SUMMARY
Impulsivity, describing action without foresight, is an important feature of several psychiatric diseases, suicidality and violent behavior. The complex origins of impulsivity hinder identification of the genes influencing both it and diseases with which it is associated. We performed exon-centric sequencing of impulsive individuals in a founder population, targeting fourteen genes belonging to the serotonin and dopamine domain. A stop codon in HTR2B that is common (MAF >1%) but exclusive to Finns was identified. Expression of the gene in the human brain was assessed, as well as the molecular functionality of the stop codon that was associated with psychiatric diseases marked by impulsivity in both population and family-based analyses. Knockout of Htr2b increased impulsive behaviors in mice, indicative of predictive validity. Our study shows the potential for identifying and tracing effects of rare alleles in complex behavioral phenotypes using founder populations, and suggests a role for HTR2B in impulsivity.
ICD therapy can effectively manage malignant arrhythmias in selected pediatric and congenital heart patients. Spurious shocks or ICD storm may increase morbidity and emphasize the need for concomitant medical and ablative therapy. ICD lead failure was relatively frequent in this population.
Improvement of acute RFCA outcomes was contemporaneous with introduction of novel technologies. Intra-atrial re-entrant tachycardia recurrence was common, and no effect on mortality was discerned, but most patients had effective palliation of symptoms. Chronic outcome predictors included the underlying disease severity, application of novel technologies and successful ablation of all targeted arrhythmia circuits.
Background-Characterization of reentrant circuits and targeting ablation sites remains difficult for intra-atrial reentrant tachycardias (IART) in congenital heart disease (CHD). Methods and Results-Electroanatomic mapping and entrainment pacing were performed before successful ablation of 18 IART circuits in 15 patients with CHD. Principal features of IART circuits were atrial septal defect (4 patients), atriotomy (3 patients), other atrial scar (3 patients), crista terminalis (3 patients), and right atrioventricular valve (5 patients). A median of 176 sites (range, 96 to 317 sites) was mapped for activation and 13 sites (range, 9 to 28 sites) for entrainment response. Postpacing intervals within 20 ms of tachycardia cycle length and stimulus-to-P-wave intervals of 0 to 90 ms (exit zones) were mapped to atrial surfaces generated by electroanatomic mapping. Criteria for entrainment were met over a median of 21 cm 2 of atrial surface (range, 2 to 75 cm 2 ), 19% (range, 1% to 81%) of total area tested. Using integrated data, relations between activation sequence and protected corridor of conduction could be inferred for 16 of 17 IARTs. Successful ablation was achieved at a site distant from the putative protected corridor in 9 of 18 (50%) circuits. Conclusions-The right atrium in CHD supports a variety of IART mechanisms. Fusion of activation and entrainment data provided insight into specific IART mechanisms relevant to ablation.
Context
Childhood trauma may predispose individuals to aggressive behavior, and both childhood trauma and aggressive behavior are associated with hypothalamicpituitary-adrenal axis dysregulation.
Objective
To determine whether there would be an interaction between genetic variation in FKBP5 and childhood trauma in predicting aggressive behavior.
Design
Cross-sectional study. Four FKBP5 single-nucleotide polymorphisms used in previous studies (rs3800373, rs9296158, rs1360780, and rs9470080) were genotyped. Three diplotypes were derived from 2 major putatively functional haplotypes regulating protein expression that were previously associated with glucocorticoid receptor sensitivity.
Setting
Penitentiary District of Abruzzo-Molise in central Italy.
Participants
A population of 583 male Italian prisoners recruited between 2005 and 2008.
Main Outcome Measures
A comprehensive analysis of aggression and impulsivity was undertaken using the Brown-Goodwin Lifetime History of Aggression (BGHA) questionnaire, the Buss-Durkee Hostility Inventory (BDHI), and the Barratt Impulsiveness Scale (BIS). A history of childhood trauma was investigated with the Childhood Trauma Questionnaire. The interaction between the FKBP5 diplotypes and childhood trauma on measures of aggression was analyzed. Analyses were replicated with a second behavioral measure of aggression: violent behavior in jail. Individual single-nucleotide polymorphism analysis was performed.
Results
Childhood trauma had a significant effect on BGHA and BDHI scores but not on BIS scores. We observed a significant influence of the FKBP5 high-expression diplotype on both a lifetime history of aggressive behavior (BGHA) (P = .012) and violent behavior in jail (P = .025) but only in individuals exposed to childhood trauma, in particular to physical abuse. No main effect of the FKBP5 diplotypes was observed.
Conclusion
These data suggest that childhood trauma and variants in the FKBP5 gene may interact to increase the risk of overt aggressive behavior.
Impulsivity, defined as the tendency to act without foresight, comprises a multitude of constructs and is associated with a variety of psychiatric disorders. Dissecting different aspects of impulsive behaviour and relating these to specific neurobiological circuits would improve our understanding of the etiology of complex behaviours for which impulsivity is key, and advance genetic studies in this behavioural domain. In this review, we will discuss the heritability of some impulsivity constructs and their possible use as endophenotypes (heritable, disease-associated intermediate phenotypes). Several functional genetic variants associated with impulsive behaviour have been identified by the candidate gene approach and re-sequencing, and whole genome strategies can be implemented for discovery of novel rare and common alleles influencing impulsivity. Via deep sequencing an uncommon
HTR2B
stop codon, common in one population, was discovered, with implications for understanding impulsive behaviour in both humans and rodents and for future gene discovery.
Emotion is critical to most aspects of human behavior, and individual differences in systems recruited to process emotional stimuli, expressed as variation in emotionality, are characteristic of several neuropsychiatric disorders. We examine the genetic origins of individual differences in emotion processing by focusing on functional variants at five genes: catechol-O-methyl transferase (COMT), serotonin transporter (SLC6A4), neuropeptide Y (NPY), a glucocorticoid receptor-regulating co-chaperone of stress proteins (FKBP5) and pituitary adenylate cyclase-activating polypeptide (PACAP). These represent a range of effects of genes on emotion as well as the variety of mechanisms and factors, such as stress, that modify these effects. The new genomic era of genome-wide association studies (GWAS) and deep sequencing may yield a wealth of new loci modulating emotion. The effects of these genes can be validated by neuroimaging, neuroendocrine and other studies accessing intermediate phenotypes, deepening our understanding of mechanisms of emotion and variation in emotionality.
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