Duplications in RB1CC1 are associated with schizophrenia; identification in large European sample sets

Schizophrenia (SCZ) is a severe and debilitating neuropsychiatric disorder with an estimated heritability of ~80%. Recently, de novo mutations, identified by next-generation sequencing (NGS) technology, have been suggested to contribute to the risk of developing SCZ. Although these studies show an overall excess of de novo mutations among patients compared with controls, it is not easy to pinpoint specific genes hit by de novo mutations as actually involved in the disease process. Importantly, support for a specific gene can be provided by the identification of additional alterations in several independent patients. We took advantage of existing genome-wide single-nucleotide polymorphism data sets to screen for deletions or duplications (copy number variations, CNVs) in genes previously implicated by NGS studies. Our approach was based on the observation that CNVs constitute part of the mutational spectrum in many human disease-associated genes. In a discovery step, we investigated whether CNVs in 55 candidate genes, suggested from NGS studies, were more frequent among 1637 patients compared with 1627 controls. Duplications in RB1CC1 were overrepresented among patients. This finding was followed-up in large, independent European sample sets. In the combined analysis, totaling 8461 patients and 112 871 controls, duplications in RB1CC1 were found to be associated with SCZ (P=1.29 × 10−5; odds ratio=8.58). Our study provides evidence for rare duplications in RB1CC1 as a risk factor for SCZ

Connected consciousness after tracheal intubation in young adults: an international multicentre cohort study

Background: Connected consciousness, assessed by response to command, occurs in at least 5% of general anaesthetic procedures and perhaps more often in young people. Our primary objective was to establish the incidence of connected consciousness after tracheal intubation in young people aged 18e40 yr. The secondary objectives were to assess the nature of these responses, identify relevant risk factors, and determine their relationship to postoperative outcomes. Methods: This was an international, multicentre prospective cohort study using the isolated forearm technique to assess connected consciousness shortly after tracheal intubation. Results: Of 344 enrolled subjects, 338 completed the study (mean age, 30 [standard deviation, 6.3] yr; 232 [69%] female). Responses after intubation occurred in 37/338 subjects (11%). Females (13%, 31/232) responded more often than males (6%, 6/106). In logistic regression, the risk of responsiveness was increased with female sex (odds ratio [OR adjusted ]¼2.7; 95% confidence interval [CI], 1.1e7.6; P¼0.022) and was decreased with continuous anaesthesia before laryngoscopy (OR adjusted ¼0.43; 95% CI, 0.20e0.96; P¼0.041). Responses were more likely to occur after a command to respond (and not to nonsense, 13 subjects) than after a nonsense statement (and not to command, four subjects, P¼0.049). Conclusions: Connected consciousness occured after intubation in 11% of young adults, with females at increased risk. Continuous exposure to anaesthesia between induction of anaesthesia and tracheal intubation should be considered t

Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture

The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained

TRPA1 mediates mechanical sensitization in nociceptors during inflammation.

Inflammation is a part of the body's natural response to tissue injury which initiates the healing process. Unfortunately, inflammation is frequently painful and leads to hypersensitivity to mechanical stimuli, which is difficult to treat clinically. While it is well established that altered sensory processing in the spinal cord contributes to mechanical hypersensitivity (central sensitization), it is still debated whether primary afferent neurons become sensitized to mechanical stimuli after tissue inflammation. We induced inflammation in C57BL/6 mice via intraplantar injection of Complete Freund's Adjuvant. Cutaneous C fibers exhibited increased action potential firing to suprathreshold mechanical stimuli. We found that abnormal responses to intense mechanical stimuli were completely suppressed by acute incubation of the receptive terminals with the TRPA1 inhibitor, HC-030031. Further, elevated responses were predominantly exhibited by a specific subgroup of C fibers, which we determined to be C-Mechano Cold sensitive fibers. Thus, in the presence of HC-030031, C fiber mechanical responses in inflamed mice were not different than responses in saline-injected controls. We also demonstrate that injection of the HC-030031 compound into the hind paw of inflamed mice alleviates behavioral mechanical hyperalgesia without affecting heat hyperalgesia. Further, we pharmacologically anesthetized the TRPA1-expressing fibers in vivo by co-injecting the membrane-impermeable sodium channel inhibitor QX-314 and the TRPA1 agonist cinnamaldehyde into the hind paw. This approach also alleviated behavioral mechanical hyperalgesia in inflamed mice but left heat hypersensitivity intact. Our findings indicate that C-Mechano Cold sensitive fibers exhibit enhanced firing to suprathreshold mechanical stimuli in a TRPA1-dependent manner during inflammation, and that input from these fibers drives mechanical hyperalgesia in inflamed mice

TRPA1-expressing fibers drive behavioral mechanical hyperalgesia.

<p>Treatment groups were divided into CFA-QX-314, saline-QX-314, CFA-QX-314+cinnamaldehyde (cinn) and saline-QX-314+cinn (concentrations were 0.2% QX and 30 µM cinn). <i>A,</i> Mechanical paw withdrawal threshold for each group in the injected paw (<i>white</i>) and uninjected paw (<i>grey</i>). <i>B,</i> Thermal paw withdrawal latency for each group in the injected paw (<i>white</i>) and uninjected paw (<i>grey</i>). *, two-way ANOVA followed by a Bonferroni post-hoc test of all four groups.</p

Inflammation increases mechanical responses of CMC fibers.

<p>Force-responses curves for <i>A,</i> CMC fibers <i>B</i>, CM fibers <i>C</i>, CMHC fibers and <i>D</i>, CMH fibers from CFA-injected and saline-injected mice. <i>E</i>, Action potentials fired by CMC fibers during a 20 mN (<i>top</i>) and 150 mN (<i>bottom</i>) mechanical stimulus, displayed in 0.5 sec bins. <i>F</i>, Scatterplot of individual C fiber responses to a 150 mN mechanical stimulus. <i>G</i>, Scatterplot of C fiber mechanical threshold, as determined by calibrated von Frey filament. <i>H</i>, Distribution of C fiber subtypes characterized from CFA-injected and saline-injected mice. *, two-way ANOVA followed by a Bonferroni post-hoc test.</p

A TRPA1 antagonist, HC-030031, alleviates mechanical hyperalgesia.

<p>Treatment groups were divided into CFA+vehicle, saline+vehicle, CFA+HC-030031 and saline+HC-030031 (100 µg HC-030031 in vehicle). <i>A,</i> Mechanical paw withdrawal threshold for each group in the injected paw (<i>white</i>) and uninjected paw (<i>grey</i>). <i>B,</i> Thermal paw withdrawal latency for each group in the injected paw (<i>white</i>) and uninjected paw (<i>grey</i>). *, two-way ANOVA followed by a Bonferroni post-hoc test of all four groups.</p