Sex genes for genomic analysis in human brain: internal controls for comparison of probe level data extraction.

BACKGROUND: Genomic studies of complex tissues pose unique analytical challenges for assessment of data quality, performance of statistical methods used for data extraction, and detection of differentially expressed genes. Ideally, to assess the accuracy of gene expression analysis methods, one needs a set of genes which are known to be differentially expressed in the samples and which can be used as a "gold standard". We introduce the idea of using sex-chromosome genes as an alternative to spiked-in control genes or simulations for assessment of microarray data and analysis methods. RESULTS: Expression of sex-chromosome genes were used as true internal biological controls to compare alternate probe-level data extraction algorithms (Microarray Suite 5.0 [MAS5.0], Model Based Expression Index [MBEI] and Robust Multi-array Average [RMA]), to assess microarray data quality and to establish some statistical guidelines for analyzing large-scale gene expression. These approaches were implemented on a large new dataset of human brain samples. RMA-generated gene expression values were markedly less variable and more reliable than MAS5.0 and MBEI-derived values. A statistical technique controlling the false discovery rate was applied to adjust for multiple testing, as an alternative to the Bonferroni method, and showed no evidence of false negative results. Fourteen probesets, representing nine Y- and two X-chromosome linked genes, displayed significant sex differences in brain prefrontal cortex gene expression. CONCLUSION: In this study, we have demonstrated the use of sex genes as true biological internal controls for genomic analysis of complex tissues, and suggested analytical guidelines for testing alternate oligonucleotide microarray data extraction protocols and for adjusting multiple statistical analysis of differentially expressed genes. Our results also provided evidence for sex differences in gene expression in the brain prefrontal cortex, supporting the notion of a putative direct role of sex-chromosome genes in differentiation and maintenance of sexual dimorphism of the central nervous system. Importantly, these analytical approaches are applicable to all microarray studies that include male and female human or animal subjects

Worldwide impact of economic cycles on suicide trends over 3 decades: Differences according to level of development. A mixed effect model study

Objectives: To investigate the trends and correlations of gross domestic product (GDP) adjusted for purchasing power parity (PPP) per capita on suicide rates in 10 WHO regions during the past 30 years. Design: Analyses of databases of PPP-adjusted GDP per capita and suicide rates. Countries were grouped according to the Global Burden of Disease regional classification system. Data sources: World Bank’s official website and WHO’s mortality database. Statistical analyses: After graphically displaying PPP-adjusted GDP per capita and suicide rates, mixed effect models were used for representing and analysing clustered data. Results: Three different groups of countries, based on the correlation between the PPP-adjusted GDP per capita and suicide rates, are reported: (1) positive correlation: developing (lower middle and upper middle income) Latin-American and Caribbean countries, developing countries in the South East Asian Region including India, some countries in the Western Pacific Region (such as China and South Korea) and high-income Asian countries, including Japan; (2) negative correlation: high-income and developing European countries, Canada, Australia and New Zealand and (3) no correlation was found in an African country. Conclusions: PPP-adjusted GDP per capita may offer a simple measure for designing the type of preventive interventions aimed at lowering suicide rates that can be used across countries. Public health interventions might be more suitable for developing countries. In high-income countries, however, preventive measures based on the medical model might prove more usefulAll authors have completed the Unified Competing Interest form. Dr. Blasco-Fontecilla acknowledges the Spanish Ministry of Health (Rio Hortega CMO8/00170; SAF2010-21849), Alicia Koplowitz Foundation and Conchita Rabago Foundation for funding his post-doctoral stage at CHRU, Montpellier, France

Affect in response to stressors and coping strategies: an ecological momentary assessment study of borderline personality disorder

Background: Affect instability is a core symptom of borderline personality disorder (BPD). Ecological momentary assessment allows for an understanding of real-time changes in affect in response to various daily stressors. The purpose of this study was to explore changes in affect in response to specific stressors and coping strategies in subjects with BPD utilizing ecological momentary assessment (EMA) methodology. Methods: Subjects (n = 50) with BPD were asked to complete real-time assessments about stressors experienced, affect felt, and coping strategies employed six times per day for a 1-week period. Mixed effect regression models were used to measure the effect of stressors and coping strategies on affect change. Results: While most stressors led to experiencing more negative affect, only being in a disagreement was independently associated with increased negative affect. Among coping strategies, only doing something good for oneself independently reduced negative affect, controlling for all other coping strategies used. Conclusions: These findings provide valuable insights into affective instability in BPD and can help inform treatment with individuals with the disorder

Association of interleukin-6 with suicidal ideation in veterans: a longitudinal perspective

IntroductionStudies showing associations between inflammation in suicide are typically cross-sectional. Present study investigated how cytokine levels track with suicidal ideation and severity longitudinally.MethodsVeterans with a diagnosis of major depressive disorder (MDD) with or without suicide attempt history (MDD/SA n = 38, MDD/NS n = 41) and non-psychiatric non-attempter controls (HC n = 33) were recruited, MDD/SA and HC groups were followed longitudinally at 3 months and 6 months. Blood plasma was collected and processed using Luminex Immunology Multiplex technology.ResultsSignificant differences in depression severity (BDI) and suicidal ideation severity (SSI) were observed across all groups at study entry, wherein MDD/SA group had the highest scores followed by MDD/NS and HC, respectively. Cytokines IL-1β, IL-4, TNF-α, IFN-γ, and IL-6 were examined at study entry and longitudinally, with IL6 levels differing significantly across the groups (p = 0.0123) at study entry. Significant differences in changes in cytokine levels between depressed attempters and the control group were detected for IL-6 (interaction F1,91.77 = 5.58, p = 0.0203) and TNF-α (F1,101.73 = 4.69, p = 0.0327). However, only depressed attempters showed a significant change, in IL-6 and TNF-α levels, decreasing over time [IL-6: b = −0.04, 95% CI = (−0.08, −0.01), p = 0.0245 and TNF-α: b = −0.02, 95% CI = (−0.04, −0.01), p = 0.0196]. Although IL-6 levels were not predictive of suicidal ideation presence [OR = 1.34, 95% CI = (0.77, 2.33), p = 0.3067], IL-6 levels were significantly associated with suicidal ideation severity (b = 0.19, p = 0.0422).DiscussionIL-6 was not associated with presence of suicidal ideation. IL-6 however, was associated with severity of ideation, suggesting that IL-6 may be useful in clinical practice, as an objective marker of heightened suicide risk

Basolateral amygdala-ventromedial prefrontal cortex connectivity predicts cognitive behavioural therapy outcome in adults with obsessive-compulsive disorder

Background: cognitive behavioural therapy (CBT), including exposure and ritual prevention, is a first-line treatment for obsessive-compulsive disorder (OCD), but few reliable predictors of CBT outcome have been identified. Based on research in animal models, we hypothesized that individual differences in basolateral amygdala-ventromedial prefrontal cortex (BLA-vmPFC) communication would predict CBT outcome in patients with OCD. Methods: we investigated whether BLA-vmPFC resting-state functional connectivity (rs-fc) predicts CBT outcome in patients with OCD. We assessed BLA-vmPFC rs-fc in patients with OCD on a stable dose of a selective serotonin reuptake inhibitor who then received CBT and in healthy control participants. Results: we included 73 patients with OCD and 84 healthy controls in our study. Decreased BLA-vmPFC rs-fc predicted a better CBT outcome in patients with OCD and was also detected in those with OCD compared with healthy participants. Additional analyses revealed that decreased BLA-vmPFC rs-fc uniquely characterized the patients with OCD who responded to CBT. Limitations: we used a sample of convenience, and all patients were receiving pharmacological treatment for OCD. Conclusion: in this large sample of patients with OCD, BLA-vmPFC functional connectivity predicted CBT outcome. These results suggest that future research should investigate the potential of BLA-vmPFC pathways to inform treatment selection for CBT across patients with OCD and anxiety disorders

Financial Hardship, Hope, and Life Satisfaction Among Un/Underemployed Individuals With Psychiatric Diagnoses: A Mediation Analysis

BackgroundIndividuals with psychiatric diagnoses who are unemployed or underemployed are likely to disproportionately experience financial hardship and, in turn, lower life satisfaction (LS). Understanding the mechanisms though which financial hardship affects LS is essential to inform effective economic empowerment interventions for this population.AimTo examine if subjective financial hardship (SFH) mediates the relationship between objective financial hardship (OFH) and LS, and whether hope, and its agency and pathways components, further mediate the effect of SFH on LS among individuals with psychiatric diagnoses seeking employment.MethodsWe conducted structured interviews with participants (N = 215) of two peer-run employment programs using indicators of OFH and SFH and standardized scales for hope (overall hope, hope agency, and hope pathways) and LS. Three structural equation models were employed to test measurement models for OFH and SFH, and mediational relationships. Covariates included gender, age, psychiatric diagnosis, race/ethnicity, education, income, employment status, SSI/SSDI receipt, and site.ResultsConfirmatory factor analysis (CFA) for items measuring OFH and SFH supported two separate hypothesized factors. OFH had a strong and significant total effect on SFH [standardized beta (B) = 0.68] and LS (B = 0.49), and a weak-to-moderate effect on hope (B = –0.31). SFH alone mediated up to 94% of the effect of OFH on LS (indirect effect B = –0.46, p < 0.01). The effect of SFH on LS through hope was small (indirect effect B = –0.09, p < 0.05), primarily through hope agency (indirect effect B = –0.13, p < 0.01) and not hope pathways. Black and Hispanic ethno-racial identification seemed to buffer the effect of financial hardship on hope and LS. Individuals identifying as Black reported significantly higher overall hope (B = 0.41–0.47) and higher LS (B = 0.29–0.46), net of the effect of OFH and SFH.ConclusionSFH is a strong mediator of the relationship between OFH and LS in our study of unemployed and underemployed individuals with psychiatric diagnoses. Hope, and particularly its agency component, further mediate a modest but significant proportion of the association between SFH and LS. Economic empowerment interventions for this population should address objective and subjective financial stressors, foster a sense of agency, and consider the diverse effects of financial hardship across ethno-racial groups

Can We Really Prevent Suicide?

Every year, suicide is among the top 20 leading causes of death globally for all ages. Unfortunately, suicide is difficult to prevent, in large part because the prevalence of risk factors is high among the general population. In this review, clinical and psychological risk factors are examined and methods for suicide prevention are discussed. Prevention strategies found to be effective in suicide prevention include means restriction, responsible media coverage, and general public education, as well identification methods such as screening, gatekeeper training, and primary care physician education. Although the treatment for preventing suicide is difficult, follow-up that includes pharmacotherapy, psychotherapy, or both may be useful. However, prevention methods cannot be restricted to the individual. Community, social, and policy interventions will also be essentia

Genome-Wide Divergence of DNA Methylation Marks in Cerebral and Cerebellar Cortices

Emerging evidence suggests that DNA methylation plays an expansive role in the central nervous system (CNS). Large-scale whole genome DNA methylation profiling of the normal human brain offers tremendous potential in understanding the role of DNA methylation in brain development and function.Using methylation-sensitive SNP chip analysis (MSNP), we performed whole genome DNA methylation profiling of the prefrontal, occipital, and temporal regions of cerebral cortex, as well as cerebellum. These data provide an unbiased representation of CpG sites comprising 377,509 CpG dinucleotides within both the genic and intergenic euchromatic region of the genome. Our large-scale genome DNA methylation profiling reveals that the prefrontal, occipital, and temporal regions of the cerebral cortex compared to cerebellum have markedly different DNA methylation signatures, with the cerebral cortex being hypermethylated and cerebellum being hypomethylated. Such differences were observed in distinct genomic regions, including genes involved in CNS function. The MSNP data were validated for a subset of these genes, by performing bisulfite cloning and sequencing and confirming that prefrontal, occipital, and temporal cortices are significantly more methylated as compared to the cerebellum.These findings are consistent with known developmental differences in nucleosome repeat lengths in cerebral and cerebellar cortices, with cerebrum exhibiting shorter repeat lengths than cerebellum. Our observed differences in DNA methylation profiles in these regions underscores the potential role of DNA methylation in chromatin structure and organization in CNS, reflecting functional specialization within cortical regions

Altered Gene Synchrony Suggests a Combined Hormone-Mediated Dysregulated State in Major Depression

Coordinated gene transcript levels across tissues (denoted “gene synchrony”) reflect converging influences of genetic, biochemical and environmental factors; hence they are informative of the biological state of an individual. So could brain gene synchrony also integrate the multiple factors engaged in neuropsychiatric disorders and reveal underlying pathologies? Using bootstrapped Pearson correlation for transcript levels for the same genes across distinct brain areas, we report robust gene transcript synchrony between the amygdala and cingulate cortex in the human postmortem brain of normal control subjects (n = 14; Control/Permutated data, p<0.000001). Coordinated expression was confirmed across distinct prefrontal cortex areas in a separate cohort (n = 19 subjects) and affected different gene sets, potentially reflecting regional network- and function-dependent transcriptional programs. Genewise regional transcript coordination was independent of age-related changes and array technical parameters. Robust shifts in amygdala-cingulate gene synchrony were observed in subjects with major depressive disorder (MDD, denoted here “depression”) (n = 14; MDD/Permutated data, p<0.000001), significantly affecting between 100 and 250 individual genes (10–30% false discovery rate). Biological networks and signal transduction pathways corresponding to the identified gene set suggested putative dysregulated functions for several hormone-type factors previously implicated in depression (insulin, interleukin-1, thyroid hormone, estradiol and glucocorticoids; p<0.01 for association with depression-related networks). In summary, we showed that coordinated gene expression across brain areas may represent a novel molecular probe for brain structure/function that is sensitive to disease condition, suggesting the presence of a distinct and integrated hormone-mediated corticolimbic homeostatic, although maladaptive and pathological, state in major depression