A Variational Bayes Discrete Mixture Test for Rare Variant Association

Recently, many statistical methods have been proposed to test for associations between rare genetic variants and complex traits. Most of these methods test for association by aggregating genetic variations within a predefined region, such as a gene. Although there is evidence that “aggregate” tests are more powerful than the single marker test, these tests generally ignore neutral variants and therefore are unable to identify specific variants driving the association with phenotype. We propose a novel aggregate rare‐variant test that explicitly models a fraction of variants as neutral, tests associations at the gene‐level, and infers the rare‐variants driving the association. Simulations show that in the practical scenario where there are many variants within a given region of the genome with only a fraction causal our approach has greater power compared to other popular tests such as the Sequence Kernel Association Test (SKAT), the Weighted Sum Statistic (WSS), and the collapsing method of Morris and Zeggini (MZ). Our algorithm leverages a fast variational Bayes approximate inference methodology to scale to exome‐wide analyses, a significant computational advantage over exact inference model selection methodologies. To demonstrate the efficacy of our methodology we test for associations between von Willebrand Factor (VWF) levels and VWF missense rare‐variants imputed from the National Heart, Lung, and Blood Institute's Exome Sequencing project into 2,487 African Americans within the VWF gene. Our method suggests that a relatively small fraction (～10%) of the imputed rare missense variants within VWF are strongly associated with lower VWF levels in African Americans.     

The association of PTSD with physical and mental health functioning and disability (VA Cooperative Study #569: the course and consequences of posttraumatic stress disorder in Vietnam-era Veteran twins)

Purpose

To assess the relationship of posttraumatic stress disorder (PTSD) with health functioning and disability in Vietnam-era Veterans.

Methods

A cross-sectional study of functioning and disability in male Vietnam-era Veteran twins. PTSD was measured by the Composite International Diagnostic Interview; health functioning and disability were assessed using the Veterans RAND 36-Item Health Survey (VR-36) and the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0). All data collection took place between 2010 and 2012.

Results

Average age of the 5,574 participating Veterans (2,102 Vietnam theater and 3,472 non-theater) was 61.0 years. Veterans with PTSD had poorer health functioning across all domains of VR-36 and increased disability for all subscales of WHODAS 2.0 (all p < .001) compared with Veterans without PTSD. Veterans with PTSD were in poorer overall health on the VR-36 physical composite summary (PCS) (effect size = 0.31 in theater and 0.47 in non-theater Veterans; p < .001 for both) and mental composite summary (MCS) (effect size = 0.99 in theater and 0.78 in non-theater Veterans; p < .001 for both) and had increased disability on the WHODAS 2.0 summary score (effect size = 1.02 in theater and 0.96 in non-theater Veterans; p < .001 for both). Combat exposure, independent of PTSD status, was associated with lower PCS and MCS scores and increased disability (all p < .05, for trend). Within-pair analyses in twins discordant for PTSD produced consistent findings.

Conclusions

Vietnam-era Veterans with PTSD have diminished functioning and increased disability. The poor functional status of aging combat-exposed Veterans is of particular concern.     

Enhanced Cytotoxicity through Conjugation of a “Clickable” Luminescent Re(I) Complex to a Cell-Penetrating Lipopeptide

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Infant rats can acquire,but not retain contextual associations in object-in-context and contextual fear conditioning paradigms

Context learning in postnatal day (PD) 16–18 rats has been taken by Revillo, Cotella, Paglini, and Arias (2015, Physiology & Behavior, 148 , 6–21) to challenge the view that the ontogeny of contextual learning is related to the development of the hippocampal system (Rudy, 1993, Behavioral Neuroscience, 107 (5), 887–891; Schiffino, Murawski, Rosen, & Stanton, 2011 Neurobiology of Learning and Memory, 95 (2), 190–198). Whether context learning is “incidental” or “reinforcement-driven” may determine the ontogeny and neural systems involved (Rudy, 2009, Learning & Memory (Cold Spring Harbor, N.Y.), 16 , 573–585). However, we have shown differential ontogeny of two different forms of incidental context learning, the context pre-exposure facilitation effect (CPFE; Jablonski, Schiffino, & Stanton, 2012, Developmental Psychobiology, 54 (7), 714–722), which emerges between PD 17 and 21; and object-in-context recognition (OiC, Ramsaran, Westbrook, & Stanton, 2016, Developmental Psychobiology, 58 (7), 883–895; Ramsaran, Sanders, & Stanton, 2016, Behavioural Brain Research, 298 , 37–47), which is present on PD17. We investigated whether this task-dissociation reflects an encoding or a retention deficit, by varying the sample-to-testing intervals for both tasks. Experiment 1A found that PD17 rats were able to perform the OiC task after short (5 min) but not long (24 hr) sample-to-test intervals. Experiments 1B and 1C found that PD17 rats trained on the CPFE are able to acquire and express context-shock associations after short but not long retention intervals. These findings suggest that pre-weanling rats encode contexts but show poor consolidation or retrieval after longer retention intervals.     

Better cognitive efficiency is associated with increased experimental anxiety

There is increased interest in the development of cognitive training targeting working memory (WM) to alleviate anxiety symptoms, but the effectiveness of such an approach is unclear. Improved understanding of the effect of cognitive training on anxiety may facilitate the development of more effective cognitive training treatment for anxiety disorders. This study uses an experimental approach to examine the interplay of WM and anxiety following WM training. Previous studies show that increased demand on WM reduces concurrent anxiety evoked by threat of shock (induced anxiety). However, improving WM pharmacologically or via exercise prevents this anxiolytic effect. Conceivably, improving WM frees up cognitive resources to process threat information, thereby increasing anxiety. The present study tested the hypothesis that practicing a high load WM (i.e., increased demand) task would improve WM, and thus, free cognitive resources to process threat of shock, resulting in more anxiety (i.e., greater startle) during a subsequent WM task. Participants were randomly assigned to two training groups. The active-training group (N = 20) was trained on a 1- (low load) & 3-back (high load) WM task, whereas the control-training group (N = 20) performed a 0-back WM task. The experimental phase, similar in both groups, consisted of a 1- & 3-back WM task performed during both threat of shock and safety. As predicted, active training improved WM accuracy and increased anxiety during the experimental 3-back WM task. Therefore, improving WM efficiency can increase anxiety, possibly by freeing WM resources to process threat information.     

Reduced P300 in depression: Evidence from a flanker task and impact on ERN,CRN, and Pe

Individuals with current depression show reduced amplitude of the P300 component of the stimulus-locked event-related potential (ERP)—an effect most often examined in oddball tasks. Although imperative stimuli in response-monitoring paradigms (e.g., the flanker task), also elicit a P300, it is unclear whether a blunted P300 can be observed in depression in these tasks. Moreover, the P300 overlaps with the correct-response negativity (CRN) and error-related negativity (ERN), and is similar to the error positivity (Pe)—response-locked ERPs frequently examined in flanker tasks. The current study examined the stimulus-locked P300 and response-monitoring ERPs on error (i.e., ERN, Pe) and correct responses (i.e., CRN) during an arrowhead flanker task in 72 individuals with a current depressive disorder and 42 never depressed healthy individuals. Consistent with findings from oddball tasks, P300 amplitude was reduced among participants with depression. Further, results indicated increased ERN and CRN, and decreased Pe, in depression. However, when the blunted P300 was included in analyses, group differences in response-monitoring ERPs were no longer evident. Accordingly, P300 amplitudes were correlated negatively with the ERN/CRN and positively with Pe in both groups. A blunted P300 in depression can be observed in speeded response tasks, and can produce apparent increases in ERN and CRN due to ERP component overlap. Further, reduced Pe in participants with depression may reflect a reduced P300 to error commission. These data highlight the central role of reduced P300 in clinical depression, and demonstrate that this effect can be observed across both stimulus- and response-locked ERPs in speeded response tasks.     

Myxoid glioneuronal tumor,PDGFRA p.K385‐mutant: clinical,radiologic, and histopathologic features

“Myxoid glioneuronal tumor, PDGFRA p.K385‐mutant” is a recently described tumor entity of the central nervous system with a predilection for origin in the septum pellucidum and a defining dinucleotide mutation at codon 385 of the PDGFRA oncogene replacing lysine with either leucine or isoleucine (p.K385L/I). Clinical outcomes and optimal treatment for this new tumor entity have yet to be defined. Here, we report a comprehensive clinical, radiologic, and histopathologic assessment of eight cases. In addition to its stereotypic location in the septum pellucidum, we identify that this tumor can also occur in the corpus callosum and periventricular white matter of the lateral ventricle. Tumors centered in the septum pellucidum uniformly were associated with obstructive hydrocephalus, whereas tumors centered in the corpus callosum and periventricular white matter did not demonstrate hydrocephalus. While multiple patients were found to have ventricular dissemination or local recurrence/progression, all patients in this series remain alive at last clinical follow‐up despite only biopsy or subtotal resection without adjuvant therapy in most cases. Our study further supports “myxoid glioneuronal tumor, PDGFRA p.K385‐mutant” as a distinct CNS tumor entity and expands the spectrum of clinicopathologic and radiologic features of this neoplasm.