LITHIUM MUTAGENICITY

ESCOLA PAULISTA MED,RUA BOTUCATU 740-3,BR-04023900 São Paulo,BRAZILESCOLA PAULISTA MED,RUA BOTUCATU 740-3,BR-04023900 São Paulo,BRAZILWeb of Scienc

BIPOLAR DISORDER FOLLOWING A LEFT BASAL-GANGLIA STROKE

ESCOLA PAULISTA MED,DEPT PSIQUIAT,RUA BOTUCATU,740-3 ANDAR,BR-04023900 São Paulo,BRAZILESCOLA PAULISTA MED,DEPT PSIQUIAT,RUA BOTUCATU,740-3 ANDAR,BR-04023900 São Paulo,BRAZILWeb of Scienc

Braz J Psychiatry

International audienc

The impact of phenotypic and genetic heterogeneity on results of genome wide association studies of complex diseases

Phenotypic misclassification (between cases) has been shown to reduce the power to detect association in genetic studies. However, it is conceivable that complex traits are heterogeneous with respect to individual genetic susceptibility and disease pathophysiology, and that the effect of heterogeneity has a larger magnitude than the effect of phenotyping errors. Although an intuitively clear concept, the effect of heterogeneity on genetic studies of common diseases has received little attention. Here we investigate the impact of phenotypic and genetic heterogeneity on the statistical power of genome wide association studies (GWAS). We first performed a study of simulated genotypic and phenotypic data. Next, we analyzed the Wellcome Trust Case-Control Consortium (WTCCC) data for diabetes mellitus (DM) type 1 (T1D) and type 2 (T2D), using varying proportions of each type of diabetes in order to examine the impact of heterogeneity on the strength and statistical significance of association previously found in the WTCCC data. In both simulated and real data, heterogeneity (presence of "non-cases") reduced the statistical power to detect genetic association and greatly decreased the estimates of risk attributed to genetic variation. This finding was also supported by the analysis of loci validated in subsequent large-scale meta-analyses. For example, heterogeneity of 50% increases the required sample size by approximately three times. These results suggest that accurate phenotype delineation may be more important for detecting true genetic associations than increase in sample size

Methylomic profiling of cortex samples from completed suicide cases implicates a role for PSORS1C3 in major depression and suicide.

This is the final version of the article. Available from Nature Publishing Group via the DOI in this record.Major depressive disorder (MDD) represents a major social and economic health issue and constitutes a major risk factor for suicide. The molecular pathology of suicidal depression remains poorly understood, although it has been hypothesised that regulatory genomic processes are involved in the pathology of both MDD and suicidality. In this study, genome-wide patterns of DNA methylation were assessed in depressed suicide completers (n=20) and compared with non-psychiatric, sudden-death controls (n=20) using tissue from two cortical brain regions (Brodmann Area 11 (BA11) and Brodmann Area 25 (BA25)). Analyses focused on identifying differentially methylated regions (DMRs) associated with suicidal depression and epigenetic variation were explored in the context of polygenic risk scores for major depression and suicide. Weighted gene co-methylation network analysis was used to identify modules of co-methylated loci associated with depressed suicide completers and polygenic burden for MDD and suicide attempt. We identified a DMR upstream of the PSORS1C3 gene, subsequently validated using bisulfite pyrosequencing and replicated in a second set of suicide samples, which is characterised by significant hypomethylation in both cortical brain regions in MDD suicide cases. We also identified discrete modules of co-methylated loci associated with polygenic risk burden for suicide attempt, but not major depression. Suicide-associated co-methylation modules were enriched among gene networks implicating biological processes relevant to depression and suicidality, including nervous system development and mitochondria function. Our data suggest that there are coordinated changes in DNA methylation associated with suicide that may offer novel insights into the molecular pathology associated with depressed suicide completers.We are grateful to all of the patients and control subjects who contributed to this study. The authors would like to acknowledge support of the Brain and Behaviour Research Foundation through a NARSAD Young Investigator Grant to TMM and from the UK Medical Research Council (MRC) (grant number MR/K013807/1) to JM. ZK would like to acknowledge funding from the NIH grant (grant number NIMH 1R21MH094771). The Douglas Bell Canada Brain Bank is supported by the FRQS through the Quebec Network on Suicide, Mood Disorders and Related Disorders, and by Brain Canada through an infrastructure grant. We acknowledge Niamh Mullins and Professor Catherine Lewis, King’s College London, for kindly supplying us with the suicide attempt GWAS data

Contribution of birth weight to mental health, cognitive and socioeconomic outcomes: two-sample Mendelian randomisation

BACKGROUND: Low birth weight is associated with adult mental health, cognitive and socioeconomic problems. However, the causal nature of these associations remains difficult to establish owing to confounding. AIMS: To estimate the contribution of birth weight to adult mental health, cognitive and socioeconomic outcomes using two-sample Mendelian randomisation, an instrumental variable approach strengthening causal inference. METHOD: We used 48 independent single-nucleotide polymorphisms as genetic instruments for birth weight (genome-wide association studies' total sample: n = 264 498) and considered mental health (attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder, bipolar disorder, major depressive disorder, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), schizophrenia, suicide attempt), cognitive (intelligence) and socioeconomic (educational attainment, income, social deprivation) outcomes. RESULTS: We found evidence for a contribution of birth weight to ADHD (OR for 1 s.d. unit decrease (~464 g) in birth weight, 1.29; 95% CI 1.03-1.62), PTSD (OR = 1.69; 95% CI 1.06-2.71) and suicide attempt (OR = 1.39; 95% CI 1.05-1.84), as well as for intelligence (β = -0.07; 95% CI -0.13 to -0.02) and socioeconomic outcomes, i.e. educational attainment (β = -0.05; 95% CI -0.09 to -0.01), income (β = -0.08; 95% CI -0.15 to -0.02) and social deprivation (β = 0.08; 95% CI 0.03-0.13). However, no evidence was found for a contribution of birth weight to the other examined mental health outcomes. Results were consistent across a wide range of sensitivity analyses. CONCLUSIONS: These findings support the hypothesis that birth weight could be an important element on the causal pathway to mental health, cognitive and socioeconomic outcomes

Deficit of cognitive inhibition in depressed elderly: a neurocognitive marker of suicidal risk

BACKGROUND: Cognitive deficits, in relation to ventral and dorsal prefrontal cortex dysfunctions, have been associated with a higher risk of suicidal acts in young adult patients. Although a public health concern, much less is known about the neurocognitive basis of suicidal behavior in elderly. Here, we aimed at assessing alterations in cognitive inhibition, a suspected major mechanism of the suicidal vulnerability, in suicidal depressed elderly.METHODS: We compared 20 currently depressed patients, aged 65 and older who recently attempted suicide to 20 elderly subjects with a current depression but no personal history of suicide attempt and 20 elderly controls. Using an extensive neuropsychological battery, we particularly examined different aspects of cognitive inhibition: access to relevant information (using the Reading with distraction task), suppression of no longer relevant information (Trail Making Test, Rule Shift Cards), and restraint of cognitive resources to relevant information (Stroop test, Hayling Sentence Completion test, Go/No-Go). RESULTS: After adjustment for age, intensity of depression, Mini-Mental State Examination score and speed of information processing, suicidal depressed elderly showed significant impairments in all 3 domains of cognitive inhibition in comparison to both control groups. LIMITATIONS: Our results need replication in a larger sample size. CONCLUSIONS: Our study suggests that the inability to inhibit neutral information access to working memory, restrain and delete irrelevant information may impair the patient\u27s capacity to respond adequately to stressful situations subsequently leading to an increased risk of suicidal behavior during late-life depression. Interventions may be developed to specifically target cognitive impairment in the prevention of suicide in depressed elderly

Association between hypovitaminosis D and cognitive inhibition impairment during major depression episode

BACKGROUND: Major depressive episode (MDE) has been associated with cognitive functioning alteration and hypovitaminosis D (hypoVD), but the relationship between hypoVD, depression, and cognition is not well understood. We aimed to compare patient with MDE with or without hypoVD in regard of cognitive functioning. METHODS: 91 patients (38.5 years old, 65.9% female) with MDE were included in a cross-sectional study and were evaluated with a complete cognitive battery. None of the participants were medicated at the time of the inclusion. Serum 25-hydroxyvitamin D was measured using LC-MS/MS method, and hypovitaminosis was defined as 25OHD < 50nmol/L. Covariates were gender, season of dosage, first MDE onset, age, body mass index and depression severity RESULTS: Patients with hypoVD demonstrated a higher stroop intereference index time underscoring that means low cognitive inhibition ability. Mutiple logistic regression confirmed that hypoVD was significantly associated with high stroop interference time index after controlling by gender, season of dosage, first MDE onset, age, body mass index and depression severity. CONCLUSION: Our results suggest that patient with MDE having hypoVD may be more prone to cognitive impairment

Differences and similarities in instant countertransference towards patients with suicidal ideation and personality disorders.

Previous findings showed that suicidal patients elicit mostly negative countertransference such as distress, hopelessness, feelings of inadequacy, and apprehension, and that a concurrent personality disorder is associated with more feelings of entrapment and mistreatment, among other adverse reactions. No studies were however conducted on instant countertransference (iCT), i.e., after a single encounter, for example in an emergency setting. We aimed to evaluate the impact of suicidal ideations, self-harm and presence of personality disorders on instant Countertransference (iCT). Caregivers rated their iCT with two validated and standardized questionnaires after a first emergency or outpatient consultation. Suicidal ideation, self-harm and personality disorders were tested as predictors for iCT in a multivariate and multilevel analysis. Thirty caregivers rated their iCT towards 321 patients. Personality disorders and suicidal ideation, but neither recent nor past history of self-harm, predicted iCT. Common iCT included tension, lack of self-confidence and feeling of being tied. iCT specifically associated with suicidal ideation included distress, lack of hope, confusion, and sense that the patient's life had little worth. In contrast, iCT towards patients with personality disorders suggested tension in the therapeutic relationship (low affiliation with patient, anger, disappointment, devaluation). Caregiver's characteristics were not considered in the analysis. Furthermore, while countertransference also includes unconscious phenomena, only conscious iCT was assessed. Patients with suicidal ideation and personality disorders elicit common but also specific negative iCT. Mental health institutions need to devote specific resources (such as clinical supervision and training) to help caregivers manage their iCT

Associations between epigenetic aging and childhood peer victimization, depression, and suicidal ideation in adolescence and adulthood: A study of two population-based samples

Background: Prior studies indicate that peer victimization (including bullying) is associated with higher risk for depression and suicidal ideation across the life course. However, molecular mechanisms underlying these associations remain unclear. This two-cohort study proposes to test whether epigenetic aging and pace of aging, as well as a DNA methylation marker of responsive to glucocorticoids, are associated to childhood peer victimization and later depressive symptoms, or suicidal ideation. Methods: Cohort 1: Epigenome-wide DNA methylation (EPIC array) was measured in saliva collected when participants were 10.47 years (standard deviation = 0.35) in a subsample of the Quebec Longitudinal Study of Child Development (QLSCD, n = 149 participants), with self-reported peer victimization at 6-8 years, depressive symptoms (mean symptoms, and dichotomized top 30% symptoms) and suicidal ideation at 15-17 years. Cohort 2: Epigenome-wide DNA methylation (EPIC array) was measured in blood collected from participants aged 45.13 years (standard deviation = 0.37) in a subsample of the 1958 British Birth cohort (1958BBC, n = 238 participants) with information on mother-reported peer victimization at 7-11 years, self-reported depressive symptoms at 50 years, and suicidal ideation at 45 years. Five epigenetic indices were derived: three indicators of epigenetic aging [Horvath's pan-tissue (Horvath1), Horvath's Skin-and-Blood (Horvath2), Pediatric-Buccal-Epigenetic age (PedBE)], pace of aging (DunedinPACE), and stress response reactivity (Epistress). Results: Peer victimization was not associated with the epigenetic indices in either cohort. In the QLSCD, higher PedBE epigenetic aging and a slower pace of aging as measured by DunedinPACE predicted higher depressive symptoms scores. In contrast, neither the Horvath1, or Horvath2 epigenetic age estimates, nor the Epistress score were associated with depressive symptoms in either cohort, and none of the epigenetic indices predicted suicidal ideation. Conclusion: The findings are consistent with epigenome-wide and candidate gene studies suggesting that these epigenetic indices did not relate to peer victimization, challenging the hypothesis that cumulative epigenetic aging indices could translate vulnerability to depressive symptoms and suicidal ideation following peer victimization. Since some indices of epigenetic aging and pace of aging signaled higher risk for depressive symptoms, future studies should pursue this investigation to further evaluate the robustness and generalization of these preliminary findings