Dominique Mouthon

Increased methylation of glucocorticoid receptor gene ( NR3C1 ) in adults with a history of childhood maltreatment: a link with the severity and type of trauma

Childhood maltreatment, through epigenetic modification of the glucocorticoid receptor gene (NR3C1), influences the hypothalamic–pituitary–adrenal axis (HPA axis). We investigated whether childhood maltreatment and its severity were associated with increased methylation of the exon 1F NR3C1 promoter, in 101 borderline personality disorder (BPD) and 99 major depressive disorder (MDD) subjects with, respectively, a high and low rate of childhood maltreatment, and 15 MDD subjects with comorbid post-traumatic stress disorder (PTSD). Childhood sexual abuse, its severity and the number of type of maltreatments positively correlated with NR3C1 methylation (P=6.16 × 10−8, 5.18 × 10−7 and 1.25 × 10−9, respectively). In BPD, repetition of abuses and sexual abuse with penetration correlated with a higher methylation percentage. Peripheral blood might therefore serve as a proxy for environmental effects on epigenetic processes. These findings suggest that early life events may permanently impact on the HPA axis though epigenetic modifications of the NR3C1. This is a mechanism by which childhood maltreatment may lead to adulthood psychopathology.

Association between violent suicidal behavior and the low activity allele of the serotonin transporter gene

There is compelling evidence that serotonin system dysfunction is associated with certain behavioral disorders, such as suicidal behavior and impulsive aggression. A functional polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) was recently identified and the presence of the short allele found to be associated with a lower level of expression of the gene, lower levels of 5-HT uptake, suicidal behavior and anxiety-related traits. We genotyped 51 West European Caucasians who had made violent suicide attempts and 139 controls of the same ethnic origin, with no history of suicidal behavior. The frequencies of the S allele and the SS genotype were significantly higher in the violent suicide attempters than in the controls. The odds ratio for the SS genotype vs the LL genotype was 3.63 (95% CI (1.27–10.40)). This suggests that a change in expression of the gene encoding the 5-HT transporter may be involved in violent suicidal behavior.

Identification of a New Locus for Generalized Epilepsy with Febrile Seizures Plus (GEFS+) on Chromosome 2q24-q33

We report the identification of a new locus for generalized epilepsy with febrile seizures plus (GEFS+). Six family members manifested isolated typical febrile seizures (FS), and five had typical FS associated with generalized epilepsy (FS+, generalized tonic/clonic seizures). Afebrile seizures occurred from childhood until the teenage years. The maximum two-point LOD score was 3.99 for markers D2S294 and D2S2314. Flanking markers place the GEFS+ locus between D2S141 and D2S116, with multipoint analysis favoring the 13-cM interval spanned by D2S294 and D2S364. This locus is the second GEFS+ locus to be reported, which suggests that this syndrome is genetically heterogeneous.

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.

Suicide attempts and the tryptophan hydroxylase gene

Tryptophan hydroxylase (TPH) is the rate-limiting enzyme of serotonin synthesis. In this case-control study, we investigated whether the TPH gene was a susceptibility factor for suicidal behavior. Seven polymorphisms spanning the entire gene were studied in a case-control study including 231 individuals who had attempted suicide and 281 controls. Significant associations were found between variants in introns 7, 8 and 9 (χ2 = 11.2, df = 1, P< 0.0008 for the allele distribution; these loci are in complete linkage disequilibrium) and in the 3′ noncoding region (χ2 = 30.94, P = 0.0014) and suicide attempt. The association was strongest for subjects who had attempted suicide by violent means and who had a history of major depression. No significant association was observed between suicide attempts and polymorphisms in the promoter, intron 1 and intron 3. The results presented here, and those of previous studies, suggest that a genetic variant of the 3′ part of the TPH gene may be a susceptibility factor for a phenotype combining suicidal behavior, mood disorder and impulsive aggression.

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.

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 antidepressants 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.

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. Cloningers 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.

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.

Weak association between blood sodium, potassium, and calcium and intensity of symptoms in major depressed patients

In previous reports, we showed that plasma and erythrocyte magnesium were increased in many drug-free hospitalized depressed patients. Furthermore, we observed that erythrocyte magnesium content was related to the intensity of the symptoms. Highly depressed patients had the highest magnesium values. Today, we report the results of plasma and erythrocyte sodium and potassium, and of total and ultrafilterable plasma calcium in 66 hospitalized patients with major depression compared to 58 healthy controls. No consistent differences in these biochemical parameters are observed between patients when separated according to intensity of anxiety, psychomotor retardation, and moral distress. Plasma sodium is higher and plasma potassium lower in female patients of all subgroups as compared to controls. Both male patients and controls have erythrocyte sodium and potassium levels that are significantly different from those of females. This clearly suggests a separation into genders in such studies. In conclusion--in contrast to blood magnesium--sodium, potassium, and calcium levels do not seem to be related to the intensity of the main clinical symptoms in hospitalized patients with major depression.