Rare genotype combination of the serotonin transporter gene associated with treatment response in severe personality disorder.

The insertion deletion (ins/del) polymorphism of the serotonin transporter gene (5-HTTLPR) has been associated with several psychiatric phenotypes and antidepressant's response. We investigated, in a large cohort of 5,608 controls and subjects suffering from various psychiatric disorders, the frequency of haplotypes and corresponding genotypes combining the 5-HTTLPR and the other serotonin transporter promoter functional variant (rs25531). We showed that rs25531 lies 18 bp 5' to the site where the 43 bp (and not 44 bp as previously described) ins/del defines the 14- and 16-repeat alleles. These polymorphisms should therefore be considered as four alleles instead of a triallelic unique locus. The very rare G-14/G-16 genotype was carried on by only three subjects. These are women with a history of suicide attempt with a psychiatric history strongly suggesting a borderline personality disorder. Two of them have shown a non-response to serotoninergic antidepressant. Interestingly, in one of them was observed a spectacular response after the introduction of bupropion. The genotyping droved our therapeutic approach, by preferring a dopaminergic over a serotoninergic agent. This study highlights the usefulness of studying very rare clinical cases as well as rare variants, in order to deal with the biological heterogeneity of spectral disorders. © 2010 Wiley-Liss, Inc.

The monoamine oxidase A gene may influence the means used in suicide attempts.

OBJECTIVE: Compelling evidence suggests that serotonin system dysfunction is associated with certain behavioral disorders, including suicidal behavior and impulsive aggression. A functional polymorphism in the promoter region of the monoamine oxidase A gene (uVNTR) was recently identified and the presence of the 2-3 alleles was found to be associated with a higher level of transcription, central nervous system serotonergic responsivity and impulsive aggression. A dinucleotide repeat in intron 2 of the gene (monoamine oxidase A-CAn) has been described previously, and is in linkage disequilibrium with the variable number of tandom repeats (VNTR). The aim of the study was to investigate, in a large sample, whether the monoamine oxidase A gene was involved in the susceptibility to suicidal behavior. METHODS: We genotyped 738 West European Caucasians, who had made suicide attempts, and 222 controls of the same ethnic origin, with no history of suicidal behavior. The two variants of the monoamine oxidase A gene have been tested. RESULTS: We did not find any association between the two monoamine oxidase A gene variants and suicidal behavior. However, the frequency of the uVNTR 2-3 alleles was significantly higher in men who had attempted suicide by violent means than in men who had used non-violent means. The odds ratio for the uVNTR 2-3 alleles versus the uVNTR 1-4 alleles was 2.17 [95% confidence interval (1.08-4.35)]. Haplotypes did not allow strengthening the effect observed with the uVNTR. CONCLUSION: These results suggest that an excess of high-activity monoamine oxidase A gene promoter alleles may be associated with traits orienting suicidal behavior towards a violent act.

Temperament personality profiles in suicidal behaviour: an investigation of associated demographic, clinical and genetic factors.

BACKGROUND: Personality traits have been suggested as possible risk factors for suicidal behaviours. Cloninger's model of personality (TCI), given its neurobiological background, might provide an ideal tool for the identification of dimensions associated with suicide attempt. METHODS: A number of 1333 suicide attempters and 589 non-suicide attempters suffering from different DSM-IV Axis I disorders were assessed using either the temperament and character inventory (TCI) or the tridimensional personality questionnaire (TPQ), as well as other self-report questionnaires evaluating dimensions associated with suicidal behaviour, such as impulsivity and anger traits. The severity of suicide attempts and the methods used were also assessed. Subjects were genotyped for polymorphisms within the key genes involved in monoaminergic pathways and the HPA axis. RESULTS: Compared with non-suicide attempters, suicide attempters scored higher for harm avoidance (HA) and novelty seeking (NS), and lower for self-directedness (SD). The difference was independent of Axis I disorders. Higher HA and NS scores were associated with a greater severity of suicidal behaviour. A multivariate model showed that HA was the single temperamental dimension independently related to suicide attempt history, beside impulsivity and anger-related traits. The genetic factors investigated did not play a significant role in modulating these temperamental dimensions. LIMITATIONS: The TCI was available for only half of the sample. CONCLUSIONS: Early detection of subjects displaying high HA and low SD, associated with high impulsivity and poor anger control, may help to prevent suicidal behaviours. Physicians should therefore be aware of these risk factors so that they can offer the best primary care intervention.

Impulsivity, aggression and suicidal behavior in unipolar and bipolar disorders.

BACKGROUND: Predictors of suicidal behaviors (SB) in bipolar (BD) and major depressive disorder (MDD) patients are poorly understood. It has been recognized that behavioral dysregulation characterizes SB with traits of impulsivity and aggression being particularly salient. However, little is known about how these traits are segregated among mood disorder patients with and without a history of suicide attempt (SA). METHODS: This article aims to compare impulsivity and aggression between 143 controls, 138 BD and 186 MDD subjects with or without a history of SA. RESULTS: BD and MDD patients showed higher impulsivity scores (BIS-10 = 57.9 vs. 44.7, p < 0.0001) and more severe lifetime aggression than controls (Lifetime History of Aggression = 7.3 vs. 3.9, p < 0.0001). Whereas impulsivity helped to distinguish MDD subjects without a history of SA from those with such a history, this was not the case in BD subjects where no difference in impulsive traits was observed between BD without and with history of SA (57.2 vs. 63.2 for BIS-10; p = 0.259). Impulsive and aggressive traits were strongly correlated in suicide attempters (independently of the diagnosis) but not in non-suicide attempters. LIMITATIONS: Dimensional traits were not characterized at different stages of illness. CONCLUSIONS: Impulsivity, as a single trait, may be a reliable suicide risk marker in MDD but not in BD patients, and its strong correlation with aggressive traits seems specifically related to SB. Our study therefore suggests that the specific dimension of impulsive aggression should be systematically assessed in mood disorder patients to address properly their suicidal risk.

Genetic linkage study of an autosomal recessive form of juvenile myoclonic epilepsy in a consanguineous Tunisian family.

Juvenile myoclonic epilepsy (JME) is the most common idiopathic generalized epilepsies (IGEs), affecting 12-30% of all epilepsies in medical centers. To date genetic linkage studies have revealed putative loci on different chromosomes, but these findings are still inconclusive about which gene precisely is responsible for the disease. Here, we report the genetic and clinical analysis of a (JME) consanguineous Tunisian family with four affected children out of eight. A genome-wide search was carried out by using the Affymetrix GeneChip Mapping 500K NspI chip. Pairewise logarithm of the odds (LOD) scores were calculated with MERLIN (1.1) assuming an autosomal recessive model, and a complementary homozygous mapping analysis was performed with AutoSNPa software. The genome-wide parametric linkage analysis showed suggestive linkage to chromosome 2q. Interactive visual analysis of SNP data using AutoSNPa revealed two large regions of shared homozygosity by descent on 2q23.3 and on 2q24.1. We decided to sequence the exons of the two genes coding for such proteins located in 2q23.3, CACNB4 and 2q24.1, KCNJ3. No nucleotide variation--comprising the previously reported mutations--was detected.

No association between non-violent suicidal behavior and the serotonin transporter promoter polymorphism.

There is compelling evidence that suicidal behavior is associated with the dysfunction of the serotonin system. A functional polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) was recently identified and the presence of the short allele was associated with lower gene expression, lower 5-HT uptake and violent suicidal behavior. Thus, we attempted to determine whether 5-HTTLPR is also involved in the susceptibility to non-violent suicidal behavior. We compared the genotype from 166 West European Caucasians who attempted suicide by a non-violent mean with 139 controls with no history of suicidal behavior from the same ethnic origin. The frequencies of the S allele and the SS genotype in the sample who attempted non-violent suicide were not statistically different to those in the controls. Thus, the genetically altered expression of the 5-HT transporter might be associated with more severe or violent suicidal behavior, but not with non-violent suicidal behavior.