B-lymphoblastic leukemia/lymphoma with MYC and BCL2 gene rearrangements shows evidence for clonal evolution and mitotic recombination.

Background: B-lymphoblastic leukemia/lymphomas (B-ALL/LBL) are uncommon neoplasms that may be associated with a variety of cytogenetic and molecular changes. The mechanisms by which these changes arise have not been fully described.

Aims/purpose: This report describes an unusual case of B-ALL/LBL with complex clonal evolution that includes BCL2 and MYC gene rearrangements.

Longitudinal study of traumatic-stress related cellular and cognitive aging.

Traumatic stress is associated with both accelerated epigenetic age and increased risk for dementia. Accelerated epigenetic age might link symptoms of traumatic stress to dementia-associated biomarkers, such as amyloid-beta (Aβ) proteins, neurofilament light (NFL), and inflammatory molecules. We tested this hypothesis using longitudinal data obtained from 214 trauma-exposed military veterans (85 % male, mean age at baseline: 53 years, 75 % White) who were assessed twice over the course of an average of 5.

PTSD and Alcohol Use Disorders Predict the Pace of Cellular Aging.

Advanced epigenetic age is associated with psychopathology and may help to explain the link between psychopathology and physical health morbidity and mortality. Using a longitudinal sample of 171 trauma-exposed Veterans, we modeled the rate of change in epigenetic age across two time points (averaging 5.58 years apart) using two epigenetic age algorithms (GrimAge and Horvath) and tested associations with posttraumatic stress disorder (PTSD), alcohol use disorder (AUD), and depression.

Acquired Amegakaryocytic Thrombocytopenia Misdiagnosed as Immune Thrombocytopenia: A Case Report.

Introduction: Acquired amegakaryocytic thrombocytopenia (AATP) is a rare bleeding disorder that causes severe thrombocytopenia with preserved hematopoiesis of other cell lineages. Many cases are misdiagnosed and treated as immune thrombocytopenia.

Case Presentation: We report a case of AATP, in a 50-year-old man, that was treated as immune thrombocytopenia for years with no clinical response.

Identifying End Users' Preferences about Structuring Pharmacogenetic Test Orders in an Electronic Health Record System.

Pharmacogenetics (PGx) testing can be used for detecting genetic variations that may affect an individual's anticipated metabolism of, or response to, medications. Although several studies have focused on developing tools for delivering results from PGx testing, there is a relative dearth of information about how to design provider-friendly electronic order-entry systems for PGx. The U.

PTSD and the klotho longevity gene: Evaluation of longitudinal effects on inflammation via DNA methylation.

Background: Longevity gene klotho (KL) is associated with age-related phenotypes including lifespan, cardiometabolic disorders, cognition, and brain morphology, in part, by conferring protection against inflammation. We hypothesized that the KL/inflammation association might be altered in the presence of psychiatric stress and operate via epigenetic pathways. We examined KL polymorphisms, and their interaction with posttraumatic stress disorder (PTSD) symptoms, in association with KL DNA methylation in blood.

An epigenome-wide association study of posttraumatic stress disorder in US veterans implicates several new DNA methylation loci.

Background: Previous studies using candidate gene and genome-wide approaches have identified epigenetic changes in DNA methylation (DNAm) associated with posttraumatic stress disorder (PTSD).

Methods: In this study, we performed an EWAS of PTSD in a cohort of Veterans (n = 378 lifetime PTSD cases and 135 controls) from the Translational Research Center for TBI and Stress Disorders (TRACTS) cohort assessed using the Illumina EPIC Methylation BeadChip which assesses DNAm at more than 850,000 sites throughout the genome. Our model included covariates for ancestry, cell heterogeneity, sex, age, and a smoking score based on DNAm at 39 smoking-associated CpGs.

Correction for multiple testing in candidate-gene methylation studies.

We compared the performance of multiple testing corrections for candidate gene methylation studies, namely Sidak (accurate Bonferroni), false-discovery rate and three adjustments that incorporate the correlation between CpGs: extreme tail theory (ETT), Gao (GEA), and Li and Ji methods. The experiment-wide type 1 error rate was examined in simulations based on Illumina EPIC and 450K data. For high-correlation genes, Sidak and false-discovery rate corrections were conservative while the Li and Ji method was liberal.

Investigation of bidirectional longitudinal associations between advanced epigenetic age and peripheral biomarkers of inflammation and metabolic syndrome.

Epigenetic age estimations based on DNA methylation (DNAm) can predict human chronological age with a high level of accuracy. These DNAm age algorithms can also be used to index advanced cellular age, when estimated DNAm age exceeds chronological age. Advanced DNAm age has been associated with several diseases and metabolic and inflammatory pathology, but the causal direction of this association is unclear.

The goddess who spins the thread of life: Klotho, psychiatric stress, and accelerated aging.

Background: Longevity gene klotho (KL) is associated with age-related phenotypes but has not been evaluated against a direct human biomarker of cellular aging. We examined KL and psychiatric stress, including posttraumatic stress disorder (PTSD), which is thought to potentiate accelerated aging, in association with biomarkers of cellular aging.

Methods: The sample comprised 309 white, non-Hispanic genotyped veterans with measures of epigenetic age (DNA methylation age), telomere length (n = 252), inflammation (C-reactive protein), psychiatric symptoms, metabolic function, and white matter neural integrity (diffusion tensor imaging; n = 185).

Linking genes, circuits, and behavior: network connectivity as a novel endophenotype of externalizing.

Background: Externalizing disorders are known to be partly heritable, but the biological pathways linking genetic risk to the manifestation of these costly behaviors remain under investigation. This study sought to identify neural phenotypes associated with genomic vulnerability for externalizing disorders.

Methods: One-hundred fifty-five White, non-Hispanic veterans were genotyped using a genome-wide array and underwent resting-state functional magnetic resonance imaging.

Posttraumatic psychopathology and the pace of the epigenetic clock: a longitudinal investigation.

Background: Posttraumatic stress disorder (PTSD) and stress/trauma exposure are cross-sectionally associated with advanced DNA methylation age relative to chronological age. However, longitudinal inquiry and examination of associations between advanced DNA methylation age and a broader range of psychiatric disorders is lacking. The aim of this study was to examine if PTSD, depression, generalized anxiety, and alcohol-use disorders predicted acceleration of DNA methylation age over time (i.

Pharmacogenetic testing in the Veterans Health Administration (VHA): policy recommendations from the VHA Clinical Pharmacogenetics Subcommittee.

Purpose: The Veterans Health Administration (VHA) Clinical Pharmacogenetics Subcommittee is charged with making recommendations about whether specific pharmacogenetic tests should be used in healthcare at VHA facilities. We describe a process to inform VHA pharmacogenetic testing policy.

Methods: After developing consensus definitions of clinical validity and utility, the Subcommittee identified salient drug-gene pairs with potential clinical application in VHA.

Accelerated DNA Methylation Age: Associations With Posttraumatic Stress Disorder and Mortality.

Objective: Recently developed indices of cellular age based on DNA methylation (DNAm) data, referred to as DNAm age, are being used to study factors that influence the rate of aging and the health correlates of these metrics of the epigenetic clock. This study evaluated associations between trauma exposure, posttraumatic stress disorder (PTSD) symptoms, and accelerated versus decelerated DNAm age among military veterans. We also examined whether accelerated DNAm age predicted mortality over the course of a 6.

The correlation of methylation levels measured using Illumina 450K and EPIC BeadChips in blood samples.

Aim: We examined concordance of methylation levels across the Illumina Infinium HumanMethylation450 BeadChip and the Infinium MethylationEPIC BeadChip.

Methods: We computed the correlation for 145 whole blood DNA samples at each of the 422,524 CpG sites measured by both chips.

Results: The correlation at some sites was high (up to r = 0.

Contributions of polygenic risk for obesity to PTSD-related metabolic syndrome and cortical thickness.

Background: Research suggests that posttraumatic stress disorder (PTSD) is associated with metabolic syndrome (MetS) and that PTSD-associated MetS is related to decreased cortical thickness. However, the role of genetic factors in these associations is unclear. This study evaluated contributions of polygenic obesity risk and PTSD to MetS and of MetS and polygenic obesity risk to cortical thickness.

COMT Val158Met polymorphism moderates the association between PTSD symptom severity and hippocampal volume.

Background: Memory-based alterations are among the hallmark symptoms of posttraumatic stress disorder (PTSD) and may be associated with the integrity of the hippocampus. However, neuroimaging studies of hippocampal volume in individuals with PTSD have yielded inconsistent results, raising the possibility that various moderators, such as genetic factors, may influence this association. We examined whether the catechol-O-methyltransferase (COMT) Val158Met polymorphism, which has previously been shown to be associated with hippocampal volume in healthy individuals, moderates the association between PTSD and hippocampal volume.

Mild traumatic brain injury is associated with reduced cortical thickness in those at risk for Alzheimer's disease.

Moderate-to-severe traumatic brain injury is one of the strongest environmental risk factors for the development of neurodegenerative diseases such as late-onset Alzheimer's disease, although it is unclear whether mild traumatic brain injury, or concussion, also confers risk. This study examined mild traumatic brain injury and genetic risk as predictors of reduced cortical thickness in brain regions previously associated with early Alzheimer's disease, and their relationship with episodic memory. Participants were 160 Iraq and Afghanistan War veterans between the ages of 19 and 58, many of whom carried mild traumatic brain injury and post-traumatic stress disorder diagnoses.

Polygenic Risk for Externalizing Psychopathology and Executive Dysfunction in Trauma-Exposed Veterans.

The frequent co-occurrence of antisocial behavior and other disinhibited phenotypes reflects a highly heritable externalizing spectrum. We examined the molecular genetic basis of this spectrum by testing polygenic associations with psychopathology symptoms, impulsive traits, and cognitive functions in two samples of primarily military veterans ( =537, =194). We also investigated whether polygenic risk for externalizing moderated the effects of trauma on these phenotypes.

5-HT2A Gene Variants Moderate the Association between PTSD and Reduced Default Mode Network Connectivity.

The default mode network (DMN) has been used to study disruptions of functional connectivity in a wide variety of psychiatric and neurological conditions, including posttraumatic stress disorder (PTSD). Studies indicate that the serotonin system exerts a modulatory influence on DMN connectivity; however, no prior study has examined associations between serotonin receptor gene variants and DMN connectivity in either clinical or healthy samples. We examined serotonin receptor single nucleotide polymorphisms (SNPs), PTSD, and their interactions for association with DMN connectivity in 134 White non-Hispanic veterans.

Accelerated DNA methylation age: Associations with PTSD and neural integrity.

Background: Accumulating evidence suggests that posttraumatic stress disorder (PTSD) may accelerate cellular aging and lead to premature morbidity and neurocognitive decline.

Methods: This study evaluated associations between PTSD and DNA methylation (DNAm) age using recently developed algorithms of cellular age by Horvath (2013) and Hannum et al. (2013).