The NRG1 exon 11 missense variant is not associated with autism in the Central Valley of Costa Rica

<p>Abstract</p> <p>Background</p> <p>We are conducting a genetic study of autism in the isolated population of the Central Valley of Costa Rica (CVCR). A novel Neuregulin 1 (NRG1) missense variant (exon 11 G>T) was recently associated with psychosis and schizophrenia (SCZ) in the same population isolate.</p> <p>Methods</p> <p>We genotyped the NRG1 exon 11 missense variant in 146 cases with autism, or autism spectrum disorder, with CVCR ancestry, and both parents when available (N = 267 parents) from 143 independent families. Additional microsatellites were genotyped to examine haplotypes bearing the exon 11 variant.</p> <p>Results</p> <p>The NRG1 exon 11 G>T variant was found in 4/146 cases including one de novo occurrence. The frequency of the variant in case chromosomes was 0.014 and 0.045 in the parental non-transmitted chromosomes. At least 6 haplotypes extending 0.229 Mb were associated with the T allele. Three independent individuals, with no personal or family history of psychiatric disorder, shared at least a 1 megabase haplotype 5' to the T allele.</p> <p>Conclusion</p> <p>The NRG1 exon 11 missense variant is not associated with autism in the CVCR.</p

Concerns about the use of polygenic embryo screening for psychiatric and cognitive traits

Private companies have begun offering services to allow parents undergoing in-vitro fertilisation to screen embryos for genetic risk of complex diseases, including psychiatric disorders. This procedure, called polygenic embryo screening, raises several difficult scientific and ethical issues, as discussed in this Personal View. Polygenic embryo screening depends on the statistical properties of polygenic risk scores, which are complex and not well studied in the context of this proposed clinical application. The clinical, social, and ethical implications of polygenic embryo screening have barely been discussed among relevant stakeholders. To our knowledge, the International Society of Psychiatric Genetics is the first professional biomedical organisation to issue a statement regarding polygenic embryo screening. For the reasons discussed in this Personal View, the Society urges caution and calls for additional research and oversight on the use of polygenic embryo screening

Differential Neuregulin 1 Cleavage in the Prefrontal Cortex and Hippocampus in Schizophrenia and Bipolar Disorder: Preliminary Findings

Neuregulin 1 (NRG1) is a key candidate susceptibility gene for both schizophrenia (SCZ) and bipolar disorder (BPD). The function of the NRG1 transmembrane proteins is regulated by cleavage. Alteration of membrane bound-NRG1 cleavage has been previously shown to be associated with behavioral impairments in mouse models lacking expression of NRG1-cleavage enzymes such as BACE1 and gamma secretase. We sought to determine whether alterations in NRG1 cleavage and associated enzymes occur in patients with SCZ and BPD.Using human postmortem brain, we evaluated protein expression of NRG1 cleavage products and enzymes that cleave at the external (BACE1, ADAM17, ADAM19) and internal (PS1-gamma secretase) sides of the cell membrane. We used three different cohorts (Controls, SCZ and BPD) and two distinct brain regions: BA9-prefrontal cortex (Controls (n = 6), SCZ (n = 6) and BPD (n = 6)) and hippocampus (Controls (n = 5), SCZ (n = 6) and BPD (n = 6)). In BA9, the ratio of the NRG1 N-terminal fragment relative to full length was significantly upregulated in the SCZ cohort (Bonferroni test, p = 0.011). ADAM17 was negatively correlated with full length NRG1 levels in the SCZ cohort (r = -0.926, p = 0.008). In the hippocampus we found significantly lower levels of a soluble 50 kDa NRG1 fragment in the two affected groups compared the control cohort (Bonferroni test, p = 0.0018). We also examined the relationship of specific symptomatology criteria with measures of NRG1 cleavage using the Bipolar Inventory of Signs and Symptoms Scale (BISS) and the Montgomery Åsberg Depression Rating Scale (MADRS). Our results showed a positive correlation between ADAM19 and psychosis (r = 0.595 p = 0.019); PS1 and mania (r = 0.535, p = 0.040); PS1 and depression (r = 0.567, p = 0.027) in BA9, and BACE1 with anxiety (r = 0.608, p = 0.03) in the hippocampus.Our preliminary findings suggest region-specific alterations in NRG1 cleavage in SCZ and BPD patients. These changes may be associated with specific symptoms in these psychiatric disorders

Schizophrenia-associated HapICE haplotype is associated with increased NRG1 type III expression and high nucleotide diversity

Excitement and controversy have followed neuregulin (NRG1) since its discovery as a putative schizophrenia susceptibility gene; however, the mechanism of action of the associated risk haplotype (HapICE) has not been identified, and specific genetic variations, which may increase risk to schizophrenia have remained elusive. Using a postmortem brain cohort from 37 schizophrenia cases and 37 controls, we resequenced upstream of the type I–IV promoters, and the HapICE repeat regions in intron 1. Relative abundance of seven NRG1 mRNA transcripts in the prefrontal cortex were determined and compared across diagnostic and genotypic groups. We identified 26 novel DNA variants and showed an increased novel variant load in cases compared with controls (χ2=7.815; P=0.05). The average nucleotide diversity (θ=10.0 × 10−4) was approximately twofold higher than that previously reported for BDNF, indicating that NRG1 may be particularly prone to genetic change. A greater nucleotide diversity was observed in the HapICE linkage disequilibrium block in schizophrenia cases (θ(case)=13.2 × 10−4; θ(control)=10.0 × 10−4). The specific HapICE risk haplotype was associated with increased type III mRNA (F=3.76, P=0.028), which in turn, was correlated with an earlier age of onset (r=−0.343, P=0.038). We found a novel intronic five-SNP haplotype ∼730 kb upstream of the type I promoter and determined that this region functions as transcriptional enhancer that is suppressed by SRY. We propose that the HapICE risk haplotype increases expression of the most brain-abundant form of NRG1, which in turn, elicits an earlier clinical presentation, thus providing a novel mechanism through which this genetic association may increase risk of schizophrenia

Disturbances in Hypothalamic-Pituitary-Adrenal Axis and Immunological Activity Differentiating between Unipolar and Bipolar Depressive Episodes

Differentiating bipolar depression (BD) from unipolar depression (UD) is difficult in clinical practice and, consequently, accurate recognition of BD can take as long as nine years. Research has therefore focused on the discriminatory capacities of biomarkers, such as markers of the hypothalamic-pituitary-adrenal (HPA) axis or immunological activity. However, no previous study included assessments of both systems, which is problematic as they may influence each other. Therefore, this study aimed to explore whether cortisol indicators and inflammatory markers were a) independently associated with and/or b) showed effect modification in relation to a lifetime (hypo)manic episode in a large sample of depressed patients.Data were derived from the Netherlands Study of Depression and Anxiety and comprised 764 patients with a DSM-IV depressive disorder at baseline, of which 124 (16.2%) had a lifetime (hypo)manic episode at the 2-year assessment, or a more recent episode at the 4-year or 6-year assessment. Baseline cortisol awakening response, evening cortisol and diurnal cortisol slope were considered as cortisol indicators, while baseline C-reactive Protein (CRP), Interleukin-6 (IL-6), and Tumor Necrosis Factor Alpha (TNF-α) were included as inflammatory markers.In depressed men and women, none of the cortisol indicators and inflammatory markers were (independently) associated with a (hypo)manic episode. However, effect modification was found of diurnal cortisol slope and CRP in relation to a (hypo)manic episode. Further analyses showed that depressed men with high levels of diurnal cortisol slope and CRP had an increased odds (OR=10.99, p=.001) of having a (hypo)manic episode. No significant differences were found in women.Our findings suggest that the combination of high diurnal cortisol slope and high CRP may differentiate between UD and BD. This stresses the importance of considering HPA-axis and immunological activity simultaneously, but more research is needed to unravel their interrelatedness

The role of DNA methylation in the pathophysiology and treatment of bipolar disorder

Bipolar disorder (BD) is a multifactorial illness thought to result from an interaction between genetic susceptibility and environmental stimuli. Epigenetic mechanisms, including DNA methylation, can modulate gene expression in response to the environment, and therefore might account for part of the heritability reported for BD. This paper aims to review evidence of the potential role of DNA methylation in the pathophysiology and treatment of BD. In summary, several studies suggest that alterations in DNA methylation may play an important role in the dysregulation of gene expression in BD, and some actually suggest their potential use as biomarkers to improve diagnosis, prognosis, and assessment of response to treatment. This is also supported by reports of alterations in the levels of DNA methyltransferases in patients and in the mechanism of action of classical mood stabilizers. In this sense, targeting specific alterations in DNA methylation represents exciting new treatment possibilities for BD, and the 'plastic' characteristic of DNA methylation accounts for a promising possibility of restoring environment-induced modifications in patients. (C) 2016 Elsevier Ltd. All rights reserved

Childhood maltreatment and inflammatory markers: a systematic review

ObjectiveChildhood maltreatment (CM) has been associated with several diseases in adult life, including diabetes, obesity and mental disorders. Inflammatory conditions have been postulated as possible mediators of this relationship. the aim was to conduct a systematic review regarding the association between CM and inflammatory markers in adulthood.MethodA literature search of the PubMed, ISI, EMBASE and PsychINFO databases was conducted. the key terms used were as follows: Child Maltreatment', Childhood Trauma', Early Life Stress', Psychological Stress', Emotional Stress', Child Abuse' and Child Neglect'. They were cross-referenced separately with the terms: C-reactive Protein (CRP)', Tumor Necrosis Factor', Cytokine', Interleukin', Inflammatory' and Inflammation'.ResultsTwenty articles remained in the review after exclusion criteria were applied. Studies showed that a history of CM was associated with increased levels of CRP, fibrinogen and proinflammatory cytokines. Increased levels of circulating CRP in individuals with a history of CM were the most robust finding among the studies. Data about anti-inflammatory mediators are still few and inconsistent.ConclusionChildhood maltreatment is associated with a chronic inflammatory state independent of clinical comorbidities. However, studies are heterogeneous regarding CM assessment and definition. Important methodological improvements are needed to better understand the potential impact of CM on inflammatory response.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Pontifical Catholic Univ Rio Grande Sul PUCRS, Ctr Studies & Res Traumat Stress NEPTE, Porto Alegre, RS, BrazilUniv Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USAUniversidade Federal de São Paulo, Interdisciplinary Lab Clin Neurosci LINC, São Paulo, BrazilUniversidade Federal de São Paulo, Interdisciplinary Lab Clin Neurosci LINC, São Paulo, BrazilWeb of Scienc

The Limits between Schizophrenia and Bipolar Disorder: What Do Magnetic Resonance Findings Tell Us?

Schizophrenia and bipolar disorder, two of the most severe psychiatric illnesses, have historically been regarded as dichotomous entities but share many features of the premorbid course, clinical profile, genetic factors and treatment approaches. Studies focusing on neuroimaging findings have received considerable attention, as they plead for an improved understanding of the brain regions involved in the pathophysiology of schizophrenia and bipolar disorder. In this review, we summarize the main magnetic resonance imaging findings in both disorders, aiming at exploring the neuroanatomical and functional similarities and differences between the two. The findings show that gray and white matter structural changes and functional dysconnectivity predominate in the frontal and limbic areas and the frontotemporal circuitry of the brain areas involved in the integration of executive, cognitive and affective functions, commonly affected in both disorders. Available evidence points to a considerable overlap in the affected regions between the two conditions, therefore possibly placing them at opposite ends of a psychosis continuum