The Tutsi genocide and transgenerational transmission of maternal stress: epigenetics and biology of the HPA axis.

OBJECTIVES: Transmission of parental post-traumatic stress disorder (PTSD) to offspring might be explained by transmission of epigenetic processes such as methylation status of the glucocorticoid receptor (GR) gene (NR3C1). METHODS: We investigated PTSD and depression severity, plasma cortisol, GR and mineralocorticoid receptor (MR) levels, and methylation status of NR3C1 and NR3C2 promoter regions in 25 women exposed to the Tutsi genocide during pregnancy and their children, and 25 women from the same ethnicity, pregnant during the same period but not exposed to the genocide, and their children. RESULTS: Transmission of PTSD to the offspring was associated with transmission of biological alterations of the HPA axis. Mothers exposed to the genocide as well as their children had lower cortisol and GR levels and higher MR levels than non-exposed mothers and their children. Moreover, exposed mothers and their children had higher methylation of the NR3C1 exon 1F than non-exposed groups. Finally, exposed mothers showed higher methylation of CpGs located within the NR3C2 coding sequence than non-exposed mothers. CONCLUSIONS: PTSD was associated with NR3C1 epigenetic modifications that were similarly found in the mothers and their offspring, modifications that may underlie the possible transmission of biological alterations of the HPA axis.

Genetic susceptibility for bipolar disorder and response to antidepressants in major depressive disorder.

The high heterogeneity of response to antidepressant treatment in major depressive disorder (MDD) makes individual treatment outcomes currently unpredictable. It has been suggested that resistance to antidepressant treatment might be due to undiagnosed bipolar disorder or bipolar spectrum features. Here, we investigate the relationship between genetic susceptibility for bipolar disorder and response to treatment with antidepressants in MDD. Polygenic scores indexing risk for bipolar disorder were derived from the Psychiatric Genomics Consortium Bipolar Disorder whole genome association study. Linear regressions tested the effect of polygenic risk scores for bipolar disorder on proportional reduction in depression severity in two large samples of individuals with MDD, treated with antidepressants, NEWMEDS (n=1,791) and STAR*D (n=1,107). There was no significant association between polygenic scores for bipolar disorder and response to treatment with antidepressants. Our data indicate that molecular measure of genetic susceptibility to bipolar disorder does not aid in understanding non-response to antidepressants.

Childhood maltreatment and methylation of the glucocorticoid receptor gene NR3C1 in bipolar disorder.

BACKGROUND: Early-life adversities represent risk factors for the development of bipolar affective disorder and are associated with higher severity of the disorder. This may be the consequence of a sustained alteration of the hypothalamic-pituitary-adrenal (HPA) axis resulting from epigenetic modifications of the gene coding for the glucocorticoid receptor (NR3C1). AIMS: To investigate whether severity of childhood maltreatment is associated with increased methylation of the exon 1F NR3C1 promoter in bipolar disorder. METHOD: A sample of people with bipolar disorder (n = 99) were assessed for childhood traumatic experiences. The percentage of NR3C1 methylation was measured for each participant. RESULTS: The higher the number of trauma events, the higher was the percentage of NR3C1 methylation (ß = 0.52, 95% CI 0.46-0.59, P<<0.0001). The severity of each type of maltreatment (sexual, physical and emotional) was also associated with NR3C1 methylation status. CONCLUSIONS: Early-life adversities have a sustained effect on the HPA axis through epigenetic processes and this effect may be measured in peripheral blood. This enduring biological impact of early trauma may alter the development of the brain and lead to adult psychopathological disorder.

Neurobiology of suicide: do biomarkers exist?

Clinical risk factors have a low predictive value on suicide. This may explain the increasing interest in potential neurobiological correlates and specific heritable markers of suicide vulnerability. This review aims to present the current neurobiological findings that have been shown to be implicated in suicide completers and to discuss how postmortem studies may be useful in characterizing these individuals. Data on the role of the main neurobiological systems in suicidality, such as the neurotransmitter families, hypothalamic-pituitary-adrenal axis, neurotrophic factors, and polyamines, are exposed at the different biochemical, genetic, and epigenetic levels. Some neuroanatomic and neuropathological aspects as well as their in vivo morphological and functional neuroimaging correlates are also described. Except for the serotoninergic system, particularly with respect to the polymorphism of the gene coding for the serotonin transporter (5-HTTLPR) and brain-derived neurotrophic factor, data did not converge to produce a univocal consensus. The possible limitations of currently published studies are discussed, as well as the scope for long-term prospective studies.

Age at onset in bipolar I affective disorder in the USA and Europe.

OBJECTIVE: To test for differences in reported age at onset (AAO) of bipolar I affective disorder in clinical samples drawn from Europe and the USA. METHODS: Admixture analysis was used to identify the model best fitting the observed AAO distributions of two large samples of bipolar I patients from Europe and USA (n = 3616 and n = 2275, respectively). Theoretical AAO functions were compared between the two samples. RESULTS: The model best fitting the observed distribution of AAO in both samples was a mixture of three Gaussian distributions. The theoretical AAO functions of bipolar I disorder differed significantly between the European and USA populations, with further analyses indicating that (i) the proportion of patients belonging to the early-onset subgroup was higher in the USA sample (63 vs. 25%) and (ii) mean age at onset (±SD) in the early-onset subgroup was lower for the USA sample (14.5 ± 4.9 vs. 19 ± 2.7 years). CONCLUSIONS: The models best describing the reported AAO distributions of European and USA bipolar I patients were remarkably stable. The intermediate- and late-onset subgroups had similar characteristics in the two samples. However, the theoretical AAO function differed significantly between the USA and European samples due to the higher proportion of patients in the early-onset subgroup and the lower mean age-at-onset in the USA sample.

A new locus on chromosome 22q13.31 linked to recessive genetic epilepsy with febrile seizures plus (GEFS+) in a Tunisian consanguineous family.

BACKGROUND: Genetic epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome with extremely variable expressivity. The aim of our study was to identify the responsible locus for GEFS+ syndrome in a consanguineous Tunisian family showing three affected members, by carrying out a genome-wide single nucleotide polymorphisms (SNPs) genotyping followed by a whole-exome sequencing. We hypothesized an autosomal recessive (AR) mode of inheritance. RESULTS: Parametric linkage analysis and haplotype reconstruction identified a new unique identical by descent (IBD) interval of 527 kb, flanking by two microsatellite markers, 18GTchr22 and 15ACchr22b, on human chromosome 22q13.31 with a maximum multipoint LOD score of 2.51. Our analysis was refined by the use of a set of microsatellite markers. We showed that one of them was homozygous for the same allele in all affected individuals and heterozygous in healthy members of this family. This microsatellite marker, we called 17ACchr22, is located in an intronic region of TBC1D22A gene, which encodes a GTPase activator activity. Whole-exome sequencing did not reveal any mutation on chromosome 22q13.31 at the genome wide level. CONCLUSIONS: Our findings suggest that TBC1D22A is a new locus for GEFS+.

Additive effects between prematurity and postnatal risk factors of suicidal behavior.

BACKGROUND: Pre- and perinatal insults increase suicide risk. The main objective of the present study is to investigate if prematurity interacts in an additive fashion with postnatal risk factors of suicidal behavior. METHOD: Sample and procedure: 857 adult suicide attempters consecutively hospitalized for a suicide attempt were included. Studied characteristics of suicide attempts included use of a violent mean, age at first suicide attempt, and number of suicide attempts. Risk factors of suicidal behavior included indexes of pre- and perinatal adversity, childhood maltreatment as measured with the Childhood Trauma Questionnaire, personality traits as measured with the Tridimensional Personality Questionnaire, and family history of suicidal behavior. STATISTICAL ANALYSES: Comparisons between the different patterns of suicide attempts characteristics were made using logistic regression with crude and adjusted odds ratios and 95% confidence intervals. RESULTS: The risk of violent suicide attempts increased significantly in patients born prematurely (OR [95%] = 2.38[1.12-5.08]). There were additive effects for very preterm birth and 1) emotional abuse (OR [95% CI] = 4.52 [1.75-11.60]), 2) novelty seeking (OR [95% CI] = 8.92[3.09-25.7]), and 3) harm avoidance (OR [95% CI] = 5.81 [2.43-13.90]) on the age at first suicide attempt, after adjustment for potential confounders. CONCLUSIONS: Very preterm birth appears to be the first step in a cascade of stressors across lifetime, which affects the risk and the severity of suicidal behavior. Furthermore, very preterm birth, childhood maltreatment and personality traits have additive effects that influence the age at onset of suicide attempt. Our findings may have potential consequences for preventive policies.

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.

Contribution of common genetic variants to antidepressant response.

BACKGROUND: Pharmacogenetic studies aiming to personalize the treatment of depression are based on the assumption that response to antidepressants is a heritable trait, but there is no compelling evidence to support this. METHODS: We estimate the contribution of common genetic variation to antidepressant response with Genome-Wide Complex Trait Analysis in a combined sample of 2799 antidepressant-treated subjects with major depressive disorder and genome-wide genotype data. RESULTS: We find that common genetic variants explain 42% (SE = .180, p = .009) of individual differences in antidepressant response. CONCLUSIONS: These results suggest that response to antidepressants is a complex trait with substantial contribution from a large number of common genetic variants of small effect.

The HLA-G low expressor genotype is associated with protection against bipolar disorder.

Implication of immune processes in bipolar disorder (BD) has recently gained increasing attention. Tolerogenic molecules, among which HLA-G plays a prominent role, mediate the modulation of such processes. The HLA-G locus is characterized by a high number of polymorphisms including a functionally relevant 14 base pair (bp) insertion/deletion (Ins/Del) allele affecting the HLA-G expression. Here, we analyzed the distribution of this polymorphism in 561 BD patients and 161 healthy and found that the HLA-G 14bp Ins/Ins genotype was significantly more prevalent in healthy controls than in patients (corrected p; pc=0.032) and that the prevalence of such protective genotype is lower among patients born during the winter season as compared to those born in other periods (pc=0.006). Possible mechanisms between low HLA G expression and resistance to infections as well as potential relationships between infections in early life and susceptibility to BD are discussed.

HPA axis genes may modulate the effect of childhood adversities on decision-making in suicide attempters.

Decision-making impairment is found in several neuropsychiatric disorders, including suicidal behavior, and has been shown to be modulated by genes. On the other hand, early trauma have/has been associated with poor mental health outcome in adulthood, in interaction with genetic factors, possibly through sustained alterations in the hypothalamic-pituitary-adrenal axis (HPA axis). Here, we aimed to investigate the effect of childhood trauma and its interaction with HPA-axis related genes on decision-making abilities in adulthood among a sample of suicide attempters. The Iowa Gambling Task (IGT) was used to assess decision-making in 218 patients with a history of suicide attempt. Participant fulfilled the Childhood Trauma Questionnaire to report traumatic childhood experiences. Patients were genotyped for single-nucleotide polymorphisms within CRHR1 and CRHR2 genes. Patients with a history of sexual abuse had significantly lower IGT scores than non-sexually abused individuals. Polymorphisms within CRHR1 and CRHR2 genes interacted with both childhood sexual abuse and emotional neglect to influence IGT performance. In conclusion, childhood sexual abuse and emotional neglect may have long-term effects on decision-making through an interaction with key HPA axis genes. Even if these results need to be replicated in other sample, impaired decision-making may thus be the dimension through which child maltreatment, in interaction with HPA axis related genes, may have a sustained negative impact on adult mental health.

Genetic predictors of response to serotonergic and noradrenergic antidepressants in major depressive disorder: a genome-wide analysis of individual-level data and a meta-analysis.

BACKGROUND: It has been suggested that outcomes of antidepressant treatment for major depressive disorder could be significantly improved if treatment choice is informed by genetic data. This study aims to test the hypothesis that common genetic variants can predict response to antidepressants in a clinically meaningful way. METHODS AND FINDINGS: The NEWMEDS consortium, an academia-industry partnership, assembled a database of over 2,000 European-ancestry individuals with major depressive disorder, prospectively measured treatment outcomes with serotonin reuptake inhibiting or noradrenaline reuptake inhibiting antidepressants and available genetic samples from five studies (three randomized controlled trials, one part-randomized controlled trial, and one treatment cohort study). After quality control, a dataset of 1,790 individuals with high-quality genome-wide genotyping provided adequate power to test the hypotheses that antidepressant response or a clinically significant differential response to the two classes of antidepressants could be predicted from a single common genetic polymorphism. None of the more than half million genetic markers significantly predicted response to antidepressants overall, serotonin reuptake inhibitors, or noradrenaline reuptake inhibitors, or differential response to the two types of antidepressants (genome-wide significance p<5×10(-8)). No biological pathways were significantly overrepresented in the results. No significant associations (genome-wide significance p<5×10(-8)) were detected in a meta-analysis of NEWMEDS and another large sample (STAR*D), with 2,897 individuals in total. Polygenic scoring found no convergence among multiple associations in NEWMEDS and STAR*D. CONCLUSIONS: No single common genetic variant was associated with antidepressant response at a clinically relevant level in a European-ancestry cohort. Effects specific to particular antidepressant drugs could not be investigated in the current study. Please see later in the article for the Editors' Summary.

Naturally occurring carboxypeptidase A6 mutations: effect on enzyme function and association with epilepsy.

Carboxypeptidase A6 (CPA6) is a member of the A/B subfamily of M14 metallocarboxypeptidases that is expressed in brain and many other tissues during development. Recently, two mutations in human CPA6 were associated with febrile seizures and/or temporal lobe epilepsy. In this study we screened for additional CPA6 mutations in patients with febrile seizures and focal epilepsy, which encompasses the temporal lobe epilepsy subtype. Mutations found from this analysis as well as CPA6 mutations reported in databases of single nucleotide polymorphisms were further screened by analysis of the modeled proCPA6 protein structure and the functional role of the mutated amino acid. The point mutations predicted to affect activity and/or protein folding were tested by expression of the mutant in HEK293 cells and analysis of the resulting CPA6 protein. Common polymorphisms in CPA6 were also included in this analysis. Several mutations resulted in reduced enzyme activity or CPA6 protein levels in the extracellular matrix. The mutants with reduced extracellular CPA6 protein levels showed normal levels of 50-kDa proCPA6 in the cell, and this could be converted into 37-kDa CPA6 by trypsin, suggesting that protein folding was not greatly affected by the mutations. Interestingly, three of the mutations that reduced extracellular CPA6 protein levels were found in patients with epilepsy. Taken together, these results provide further evidence for the involvement of CPA6 mutations in human epilepsy and reveal additional rare mutations that inactivate CPA6 and could, therefore, also be associated with epileptic phenotypes.

Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32.

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, P(meta) = 2.5 × 10(-9), OR[T] = 0.81) and 17q21.32 (rs72823592, P(meta) = 9.3 × 10(-9), OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, P(meta) = 9.1 × 10(-9), OR[T] = 0.68) and at 1q43 for JME (rs12059546, P(meta) = 4.1 × 10(-8), OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, P(meta) = 4.0 × 10(-6)) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndromes.

Genetics of temporal lobe epilepsy: a review.

Temporal lobe epilepsy (TLE) is usually regarded as a polygenic and complex disorder. To understand its genetic component, numerous linkage analyses of familial forms and association studies of cases versus controls have been conducted since the middle of the nineties. The present paper lists genetic findings for TLE from the initial segregation analysis to the most recent results published in May 2011. To date, no genes have been clearly related to TLE despite many efforts to do so. However, it is vital to continue replication studies and collaborative attempts to find significant results and thus determine which gene variant combination plays a definitive role in the aetiology of TLE.

Magnetic resonance imaging correlates of first-episode psychosis in young adult male patients: combined analysis of grey and white matter.

BACKGROUND: Several patterns of grey and white matter changes have been separately described in young adults with first-episode psychosis. Concomitant investigation of grey and white matter densities in patients with first-episode psychosis without other psychiatric comorbidities that include all relevant imaging markers could provide clues to the neurodevelopmental hypothesis in schizophrenia. METHODS: We recruited patients with first-episode psychosis diagnosed according to the DSM-IV-TR and matched controls. All participants underwent magnetic resonance imaging (MRI). Voxel-based morphometry (VBM) analysis and mean diffusivity voxel-based analysis (VBA) were used for grey matter data. Fractional anisotropy and axial, radial and mean diffusivity were analyzed using tract-based spatial statistics (TBSS) for white matter data. RESULTS: We included 15 patients and 16 controls. The mean diffusivity VBA showed significantly greater mean diffusivity in the first-episode psychosis than in the control group in the lingual gyrus bilaterally, the occipital fusiform gyrus bilaterally, the right lateral occipital gyrus and the right inferior temporal gyrus. Moreover, the TBSS analysis revealed a lower fractional anisotropy in the first-episode psychosis than in the control group in the genu of the corpus callosum, minor forceps, corticospinal tract, right superior longitudinal fasciculus, left middle cerebellar peduncle, left inferior longitudinal fasciculus and the posterior part of the fronto-occipital fasciculus. This analysis also revealed greater radial diffusivity in the first-episode psychosis than in the control group in the right corticospinal tract, right superior longitudinal fasciculus and left middle cerebellar peduncle. LIMITATIONS: The modest sample size and the absence of women in our series could limit the impact of our results. CONCLUSION: Our results highlight the structural vulnerability of grey matter in posterior areas of the brain among young adult male patients with first-episode psychosis. Moreover, the concomitant greater radial diffusivity within several regions already revealed by the fractional anisotropy analysis supports the idea of a late myelination in patients with first-episode psychosis.

La conducta suicida se asocia a una reducción el área del cuerpo calloso / Suicidal behavior is associated with reduced corpus callosum area

Antecedentes. El tamaño del cuerpo calloso (CC) se ha relacionado con la presencia de déficits cognitivos y emocionales en diversos trastornos neuropsiquiátricos y del estado de ánimo. Dado que estos déficits se observan también en la conducta suicida, hemos investigado específicamente la asociación entre la atrofia del CC y dicha conducta. Métodos. Estudiamos a 435 individuos diestros, sin demencia, de una cohorte de base comunitaria formada por personas de edad igual o superior a 65 años (estudio ESPRIT). Dividimos a los participantes en 3 grupos: individuos con intentos de suicidio (n=21), individuos de control afectivos (CA) (n=180) sin antecedentes de intentos de suicidio pero con antecedentes de depresión, e individuos de control sanos (CS) (n=234). Se utilizaron imágenes de resonancia magnética con ponderación T1 para medir las áreas mesosagitales del CC anterior, medio y posterior. Se aplicó un análisis de covarianza multivariado para comparar las áreas del CC de los 3 grupos. Resultados. Los análisis multivariados, con un ajuste en cuanto a edad, sexo, trauma infantil, traumatismo craneal y volumen encefálico total, mostraron que el área del tercio posterior del CC era significativamente menor en los individuos con intentos de suicidio, en comparación con los CA (p=0,020) y los CS (p=0,010). No se observaron diferencias significativas entre CA y CS. No hubo diferencias en cuanto a los tercios anterior y medio del CC. Conclusiones. Nuestros resultados resaltan la presencia de un tamaño reducido del tercio posterior del CC en los individuos con antecedentes de suicidio, lo cual sugiere una disminución de la conectividad interhemisférica y un posible papel del CC en la fisiopatología de la conducta suicida. Serán necesarios nuevos estudios para confirmar estos resultados y esclarecer las alteraciones celulares subyacentes que conducen a estas diferencias morfométricas (AU)

Background. Corpus callosum (CC) size has been associated with cognitive and emotional deficits in a range of neuropsychiatric andmood disorders. As such deficits are also found in suicidal behavior, we investigated specifically the association between CC atrophy and suicidal behavior. Methods. We studied 435 right-handed individuals without dementia from a cohort of community-dwelling persons aged 65 years and over (the ESPRIT study). They were divided in three groups: suicide attempters (n=21), affective control subjects (AC) (n=180) without history of suicide attempt but with a history of depression, and healthy control subjects (HC) (n=234). T1-weighted magnetic resonance images were traced to measure the midsagittal areas of the anterior, mid, and posterior CC. Multivariate analysis of covariance was used to compare CC areas in the 3 groups. Results. Multivariate analyses adjusted for age, gender, childhood trauma, head trauma, and total brain volume showed that the area of the posterior third of CC was significantly smaller in suicide attempters than in AC (P=.020) and HC (P=.010) individuals. No significant differences were found between AC and HC. No differences were found for the anterior and mid thirds of the CC. Conclusions. Our findings emphasize a reduced size of the posterior third of the CC in subjects with a history of suicide, suggesting a diminished interhemispheric connectivity and a possible role of CC in the pathophysiology of suicidal behavior. Further studies are needed to strengthen these results and clarify the underlying cellular changes leading to these morphometric differences (AU)

Depression in elderly persons subject to childhood maltreatment is not modulated by corpus callosum and hippocampal loss.

Childhood adversity has been observed to engender structural changes in the hippocampus and corpus callosum associated with increased risk for depression in childhood and early adulthood. This study investigated this association in the elderly. Corpus callosum area and hippocampal volume were measured from structural MRI in 427 community dwelling elderly. Information on childhood adversity was obtained in the course of a clinical examination using a questionnaire covering multiple aspects of abuse. Multivariate analyses found a significant increase in corpus callosum area and hippocampal volume in subjects exposed to mental disorder in parents and poverty, respectively. No association was found with childhood sexual and physical abuse.

Genetic overlap between schizophrenia and bipolar disorder: a study with AKT1 gene variants and clinical phenotypes.

INTRODUCTION: A number of epidemiological and genetic studies suggests an overlap of Schizophrenia and Bipolar disorder across the traditional binary classification. AKT1 gene variants were previously shown to be associated with schizophrenia. In this study, our aim was to determine whether AKT1 gene variants are associated with particular phenotypes for schizophrenia (SCZ) and bipolar disorder (BPD). METHODS: This study included 529 subjects of European ancestry: 364 patients suffering from SCZ, BPD or schizoaffective disorder and 165 healthy controls. BPD patients were additionally subdivided into two groups: BPD with or without psychosis. Six AKT1 variants were assessed in a case-control study and allelic associations were analyzed. Moreover, meta-analyses were performed for those variants found in case-control studies of schizophrenia and schizoaffective disorder. RESULTS: Nominal associations were found for three AKT1 gene variants, namely rs3803300, rs2494732 and rs2498804, in the four phenotypes. Two SNP survived Bonferroni corrections for multiple testing: rs3803300 (p<0.001) and rs2498804 (p<0.03) in group 1 (BPD without psychosis). In group 2 (BPD with psychosis) and in group 4 (SCZ), rs3803300 was significant but did not survive multiple testing. While rs2494732 was associated with the presence of psychosis (group-2, 3 and 4), rs2498804 was associated with affective symptoms (groups-1, 2 and 3). One meta-analysis found a significant level of association between rs3803300 and schizophrenia in Asian subjects. CONCLUSION: AKT1 gene variations appeared to impact the risk for a class of psychiatric symptoms, comprising SCZ and BPD. Our findings support the view that AKT1 genetic variants are shared by both BPD and SCZ.

Protein levels of ß-catenin and activation state of glycogen synthase kinase-3ß in major depression. A study with postmortem prefrontal cortex.

BACKGROUND: The Wnt/GSK3ß signaling pathway was implicated in mood disorders. Beta-catenin is a protein targeted by this signaling axis. We aimed to examine whether there is an abnormality in this signaling axis in major depression. METHODS: Postmortem brains from 20 depressed and 20 non-depressed subjects were used. In both groups, suicide and non-suicide were included in equal number. Protein levels of ß-catenin, tGSK3ß and ser(9)-pGSK3ß were determined in prefrontal cortex. RESULTS: ANOVA yielded significant variations between groups in ß-catenin (F(3,36)=19.5; p<0.001) and pGSK3ß protein (F(3,36)=14.3; p<0.001) and in tGSK3ß-to-pGSK3ß ratio (F(3,36)=10.9; p<0.001). Fisher tests showed decrease in both groups of MDD and MDD with suicide (MDD+S) for ß-catenin (p<0.001) and pGSK3ß levels (p<0.001) respectively. The tGSK3ß-to-pGSK3ß ratio was increased in MDD and MDD+S subjects (p<0.001). A negative correlation was observed between ß-catenin levels and the activation state of the GSK3ß (r2=0.358; p<0.005). LIMITATIONS: The sample was small and only a fraction of s(9)-pGSK3ß, albeit significant, was used and; the mood state at the time of death was unknown. CONCLUSIONS: The study observed a dysregulation of Wnt/GSK3ß signaling associated with a lifetime of major depression. The study may have relevance in further development of drugs based on GSK3ß inhibition.