Mechanisms of congenital heart disease caused by NAA15 haploinsufficiency

Rationale: NAA15 is a component of the N-terminal (Nt) acetyltransferase complex, NatA. The mechanism by which NAA15 haploinsufficiency causes congenital heart disease (CHD) remains unknown. To better understand molecular processes by which NAA15 haploinsufficiency perturbs cardiac development, we introduced NAA15 variants into human induced pluripotent stem cells (iPSCs) and assessed the consequences of these mutations on RNA and protein expression. Objective: We aim to understand the role of NAA15 haploinsufficiency in cardiac development by investigating proteomic effects on NatA complex activity, and identifying proteins dependent upon a full amount of NAA15. Methods and Results: We introduced heterozygous LoF, compound heterozygous and missense residues (R276W) in iPS cells using CRISPR/Cas9. Haploinsufficient NAA15 iPS cells differentiate into cardiomyocytes, unlike NAA15-null iPS cells, presumably due to altered composition of NatA. Mass spectrometry (MS) analyses reveal ~80% of identified iPS cell NatA targeted proteins displayed partial or complete Nt-acetylation. Between null and haploinsufficient NAA15 cells Nt-acetylation levels of 32 and 9 NatA-specific targeted proteins were reduced, respectively. Similar acetylation loss in few proteins occurred in NAA15 R276W iPSCs. In addition, steady-state protein levels of 562 proteins were altered in both null and haploinsufficient NAA15 cells; eighteen were ribosomal-associated proteins. At least four proteins were encoded by genes known to cause autosomal dominant CHD. Conclusions: These studies define a set of human proteins that requires a full NAA15 complement for normal synthesis and development. A 50% reduction in the amount of NAA15 alters levels of at least 562 proteins and Nt-acetylation of only 9 proteins. One or more modulated proteins are likely responsible for NAA15-haploinsufficiency mediated CHD. Additionally, genetically engineered iPS cells provide a platform for evaluating the consequences of amino acid sequence variants of unknown significance on NAA15 function

Genome-wide association meta-analysis of 78,308 individuals identifies new loci and genes influencing human intelligence

Intelligence is associated with important economic and health-related life outcomes1. Despite intelligence having substantial heritability2 (0.54) and a confirmed polygenic nature, initial genetic studies were mostly underpowered3,4,5. Here we report a meta-analysis for intelligence of 78,308 individuals. We identify 336 associated SNPs (METAL P < 5 × 10−8) in 18 genomic loci, of which 15 are new. Around half of the SNPs are located inside a gene, implicating 22 genes, of which 11 are new findings. Gene-based analyses identified an additional 30 genes (MAGMA P < 2.73 × 10−6), of which all but one had not been implicated previously. We show that the identified genes are predominantly expressed in brain tissue, and pathway analysis indicates the involvement of genes regulating cell development (MAGMA competitive P = 3.5 × 10−6). Despite the well-known difference in twin-based heritability2 for intelligence in childhood (0.45) and adulthood (0.80), we show substantial genetic correlation (rg = 0.89, LD score regression P = 5.4 × 10−29). These findings provide new insight into the genetic architecture of intelligence

Reevaluating suicidal behaviors: comparing assessment methods to improve risk evaluations

This study examined suicide assessment validity by comparing methods of measuring current risk associated with past suicidal behaviors. Three independent samples (Ns\ua0=\ua0359, 1007, and 713; aged 18–76\ua0years) all included participants covering a broad spectrum of suicidality. Information theory, item response theory, general linear modeling, and linear regression modeling tested seven competing methods/models of assessing past suicidal behaviors in relation to current suicidality. In contrast to contemporary theories, ANOVA results showed suicide plans can indicate higher risk than suicide attempts when intent to die is higher. Contrary to popular practice, evidence demonstrated that defining risk by suicide ideation (yes/no), attempts or serious attempts (yes/no), are false dichotomies, were the least valid models tested, and failed to explain substantial explainable variance in suicidality/risk. A newly proposed model, differentiating behaviors with or without intent to die, was the most efficacious dichotomous method. However, as predicted, continuous variables were superior to dichotomous. The proposed suicidal barometer model (SBM) exhibited robust evidence as the best available model for evaluating suicidal behaviors in all samples (100 % probability), explaining 47–61\ua0% of suicidality variance and provided incremental improvement in risk evaluations. Findings were consistent by sample, sex, age-group, ethnicity, and psychiatric history. This study, and related evidence, demonstrate that there is a clear and present need for updating measures, clinical training and core competencies, for valid assessment and risk formulation

Hunter DBT Project: randomized controlled trial of dialectical behaviour therapy in women with borderline personality disorder

Objective: Deliberate self-harm (DSH) is common in Borderline Personality Disorder, may be due to a variety of reasons, and is associated with different degrees of suicidal intent. Understanding the reasons for episodes of DSH in this population may be helpful in developing interventions to reduce the rate of DSH or to assist in the clinical judgement of suicidal intention after DSH has occurred. Methods: The Parasuicide History Interview, version 2 (PHI-2) was used to determine the reasons for DSH events in 70 Australian women diagnosed with Borderline Personality Disorder. Factor analysis of the responses identified four empirically derived component factors. Multivariate models were developed to identify the independent predictors of suicidal deliberate self-harm (S-DSH) versus non-suicidal deliberate self-harm (NS-DSH) events. Results: Participants and raters showed strong agreement in classifying S-DSH and NS-DSH events. Methods used that involved self-poisoning, jumping or stabbing showed increased risk for S-DSH, adjusted odds ratio 12.07 (95% CI 2.17, 67.29), compared to the referent group, external damage to skin with no rescue contact being sought. Although no grouping of reasons were independently significant, the lower the effectiveness of the DSH event to resolve the reasons for the event, the higher the risk of it having been a S-DSH event. Conclusion: In clinical situations, any Borderline Personality Disorder patient seeking help or medical attention, using any method other than superficial external injury to skin, or reporting a failure to effectively resolve the reasons for the DSH event, should be considered as likely to have had a S-DSH event (greater suicidal intention). However, specific reasons for the DSH event, or individual subject characteristics, did not meaningfully distinguish S-DSH from NS-DSH events

Eyes on Asia (2012)

Introduction to the section 'Eyes on Asia' (curator E.Pollacchi) and presentation of each of the selected films. The catalogue is a bilingual English/Norwegian publication which is widely used as a reference material within nordic european countries

Graded response model analyses of the Suicidal ABC Scale and the Suicidal Behaviors Questionnaire-Revised.

<p>N = 1,720; WTD = wish to die; WTLr = wish to live reverse-scored; Ideation = suicidal ideation; Prediction = prediction of suicide attempts; Debate = internal suicidal debate; Behaviors = history of suicidal behaviors (SABCS uses SBM scoring; SBQ-R uses Osman et al. scoring [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0127442#pone.0127442.ref034" target="_blank">34</a>]); Comm. = communication of suicidality; a = item discrimination level; b_L = lowest item difficulty threshold; b_U = upper item difficulty threshold; IF = information function; Pct. = percentage of total scale information.</p><p>Graded response model analyses of the Suicidal ABC Scale and the Suicidal Behaviors Questionnaire-Revised.</p

Psychometric properties of the Suicidal ABC Scale and the Suicidal Behaviors Questionnaire-Revised.

<p>Study 1, n = 359; Study 2, n = 1007; Study 3, n = 713; Study 4, clinical sample, n = 72; SABCS-4 = 4-item SABCS; T2 = Time 2, n = 54. α = Cronbach’s α; S-B = Spearman-Brown prophecy coefficient; SE_m = standard error of measurement.</p><p>^†Studies used different response ranges for some SABCS items.</p><p>Psychometric properties of the Suicidal ABC Scale and the Suicidal Behaviors Questionnaire-Revised.</p

Factor loadings and communalities of Suicidal ABC Scale items.

<p>S1 = Study 1 (n = 359), S2 = Study 2 (n = 1007), S3 = Study 3 (n = 713), S4 = Study 4 (n = 72). Ideation = suicidal ideation, WTD = wish to die, Prediction = prediction of future suicide attempts, WTLr = wish to live reverse-scored, Debate = internal suicidal debate, Behaviors = history of suicidal behaviors, Variance = percentage of total trait variance explained by the retained factor.</p><p>Factor loadings and communalities of Suicidal ABC Scale items.</p

Item information curves: A = Suicidal ABC Scale, B = Suicidal Behaviors Questionnaire-Revised.

<p>Item information curves: A = Suicidal ABC Scale, B = Suicidal Behaviors Questionnaire-Revised.</p

The suicidal barometer model with descriptions of suicidality levels based on item response theory analyses.

<p>WTL = wish to live, WTD = wish to die.</p