NCAM1, TACR1 and NOS Genes and Temperament: A Study on Suicide Attempters and Controls

Suicide, one of the leading causes of death among young adults, seems to be plausibly modulated by both genetic and personality factors. The aim of this study was to dissect the potential association between genetics and temperament in a sample of 111 suicide attempters and 289 healthy controls. We focused on 4 genes previously investigated in association with suicide on the same sample: the nitric oxide synthase 1 and 3 (NOS1 and NOS3), the neuronal cell adhesion molecule 1 (NCAM1), and the tachykinin receptor 1 (TACR1) genes. In particular, we investigated whether a set of genetic variants in these genes (NOS1 : rs2682826, rs1353939, rs693534; NOS3 : rs2070744, rs1799983, rs891512; NCAM1 : rs2301228, rs1884, rs1245113, rs1369816, rs2196456, rs584427; TACR1 : rs3771810, rs3771825, rs726506, rs1477157) were associated with temperamental traits at the Temperament and Character Inventory (TCI). No strong evidence was found for the association between TCI personality traits and the polymorphisms considered in the 4 genes, with the exception of an association between reward dependence trait and the rs2682826 SNP in NOS1 in the healthy sample. However, this result could be plausibly interpreted as a false-positive finding. In conclusion, our study did not support the thesis of a direct modulation of these genes on temperament; however, further studies on larger samples are clearly required in order to confirm our preliminary findings and to exclude any possible minor influence. Copyright (C) 2011 S. Karger AG, Base

Antipsychotic Response in the First Week Predicts Later Efficacy

Background and Aims: Time of onset of antipsychotic action is still a debated matter. We aimed to replicate and extend previous findings that early response can predict subsequent non-response. Methods: 86 acutely psychotic patients treated with haloperidol were studied. Results: A PANSS reduction = 23% at 1 week of treatment predicts response at 3 weeks, with a specificity of 84% and a sensitivity of 86%. Conclusion: Our results confirm that an early response to antipsychotic treatment accurately predicts the treatment effectiveness and extends it to a prediction performed as early as 1 week. Copyright (c) 2012 S. Karger AG, Base

No association of a set of candidate genes on haloperidol side effects.

We previously investigated a sample of patients during an active phase of psychosis in the search for genetic predictors of haloperidol induced side effects. In the present work we extend the genetic association analysis to a wider panel of genetic variations, including 508 variations located in 96 genes. The original sample included 96 patients. An independent group of 357 patients from the CATIE study served as a replication sample. Outcomes in the investigation sample were the variation through time of: 1) the ESRS and UKU total scores 2) ESRS and UKU subscales (neurologic and psychic were included) related to tremors and 3) ESRS and UKU subscales that do not relate to tremors. Outcome in the replication sample was the presence vs absence of motoric side effects from baseline to visit 1 (~ one month of treatment) as assessed by the AIMS scale test. Rs2242480 located in the CYP3A4 was associated with a different distribution of the UKU neurologic scores through time (permutated p = 0.047) along with a trend for a different haloperidol plasma levels (lower in CC subjects). This finding was not replicated in the CATIE sample. In conclusion, we did not find conclusive evidence for a major association between the investigated variations and haloperidol induced motoric side effects

Tyrosine Hydroxylase and DOPA Decarboxylase Gene Variants in Personality Traits

Personality influences several characteristics of normal and pathologic behaviors and it is associated with neurotransmitter systems that are under genetic control. The dopaminergic system has been proposed to play a role in the modulation of personality traits. In the present study, variants of the tyrosine hydroxylase (TH) and DOPA decarboxylase (DDC) genes (for TH: rs3842727, rs6356; for DDC: rs1451371, rs1470750, rs998850) were investigated in 111 suicide attempters and 289 healthy subjects to assess the involvement of the dopaminergic synthesis pathway in personality traits. No strong evidence was found for the associations between personality and TH or DDC in overall tests. An interaction effect of genotype and diagnosis was present, with TH and DDC SNPs having a greater effect on the respective personality dimensions in the group of suicide attempters. Because of the risk of false positives, these findings should be interpreted with highest caution. Direct replication attempts within independent groups of suicide attempters will help to resolve this question. Copyright (C) 2009 S. Karger AG, Base

Association study of suicidal behavior and affective disorders with a genetic polymorphism in ABCG1, a positional candidate on chromosome 21q22.3

The gene that codes for the ABC transporter ABCG1 is located in a chromosomal susceptibility region (21q22.3) for affective disorders. Genetic variations in ABCG1 have been associated with affective disorders in Japanese males. In this study, we investigated the distribution of a G2457A polymorphism in patients with affective disorders, suicide attempters with various psychiatric diagnoses and healthy subjects, We initially found a trend towards a modest association with affective disorders in males (p = 0.046 for allele frequencies and p = 0.046 for AA versus GG). We conducted a replication study with independent patients and controls, There was no association with affective disorders, either in the replication or in the combined group, Furthermore, we found no association with suicidal behavior, These findings do not support the hypothesis that ABCG1 is a susceptibility gene for affective disorders or suicidal behavior. Copyright (C) 2000 S. Karger AG, Basel

Proton magnetic resonance spectroscopy in common dementias : current status and perspectives

Dementia occurs mainly in the elderly and is associated with cognitive decline and impairment of activities of daily living. The most common forms of dementia are Alzheimer’s disease (AD), vascular dementia (VD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). To date, there are no causal options for therapy, but drug and non-drug treatments can positively modulate the course of the disease. Valid biomarkers are needed for the earliest possible and reliable diagnosis, but so far, such biomarkers have only been established for AD and require invasive and expensive procedures. In this context, proton magnetic resonance spectroscopy (1H-MRS) provides a non-invasive and widely available technique for investigating the biochemical milieu of brain tissue in vivo. Numerous studies have been conducted for AD, but for VD, DLB, and FTD the number of studies is limited. Nevertheless, MRS can detect measurable metabolic alterations in common dementias. However, most of the studies conducted are too heterogeneous to assess the potential use of MRS technology in clinical applications. In the future, technological advances may increase the value of MRS in dementia diagnosis and treatment. This review summarizes the results of MRS studies conducted in common dementias and discusses the reasons for the lack of transfer into clinical routine.Publikationsfond ML

Plasma protein biomarkers for depression and schizophrenia by multi analyte profiling of case-control collections.

Despite significant research efforts aimed at understanding the neurobiological underpinnings of psychiatric disorders, the diagnosis and the evaluation of treatment of these disorders are still based solely on relatively subjective assessment of symptoms. Therefore, biological markers which could improve the current classification of psychiatry disorders, and in perspective stratify patients on a biological basis into more homogeneous clinically distinct subgroups, are highly needed. In order to identify novel candidate biological markers for major depression and schizophrenia, we have applied a focused proteomic approach using plasma samples from a large case-control collection. Patients were diagnosed according to DSM criteria using structured interviews and a number of additional clinical variables and demographic information were assessed. Plasma samples from 245 depressed patients, 229 schizophrenic patients and 254 controls were submitted to multi analyte profiling allowing the evaluation of up to 79 proteins, including a series of cytokines, chemokines and neurotrophins previously suggested to be involved in the pathophysiology of depression and schizophrenia. Univariate data analysis showed more significant p-values than would be expected by chance and highlighted several proteins belonging to pathways or mechanisms previously suspected to be involved in the pathophysiology of major depression or schizophrenia, such as insulin and MMP-9 for depression, and BDNF, EGF and a number of chemokines for schizophrenia. Multivariate analysis was carried out to improve the differentiation of cases from controls and identify the most informative panel of markers. The results illustrate the potential of plasma biomarker profiling for psychiatric disorders, when conducted in large collections. The study highlighted a set of analytes as candidate biomarker signatures for depression and schizophrenia, warranting further investigation in independent collections

High-risk allele for herpes labialis severity at the IFNL3/4 locus is associated with vestibular neuritis

Objective: Vestibular neuritis (VN) is a peripheral vestibular disorder leading to a sudden loss of unilateral vestibular function. Although the underlying etiological mechanisms for disease development are not yet known, there is evidence that a latent infection with herpes simplex virus type 1 (HSV-1) might be involved. The polymorphism rs12979860 has been associated with the severity of recurrent herpes labialis and hepatitis C virus (HCV) clearance and treatment outcome and is located within the first intron of the IFNL4 gene on chromosome 19.q13.2. This case control study was conducted to evaluate the association of rs12979860 with VN occurrence. Methods: DNA was extracted from EDTA blood of 151 VN patients and 1,775 healthy controls. Genotyping of rs12979860 was performed using iPLEX and MassARRAY Matrix Assisted Laser Desorption Ionization—Time of Flight (MALDI-TOF) mass spectrometry. For association analyses, an additive, dominant and recessive logistic regression model was calculated, using age and sex as covariates. Results: A significant association of rs12979860 with VN was obtained for the additive [OR = 1.51 (1.18–1.92); p = 9.23 × 10−4] and dominant models [OR = 2.15 (1.48–3.13); p = 5.86 × 10−5], with the T allele being more frequent in the VN group. Conclusion: By detecting a significant association of the rs12979860-T risk allele for herpes labialis severity with susceptibility to VN, this study gives further indirect evidence for an involvement of HSV-1 in VN pathology, thereby strengthening the virus hypothesis.Publikationsfond ML

High-risk Allele for Herpes Labialis Severity at the IFNL3/4 Locus is Associated With Vestibular Neuritis

Objective: Vestibular neuritis (VN) is a peripheral vestibular disorder leading to a sudden loss of unilateral vestibular function. Although the underlying etiological mechanisms for disease development are not yet known, there is evidence that a latent infection with herpes simplex virus type 1 (HSV-1) might be involved. The polymorphism rs12979860 has been associated with the severity of recurrent herpes labialis and hepatitis C virus (HCV) clearance and treatment outcome and is located within the first intron of the IFNL4 gene on chromosome 19.q13.2. This case control study was conducted to evaluate the association of rs12979860 with VN occurrence. Methods: DNA was extracted from EDTA blood of 151 VN patients and 1,775 healthy controls. Genotyping of rs12979860 was performed using iPLEX and MassARRAY Matrix Assisted Laser Desorption Ionization—Time of Flight (MALDI-TOF) mass spectrometry. For association analyses, an additive, dominant and recessive logistic regression model was calculated, using age and sex as covariates. Results: A significant association of rs12979860 with VN was obtained for the additive [OR = 1.51 (1.18–1.92); p = 9.23 × 10−4] and dominant models [OR = 2.15 (1.48–3.13); p = 5.86 × 10−5], with the T allele being more frequent in the VN group. Conclusion: By detecting a significant association of the rs12979860-T risk allele for herpes labialis severity with susceptibility to VN, this study gives further indirect evidence for an involvement of HSV-1 in VN pathology, thereby strengthening the virus hypothesis