of melanocortins and their influence on the hypothalamic-pituitary-adrenal axis, the melanocortin 5 receptor gene is a plausible candidate gene for bipolar disorder. We tested the hypothesis that the potential functional variation Phe209Leu confers susceptibility to bipolar disorder in a case-control study. METHODS: Genotypes for two variations in the coding region and one variation approximately 7 kb upstream from the coding region were obtained from 345 unrelated bipolar I patients and 275 control samples. Genotypes and allele frequencies were compared between groups using chi(2) contingency analysis. RESULTS: Allele frequencies of the Phe209Leu polymorphism did not differ significantly between bipolar patients and controls (P=0.679). Allele frequencies of the C744T and the intergenic A/G polymorphism did not differ significantly between bipolar patients and controls. All variations were in strong linkage disequilibrium. CONCLUSION: Variations in the melanocortin 5 receptor gene are unlikely to confer susceptibility to bipolar disorder in this sample. Further studies are required to elucidate the susceptibility locus for bipolar disorder on chromosome 18p11.     

Lack of genetic association between the phospholipase A2 gene and bipolar mood disorder in a European multicentre case-control study

The possible association between phospholipase A2 gene and bipolar mood disorder was examined in 557 bipolar patients and 725 controls (all personally interviewed), recruited from seven countries (Belgium, Bulgaria, Croatia, Germany, Greece, Italy, and UK). The frequencies of the eight alleles that were identified did not differ between patients and control individuals in the whole population, while the power to detect an association based on our sample was relatively high. Some differences were noted among the various ethnic groups, but no significant trends existed, suggesting that population stratification by country may not be responsible for a type II error. On the basis of these results, mutations of the phospholipase A2 gene, at least in the region close to the polymorphism examined between exons 1 and 2, are not involved in the pathogenesis of bipolar mood disorder.     

Lack of association between the corticotrophin-releasing hormone receptor 2 gene and panic disorder

Panic disorder is classified as an anxiety disorder and affects 1-3% of the population. An individual suffering from such a disorder may experience unexpected recurrent panic attacks and fear of future attacks. Twin and family studies have pointed towards a strong heritability of the disorder. Stress response and anxiety are thought to be mediated, at least in part, by the corticotrophin-releasing hormone (CRH), which is known to be a regulator of the hypothalamic-pituitary-adrenal pathway. To search for markers conferring genetic susceptibility to panic disorder, we typed three polymorphisms of the CRHR2 gene - CRHR2(CA), CRHR2(GT), and CRHR2(GAT) - in 466 individuals, 183 of whom had DSM-IV panic disorder. Seventy-five case-controls and 101 triad families plus 13 siblings were examined. Case-control association analyses using chi(2) tests yielded no difference in the distribution of the alleles. Linkage analysis using the Transmission Disequilibrium Test showed no preferential transmission of alleles for any of the three markers. Haplotype analysis indicated that allele 7 of CRHR2 (GAT) and 8 of CRHR2 (GT) are in almost complete linkage disequilibrium (P = 0.000 000 1). Although both neurobiology and chromosomal location point to the CHRH2 receptor gene as a candidate for panic disorder, our study indicates that the CRHR2 polymorphisms examined do not confer susceptibility to panic disorder. Further studies investigating additional polymorphisms in this gene and other components of the CRH signalling system may prove useful.     

A weak association between TH and DRD2 genes and bipolar affective disorder in a Spanish sample.

Genetic factors play an important role in the aetiology of bipolar affective disorder (BP). So far, results of linkage studies have been largely disappointing. We have searched for a possible association between polymorphic DNA markers of two candidate genes (tyrosine hydroxylase, TH; dopamine D2 receptor gene, DRD2) and BP in a population from central Spain. Our results are consistent with the existence of a weak association between these two genes and BP, in such a way that TH and DRD2 could be considered as minor genes contributing to susceptibility.     

Lack of association between bipolar disorder and tyrosine hydroxylase

Tyrosine hydroxylase (TH) is a candidate gene extensively explored in several association studies of bipolar disorder (BD). However, because of conflicting results of independent studies and low statistical power of individual studies to detect small differences between cases and controls, reliable conclusions are difficult to formulate. A method to obtain more reliable conclusions about the involvement of the TH locus in the etiology of BD is meta-analysis. We undertook a meta-analysis of studies that investigated the association between BD and TH genetic markers. The studies were identified by means of computerized searches of several databases, and the scanning of review articles and the reference lists of the primary articles identified. More than 60 publications were reviewed, and 9 relevant articles were included in this meta-analysis, with an overall sample of 1,069 subjects (547 cases and 522 normal controls). The overall odds ratio (and confidence interval) based on combining the results of the studies was 1.02 (0.68–1.54). Test of the null hypothesis that the mean log odds ratio equals zero (χ² = 0.11; 5 df; P > 0.05) indicated that there was no overall association between bipolar disorder and tyrosine hydroxylase. Am. J. Med. Genet. 74:348–352, 1997. © 1997 Wiley-Liss, Inc.     

Lack of an association between 5‐HT1A receptor gene structural polymorphisms and suicide victims

A serotonergic dysfunction in the brain has been reported to be involved in suicidal behavior independently of the presence of a specific psychiatric disorder. Serotonin 1A (5‐HT_1A) receptors are known to be located on serotonergic nerve terminals and to be involved in the presynaptic regulation of serotonin release. Genetic factors partly explain the risks for suicide, and a suicide completion group is thought to be more uniform than a suicide attempt group. To explore the hypothesis that the 5‐HT_1A receptor‐induced serotonergic dysfunction is implicated genetically in suicide, we focused on the structural polymorphisms, Pro16Leu and Gly272Asp, of the 5‐HT_1A receptor gene, and examined the association between suicide victims who completed suicide and these two polymorphisms. In both polymorphisms, we found no significant difference in genotype distribution or allele frequencies between suicide victims and controls. These findings suggest that neither of these two polymorphisms is associated with suicide victims and it is unlikely that the 5‐HT_1A receptor gene is implicated in the susceptibility to suicide. © 2002 Wiley‐Liss, Inc.     

A European multicenter association study of HTR2A receptor polymorphism in bipolar affective disorder

The available data on the role of 5-HT in a variety of behaviors support the hypothesis that a dysfunction in brain serotoninergic system activity contributes to vulnerability to major depression. The diversity in the electrophysiological actions of 5-HT in the central nervous system can now be categorized according to receptor subtypes and their respective effector mechanisms. In particular, the implication of central postsynaptic 5-HT2A receptor in affective disorders has been supported by findings consistent with the hypothesis of 5-HT2A receptor up-regulation in depression. For these reasons, the 5-HT2A receptor (HTR2A) gene can be considered as a candidate gene in bipolar affective disorder (BPAD). We tested the possible genetic contribution of the polymorphic DNA variation T102C in exon 1 of HTR2A (chromosome 13q14-21) gene in a large European multicentric case-control sample. Allele and genotype frequencies, as well as homo-heterozygote distributions were compared between the two groups of 309 bipolar affective disorder patients and 309 matched controls. No significant differences were observed in the allelic and genotypic (also for homo-heterozygote) distribution between BPAD and controls. These results indicate that, in our sample, the 5-HT2A receptor polymorphism studied is unlikely to play a major role in the genetic susceptibility to BPAD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:136-140, 2000.     

Lack of association of dopamine D4 receptor gene polymorphisms with ADHD subtypes in a population sample of twins.

Attention-deficit hyperactivity disorder (ADHD) is a common, highly heritable syndrome of childhood characterized by problems with inattention, hyperactivity, and impulsivity. A variety of case control and family-based transmission distortion genetic studies of ADHD have focused on the possible involvement of polymorphisms of the DRD4 receptor gene. The majority of studies have examined the association of variously defined ADHD with an exon 3 polymorphism containing a variable number of imperfect 48 base pair repeats. Recently, McCracken et al. [2000: Mol Psych 5:531-536] reported an association of the DSM-IV primarily inattentive ADHD subtype with a 5' 120 base pair repeat polymorphism in the DRD4 gene. In this report, we test for the possible association of these two polymorphisms with population-derived samples of DSM-IV ADHD subtypes. Furthermore, we extend previous studies by testing for associations with ADHD subtypes derived from latent-class analysis of interview responses. In contrast to most, but not all, previous studies, we failed to demonstrate any significant association of the exon 3 7-repeat allele with ADHD. Nor did we replicate the association of the 5'120 base pair repeat polymorphism. We do find a significant association of the exon 3 3-repeat allele with a novel talkative/impulsive latent-class-defined subtype of ADHD.     

No association between 5HT-2A and bipolar disorder irrespective of genomic imprinting.

Recent evidence that 5HT-2A may be subjected to genomic imprinting prompted us to examine a collection of Irish family trios (an affected individual and both parents) for evidence of an association between 5HT-2A and bipolar disorder. Family trios offer an advantage over case control studies in regard to genomic imprinting since with family trios it is possible to trace the path of alleles from the parents to the offspring. Using haplotype-based haplotype relative risk (HHRR) and transmission/disequilibrium (TDT) analyses, no evidence was found for an association of 5HT-2A with bipolar affective disorder under the assumption of no imprinting and of imprinting.     

No association between genetic variants at the GRIN1 gene and bipolar disorder in a German sample

Disturbed glutamatergic neurotransmission has been implicated in the pathogenesis of schizophrenia and bipolar disorder, with the N-methy-D-aspartate receptors being in the focus of research. The NR1 subunit, which is encoded by the gene GRIN1, plays a key role in the functionality of N-methy-D-aspartate receptors. We tested the association between GRIN1 and bipolar disorder in a sample of German descent, consisting of 306 bipolar disorder patients and 319 population-based controls. No significant association was found. In accordance with our recent findings, we hypothesized that restricting case definition to individuals with a history of persecutory delusions might clarify the relationship between bipolar disorder and GRIN1. This stratified analysis did not yield any significant association either. Our results do not support an association of the GRIN1 gene with bipolar disorder in the German population.     

Alcohol use disorder and GABAB receptor gene polymorphisms in an Italian sample: haplotype frequencies,linkage disequilibrium and association studies

Background: Alcohol use disorder (AUD) is a complex trait with genetic and environmental influences. Several gene variants have been associated with the risk for AUD, including genes encoding the sub-units of the γ-aminobutyric acid (GABA) receptors.

Aim: This study evaluated whether specific single nucleotide polymorphisms (SNPs) in genes encoding GABA_B receptor sub-units can be considered as candidates for the risk of AUD.

Subjects and methods: Seventy-four AUD subjects and 128 Italian controls were genotyped for 10 SNPs in genes encoding GABA-B1 and GABA-B2 sub-units (GABBR1 and GABBR2). Allele, genotype, and haplotype frequencies were tested for the association with the AUD trait.

Results: A significant difference between AUD individuals and controls was observed at genotype level for rs2900512 of GABBR2 gene. The homozygous T/T genotype was not found in the controls, whereas it was over-represented in the AUD individuals. Under the recessive model (T/T vs C/T?+?C/C) this result was statistically significant, as well as the Odds Ratio for the association with the AUD trait.

Conclusions: The results provide preliminary data on the association between GABA_B receptor gene variation and risk of AUD. To confirm this finding, studies with larger samples and additional characterisation of the phenotypic AUD trait are required.     

Lack of association between bipolar affective disorder and tyrosine hydroxylase DNA marker

Sixty-eight patients with bipolar affective disorder and 88 controls were investigated for genetic association of tyrosine hydroxylase (TH) restriction fragment length polymorphisms (RFLPs). No significant association between bipolar affective disorder and TH was found. Thus the hypothesis that TH is involved in the pathogenesis of bipolar affective disorder was not supported. © 1993 Wiley-Liss, Inc.     

5-HT2a receptor polymorphism gene in bipolar disorder and harm avoidance personality trait

The pupose of this study was to investigate the relationship between bipolar disorder and the harm avoidance personality trait (HA), and the genetic contribution of the polymorphic DNA variation T102C in exon 1 of 5-HTR2a (chromosome 13q14-21) in bipolar disorder and HA personality trait. Forty bipolar patients and 89 normal subjects completed the TPQ questionnaire and were genotyped for 5-HT2a. Bipolar patients scored higher than normal subjects on the HA dimension. However, no contribution of the 5-HTR2a polymorphism on the bipolar disorder or on the HA personality trait emerged. Despite the limited sample size, these results exclude a major effect of the 5-HTR2a polymorphism on bipolar disorder and HA personality trait but not a minor effect.     

No association between genetic variants at the ASCT1 gene and schizophrenia or bipolar disorder in a German sample

Altered glutamatergic neurotransmission is considered a potential etiological factor of schizophrenia (SCZ) and affective disorders. The gene ASCT1 (SLC1A4) coding for a Na+-dependent neutral aminoacid transporter is a member of the glutamate transporter superfamily and is located on 2p13-14, a region showing linkage to both SCZ and bipolar disorder (BD). ASCT1 can thus be considered a candidate gene for both disorders. In a German sample, we tested for association between ASCT1 and both SCZ and BD. Allele and haplotype frequencies, however, did not differ between cases and controls. Recent findings on the associations between brainderived neurotrophic factor (BDNF) and SCZ and between G72/G30 and BD suggest that SCZ patients with a history of major depressive episodes (MDE) outside psychotic episodes and BD cases with a history of persecutory delusions constitute genetically distinct subgroups of these disorders. Thus, we hypothesized that restricting case definition to those 95 SCZ individuals with MDE and to those 107 BD patients with a history of persecutory delusions might clarify the relationship between BD, SCZ and ASCT1. However, these stratification approaches did not yield any significant association either. Allele and haplotype frequencies did not differ between cases and controls. Our results do not support an association of the ASCT1 gene with BD or SCZ in the German population.     

Lack of an association between 5-HT1A receptor gene structural polymorphisms and suicide victims

A serotonergic dysfunction in the brain has been reported to be involved in suicidal behavior independently of the presence of a specific psychiatric disorder. Serotonin 1A (5-HT1A) receptors are known to be located on serotonergic nerve terminals and to be involved in the presynaptic regulation of serotonin release. Genetic factors partly explain the risks for suicide, and a suicide completion group is thought to be more uniform than a suicide attempt group. To explore the hypothesis that the 5-HT1A receptor-induced serotonergic dysfunction is implicated genetically in suicide, we focused on the structural polymorphisms, Pro16Leu and Gly272Asp, of the 5-HT1A receptor gene, and examined the association between suicide victims who completed suicide and these two polymorphisms. In both polymorphisms, we found no significant difference in genotype distribution or allele frequencies between suicide victims and controls. These findings suggest that neither of these two polymorphisms is associated with suicide victims and it is unlikely that the 5-HT1A receptor gene is implicated in the susceptibility to suicide.