Tricia Sicard

Glutamate receptor gene (GRIN2B) associated with reduced anterior cingulate glutamatergic concentration in pediatric obsessive-compulsive disorder

In this preliminary study, 16 psychotropic-naïve pediatric patients with obsessive-compulsive disorder (OCD) were studied using magnetic resonance spectroscopy (MRS) and genotyped for six candidate polymorphisms in two glutamate system genes. A significant association was identified between the rs1019385 polymorphism of the glutamate receptor, ionotropic, N-methyl-d-aspartate 2B (GRIN2B) and decreased anterior cingulate cortex (ACC) glutamatergic concentration (Glx) but not with occipital Glx. These results suggest that GRIN2B may be associated with Glx in the ACC, a region consistently implicated in OCD.

Serotonin 2A receptor gene is associated with personality traits, but not to disorder, in patients with borderline personality disorder

Borderline personality disorder (BPD) is a chronic, disabling, and high-risk mental disorder characterized by a pervasive pattern of instability in regulation of emotion, interpersonal relationships, self-image, and impulse control beginning in early adulthood. BPD affects about 1%-2% of the general population and has a high mortality rate as a result of suicide and impulsive behaviour. The serotonin 2A receptor gene (HTR2A) is considered a candidate gene for BPD because multiple lines of evidence suggest that it plays an important role in suicide, impulsivity and emotional liability. To test for an association between HTR2A and BPD, we genotyped four polymorphisms, rs6313 (T102C), rs4941573, rs2296972 and rs6314 (His452Tyr), in 111 Caucasian patients with BPD and 287 Caucasian healthy controls. The program UNPHASED was used to compare allele and haplotype frequencies between cases and controls. We did not find a significant association between HTR2A and BPD based on allele, genotype or haplotype analyses. However, there were significant associations between HTR2A and personality traits in the BPD patients. The C allele of rs6313 and the A allele of rs4941573 associated with a higher Extraversion score. Our results suggest that the serotonin 2A receptor gene may not play a major role in the aetiology of borderline personality disorder, but may have a role in personality traits.

Genetic predictors of response to treatment with citalopram in depression secondary to traumatic brain injury

Objectives: To determine which serotonergic system-related single nucleotide polymorphisms (SNPs) predicted variation in treatment response to citalopram in depression following a traumatic brain injury (TBI). Methods: Ninety (50 M/40 F, aged 39.9, SD = 18.0 years) post-TBI patients with a major depressive episode (MDE) were recruited into a 6-week open-label study of citalopram (20 mg/day). Six functional SNPs in genes related to the serotonergic system were examined: serotonin transporter (5HTTLPR including rs25531), 5HT1A C-(1019)G and 5HT2A T-(102)C, methylene tetrahydrofolate reductase (MTHFR) C-(677)T, brain-derived neurotrophic factor (BDNF) val66met and tryptophan hydroxylase-2 (TPH2) G-(703)T. Regression analyses were performed using the six SNPs as independent variables: Model 1 with response (percentage Hamilton Depression (HAMD) change from baseline to endpoint) as the dependent variable and Model 2 with adverse event index as the dependent variable (Bonferroni corrected p-value < 0.025). Results: MTHFR and BDNF SNPs predicted greater treatment response (R2= 0.098, F = 4.65, p = 0.013). The 5HTTLPR predicted greater occurrence of adverse events (R2= 0.069, F = 5.72, p = 0.020). Conclusion: Results suggest that polymorphisms in genes related to the serotonergic system may help predict short-term response to citalopram and tolerability to the medication in patients with MDE following a TBI.

GENE-GENE INTERACTION BETWEEN MAOA AND COMT IN SUICIDAL BEHAVIOR

Several lines of evidence suggest that suicidal behavior is associated with altered noradrenergic neurotransmission. Noradrenaline (NA) is catabolized by monoamine oxidase A (MAOA) and cathecol-O-methyl transferase (COMT). We hypothesized that the genes encoding MAOA and COMT might contain genetic variation conferring increased risk for attempted suicide. In order to test this hypothesis, we genotyped the 941T > G and the promoter VNTR polymorphisms in the MAOA gene and the Val 108/158 Met COMT polymorphism in 305 families with at least one member having bipolar disorder (BD). No association with history of suicide attempt was found either in the MAOA polymorphisms (VNTR:LRS = 1.90, d.f. = 1, p = 0.16; 941T > G:LRS = 1.39, d.f. = 1, p = 0.23), or with the Val 158 Met polymorphism (LRS = 1.61, d.f.=1, p = 0.20). When we performed the haplotype analysis for MAOA gene, we found no association between suicide attempt and haplotype distribution (LRS = 3.07, d.f. = 2, p = 0.21). As both genes are involved in degrading noradreanline, we also tested the hypothesis of epistasis between MAOA polymorphisms and Val158Met, however, no additive effect was found in conferring risk for suicide attempt. These findings suggest that MAOA and COMT genes may not influence suicidal behavior in patients with bipolar disorder.

Glutamate System Genes Associated with Ventral Prefrontal and Thalamic Volume in Pediatric Obsessive-Compulsive Disorder

This pilot study was undertaken to determine if there was a significant association between specific glutamate system genes and regional volumes of interest implicated in the pathogenesis of obsessive-compulsive disorder (OCD). Volumetric magnetic resonance imaging (MRI) and genotyping of seven polymorphisms in two genes, glutamate receptor, ionotropic, N-methyl-d-aspartate 2B (GRIN2B) and solute linked carrier, family 1, member 1 (SLC1A1) were conducted in 31 psychotropic-naïve pediatric OCD patients. The rs1805476 variant of GRIN2B was associated with left but not right orbital frontal cortex (OFC) (p = 0.04) and right but not left anterior cingulate cortex (ACC) volume (p = 0.02). The SLC1A1 rs3056 variant was associated with increased total (p = 0.01), left (p = 0.02) and right (p = 0.02) thalamic volume. These results suggest that GRIN2B and SLC1A1 may be associated with regional volumetric alterations in OFC, ACC, and thalamus in children with OCD.

The serotonin transporter polymorphisms and major depression following traumatic brain injury

Objective: The purpose of this study was to examine the role of the serotonin transporter gene polymorphisms on the risk of major depression following traumatic brain injury (TBI). Methods: Seventy-five patients who had sustained a TBI and who met the Diagnostic and Statistical Manual of Mental Disorders (4th ed) (DSM-IV) criteria for mood disorder due to TBI were compared to 99 controls with TBI but no mood disorder. The severity of depression was rated using the Hamilton Depression Rating Scale (HAMD) for the depressed patients. All patients were genotyped for the serotonin transporter gene-linked polymorphic region (5-HTTLPR) with the assay for the rs25531 allelic variant. Results: The distribution of genotype frequencies was not different between the depressed and control groups (χ2= 1.43, df= 2, p= 0.488) and for the depressed patients there was no association between HAMD scores and the polymorphisms (t-test = 1.71, df= 68, p= 0.092). Conclusion: There was no evidence of association between the serotonin transporter gene polymorphisms and depression post-TBI. Future research is indicated into the possible role of other candidate genes as risk factors for depression in this population.

Further evidence of MAO-A gene variants associated with bipolar disorder†

The aim of this study was to investigate MAOA gene variants in bipolar disorder by using a family‐based association approach. The first sample included 331 nuclear families from Western and Central Canada with at least 1 offspring affected with bipolar disorder comprising a total of 1,044 individuals. All subjects were genotyped for MAOA–941T > G and −uVNTR gene variants using PCR techniques. Haplotype TDT was statistically significant (LRS = 12.17; df = 3; P = 0.0068; permutation global significance = 0.00098), with the T‐4 haplotype significantly associated with bipolar disorder (OR = 1.63, 95% CI = 1.11–2.37). Single marker analysis evidenced a borderline association for MAOA–941T > G (P = 0.04), but not for the uVNTR. Pooling the Canadian sample with a second previously reported Italian sample genotyped for the uVNTR variant, negative results were obtained as well. No different results were detected when analyzing female subjects separately. In conclusion, our family‐based association study gives mild but further support of the involvement of MAOA variants in bipolar disorder.

P.1.24 Serotonin transporter gene and adverse life events in adult ADHD

Serotonin Transporter Gene and Adverse Life Events in Adult ADHD Daniel J. Muller, Laura Mandelli, Alessandro Serretti,* Colin G. DeYoung, Vincenzo De Luca, Tricia Sicard, Subi Tharmalingam, Jurgen Gallinat, Pierandrea Muglia, Diana De Ronchi, Umesh Jain, and James L. Kennedy** Department of Psychiatry, Charite University Medicine Berlin, Campus Mitte, Berlin, Germany Neurogenetics Section, Centre for Addiction and Mental Health (CAMH), University of Toronto, Ontario, Canada Institute of Psychiatry, University of Bologna, Bologna, Italy Department of Psychology, Yale University, New Haven, Connecticut