ABSTRACT
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 (Aß) 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 5.6 years. Cross-lagged panel mediation models evaluated measures of lifetime posttraumatic stress disorder and internalizing and externalizing comorbidity (assessed at Time 1; T1) in association with T1 epigenetic age (per the GrimAge algorithm) and T1 plasma markers of neuropathology along with bidirectional temporal paths between T1 and T2 epigenetic age and the plasma markers. Results revealed that a measure of externalizing comorbidity was associated with accelerated epigenetic age (ß = 0.30, p <.01), which in turn, was associated with subsequent increases in Aß-40 (ß = 0.20, p <.001), Aß-42 (ß = 0.18, p <.001), and interleukin-6 (ß = 0.18, p <.01). T1 advanced epigenetic age and the T1 neuropathology biomarkers NFL and glial fibrillary acidic protein predicted worse performance on T2 neurocognitive tasks assessing working memory, executive/attentional control, and/or verbal memory (ps = 0.03 to 0.009). Results suggest that advanced GrimAge is predictive of subsequent increases in neuropathology and inflammatory biomarkers as well as worse cognitive function, highlighting the clinical significance of this biomarker with respect to cognitive aging and brain health over time. The finding that advanced GrimAge mediated the association between psychiatric comorbidity and future neuropathology is important for understanding potential pathways to neurodegeneration and early identification of those at greatest risk.
Subject(s)
Cognitive Aging , Cognitive Dysfunction , Dementia , Male , Humans , Middle Aged , Female , Longitudinal Studies , Amyloid beta-Peptides , Biomarkers , AgingABSTRACT
Importance: Selecting effective antidepressants for the treatment of major depressive disorder (MDD) is an imprecise practice, with remission rates of about 30% at the initial treatment. Objective: To determine whether pharmacogenomic testing affects antidepressant medication selection and whether such testing leads to better clinical outcomes. Design, Setting, and Participants: A pragmatic, randomized clinical trial that compared treatment guided by pharmacogenomic testing vs usual care. Participants included 676 clinicians and 1944 patients. Participants were enrolled from 22 Department of Veterans Affairs medical centers from July 2017 through February 2021, with follow-up ending November 2021. Eligible patients were those with MDD who were initiating or switching treatment with a single antidepressant. Exclusion criteria included an active substance use disorder, mania, psychosis, or concurrent treatment with a specified list of medications. Interventions: Results from a commercial pharmacogenomic test were given to clinicians in the pharmacogenomic-guided group (n = 966). The comparison group received usual care and access to pharmacogenomic results after 24 weeks (n = 978). Main Outcomes and Measures: The co-primary outcomes were the proportion of prescriptions with a predicted drug-gene interaction written in the 30 days after randomization and remission of depressive symptoms as measured by the Patient Health Questionnaire-9 (PHQ-9) (remission was defined as PHQ-9 ≤ 5). Remission was analyzed as a repeated measure across 24 weeks by blinded raters. Results: Among 1944 patients who were randomized (mean age, 48 years; 491 women [25%]), 1541 (79%) completed the 24-week assessment. The estimated risks for receiving an antidepressant with none, moderate, and substantial drug-gene interactions for the pharmacogenomic-guided group were 59.3%, 30.0%, and 10.7% compared with 25.7%, 54.6%, and 19.7% in the usual care group. The pharmacogenomic-guided group was more likely to receive a medication with a lower potential drug-gene interaction for no drug-gene vs moderate/substantial interaction (odds ratio [OR], 4.32 [95% CI, 3.47 to 5.39]; P < .001) and no/moderate vs substantial interaction (OR, 2.08 [95% CI, 1.52 to 2.84]; P = .005) (P < .001 for overall comparison). Remission rates over 24 weeks were higher among patients whose care was guided by pharmacogenomic testing than those in usual care (OR, 1.28 [95% CI, 1.05 to 1.57]; P = .02; risk difference, 2.8% [95% CI, 0.6% to 5.1%]) but were not significantly higher at week 24 when 130 patients in the pharmacogenomic-guided group and 126 patients in the usual care group were in remission (estimated risk difference, 1.5% [95% CI, -2.4% to 5.3%]; P = .45). Conclusions and Relevance: Among patients with MDD, provision of pharmacogenomic testing for drug-gene interactions reduced prescription of medications with predicted drug-gene interactions compared with usual care. Provision of test results had small nonpersistent effects on symptom remission. Trial Registration: ClinicalTrials.gov Identifier: NCT03170362.
Subject(s)
Antidepressive Agents , Depressive Disorder, Major , Drug Interactions , Inappropriate Prescribing , Pharmacogenomic Testing , Antidepressive Agents/metabolism , Antidepressive Agents/pharmacology , Antidepressive Agents/therapeutic use , Clinical Decision-Making , Depressive Disorder, Major/drug therapy , Depressive Disorder, Major/genetics , Drug Interactions/genetics , Female , Humans , Inappropriate Prescribing/prevention & control , Male , Middle Aged , Pharmacogenetics , Remission Induction , Treatment Outcome , United States , United States Department of Veterans AffairsABSTRACT
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. Members met monthly to discuss each drug-gene pair, the evidence of clinical utility for the associated pharmacogenetic test, and any VHA-specific testing considerations. The Subcommittee classified each test as strongly recommended, recommended, or not routinely recommended before drug initiation. RESULTS: Of 30 drug-gene pair tests reviewed, the Subcommittee classified 4 (13%) as strongly recommended, including HLA-B*15:02 for carbamazepine-associated Stevens-Johnston syndrome and G6PD for rasburicase-associated hemolytic anemia; 12 (40%) as recommended, including CYP2D6 for codeine toxicity; and 14 (47%) as not routinely recommended, such as CYP2C19 for clopidogrel dosing. CONCLUSION: Only half of drug-gene pairs with high clinical validity received Subcommittee support for policy promoting their widespread use across VHA. The Subcommittee generally found insufficient evidence of clinical utility or available, effective alternative strategies for the remainders. Continual evidence review and rigorous outcomes research will help promote the translation of pharmacogenetic discovery to healthcare.
Subject(s)
Clopidogrel/adverse effects , Pharmacogenetics/statistics & numerical data , Stevens-Johnson Syndrome/epidemiology , Veterans Health/statistics & numerical data , Clopidogrel/therapeutic use , Cytochrome P-450 CYP2C19/genetics , Cytochrome P-450 CYP2D6/genetics , Genotype , Glucosephosphate Dehydrogenase/genetics , HLA-B15 Antigen/genetics , Humans , Pharmacogenomic Testing , Stevens-Johnson Syndrome/genetics , United States , United States Department of Veterans Affairs/statistics & numerical data , VeteransABSTRACT
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.e. an increasing pace, or rate of advancement, of the epigenetic clock). METHODS: Genome-wide DNA methylation and a comprehensive set of psychiatric symptoms and diagnoses were assessed in 179 Iraq/Afghanistan war veterans who completed two assessments over the course of approximately 2 years. Two DNA methylation age indices (Horvath and Hannum), each a weighted index of an array of genome-wide DNA methylation probes, were quantified. The pace of the epigenetic clock was operationalized as change in DNA methylation age as a function of time between assessments. RESULTS: Analyses revealed that alcohol-use disorders (p = 0.001) and PTSD avoidance and numbing symptoms (p = 0.02) at Time 1 were associated with an increasing pace of the epigenetic clock over time, per the Horvath (but not the Hannum) index of cellular aging. CONCLUSIONS: This is the first study to suggest that posttraumatic psychopathology is longitudinally associated with a quickened pace of the epigenetic clock. Results raise the possibility that accelerated cellular aging is a common biological consequence of stress-related psychopathology, which carries implications for identifying mechanisms of stress-related cellular aging and developing interventions to slow its pace.
Subject(s)
Cellular Senescence , DNA Methylation , Epigenesis, Genetic , Psychopathology , Stress Disorders, Post-Traumatic/genetics , Adult , Cross-Sectional Studies , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Longitudinal Studies , Male , Regression Analysis , Stress Disorders, Post-Traumatic/psychology , Trauma Severity Indices , United States , United States Department of Veterans Affairs , Young AdultABSTRACT
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. Genetic susceptibility was assessed using an independently developed polygenic score (PS) for externalizing, and functional neural networks were identified using graph theory based network analysis. Tasks of inhibitory control and psychiatric diagnosis (alcohol/substance use disorders) were used to measure externalizing phenotypes. RESULTS: A polygenic externalizing disorder score (PS) predicted connectivity in a brain circuit (10 nodes, nine links) centered on left amygdala that included several cortical [bilateral inferior frontal gyrus (IFG) pars triangularis, left rostral anterior cingulate cortex (rACC)] and subcortical (bilateral amygdala, hippocampus, and striatum) regions. Directional analyses revealed that bilateral amygdala influenced left prefrontal cortex (IFG) in participants scoring higher on the externalizing PS, whereas the opposite direction of influence was observed for those scoring lower on the PS. Polygenic variation was also associated with higher Participation Coefficient for bilateral amygdala and left rACC, suggesting that genes related to externalizing modulated the extent to which these nodes functioned as communication hubs. CONCLUSIONS: Findings suggest that externalizing polygenic risk is associated with disrupted connectivity in a neural network implicated in emotion regulation, impulse control, and reinforcement learning. Results provide evidence that this network represents a genetically associated neurobiological vulnerability for externalizing disorders.
Subject(s)
Amygdala/physiopathology , Endophenotypes , Executive Function/physiology , Genetic Predisposition to Disease/genetics , Gyrus Cinguli/physiopathology , Inhibition, Psychological , Nerve Net/physiopathology , Prefrontal Cortex/physiopathology , Substance-Related Disorders/genetics , Substance-Related Disorders/physiopathology , Adult , Amygdala/diagnostic imaging , Connectome , Corpus Striatum/diagnostic imaging , Corpus Striatum/physiopathology , Emotional Regulation/physiology , Female , Gyrus Cinguli/diagnostic imaging , Hippocampus/diagnostic imaging , Hippocampus/physiopathology , Humans , Impulsive Behavior/physiology , Magnetic Resonance Imaging , Male , Middle Aged , Nerve Net/diagnostic imaging , Prefrontal Cortex/diagnostic imaging , Reinforcement, Psychology , Substance-Related Disorders/diagnostic imaging , Veterans , Young AdultABSTRACT
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 (nâ¯=â¯252), inflammation (C-reactive protein), psychiatric symptoms, metabolic function, and white matter neural integrity (diffusion tensor imaging; nâ¯=â¯185). Genotyping and DNA methylation were obtained on epi/genome-wide beadchips. RESULTS: In gene by environment analyses, two KL variants (rs9315202 and rs9563121) interacted with PTSD severity (peak corrected pâ¯=â¯0.044) and sleep disturbance (peak corrected pâ¯=â¯0.034) to predict advanced epigenetic age. KL variant, rs398655, interacted with self-reported pain in association with slowed epigenetic age (corrected pâ¯=â¯0.048). A well-studied protective variant, rs9527025, was associated with slowed epigenetic age (pâ¯=â¯0.046). The peak PTSD interaction term (with rs9315202) also predicted C-reactive protein (pâ¯=â¯0.049), and white matter microstructural integrity in two tracts (corrected psâ¯=â¯0.005 - 0.035). This SNP evidenced a main effect with an index of metabolic syndrome severity (pâ¯=â¯0.015). Effects were generally accentuated in older subjects. CONCLUSIONS: Rs9315202 predicted multiple biomarkers of cellular aging such that psychiatric stress was more strongly associated with cellular aging in those with the minor allele. KL genotype may contribute to a synchronized pathological aging response to stress and could be a therapeutic target to alter the pace of cellular aging.
Subject(s)
Cellular Senescence/genetics , Glucuronidase/genetics , Stress, Psychological/metabolism , Adult , Aging/genetics , Aging/metabolism , Alleles , Brain/metabolism , C-Reactive Protein/analysis , Cellular Senescence/physiology , DNA Methylation/genetics , Diffusion Tensor Imaging/methods , Epigenesis, Genetic/genetics , Female , Genotype , Glucuronidase/metabolism , Humans , Klotho Proteins , Longevity/genetics , Longevity/physiology , Male , Stress Disorders, Post-Traumatic/metabolism , Stress, Psychological/genetics , Telomere Homeostasis/genetics , Telomere Homeostasis/physiology , Veterans , White Matter/metabolismABSTRACT
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 6.5-year medical record review period. METHODS: Three hundred thirty-nine genotype-confirmed white, non-Hispanic, middle-aged, trauma-exposed veterans underwent psychiatric assessment and genome-wide DNAm analysis. DNAm age was calculated using a previously validated algorithm. Medical records were available for a subset of 241 veterans and were reviewed approximately 6.5 years after DNA collection and PTSD assessment. RESULTS: PTSD hyperarousal symptoms were associated with accelerated DNAm age (ß = 0.20, p = .009) but trauma exposure and total PTSD severity were not. Accelerated DNAm age was also associated with 13% increased risk for all-cause mortality (hazard ratio = 1.13, 95% confidence interval = 1.01-1.26) during the medical record review period. CONCLUSIONS: Findings of this study replicate the association between PTSD and accelerated DNAm age and suggest that this effect may be specific to the hyperarousal symptom cluster. Results point to the potential utility of DNAm age algorithms for identifying individuals who are aging at an accelerated rate and for determining the factors that influence this process.
Subject(s)
Cellular Senescence/physiology , DNA Methylation/physiology , Mortality , Stress Disorders, Post-Traumatic/metabolism , Veterans , Adult , Female , Humans , Male , Middle Aged , Stress Disorders, Post-Traumatic/physiopathologyABSTRACT
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. Whole-genome polygenic risk scores for the development of Alzheimer's disease were calculated using summary statistics from the largest Alzheimer's disease genome-wide association study to date. Results showed that mild traumatic brain injury moderated the relationship between genetic risk for Alzheimer's disease and cortical thickness, such that individuals with mild traumatic brain injury and high genetic risk showed reduced cortical thickness in Alzheimer's disease-vulnerable regions. Among males with mild traumatic brain injury, high genetic risk for Alzheimer's disease was associated with cortical thinning as a function of time since injury. A moderated mediation analysis showed that mild traumatic brain injury and high genetic risk indirectly influenced episodic memory performance through cortical thickness, suggesting that cortical thinning in Alzheimer's disease-vulnerable brain regions is a mechanism for reduced memory performance. Finally, analyses that examined the apolipoprotein E4 allele, post-traumatic stress disorder, and genetic risk for schizophrenia and depression confirmed the specificity of the Alzheimer's disease polygenic risk finding. These results provide evidence that mild traumatic brain injury is associated with greater neurodegeneration and reduced memory performance in individuals at genetic risk for Alzheimer's disease, with the caveat that the order of causal effects cannot be inferred from cross-sectional studies. These results underscore the importance of documenting head injuries even within the mild range as they may interact with genetic risk to produce negative long-term health consequences such as neurodegenerative disease.
Subject(s)
Alzheimer Disease/pathology , Brain Injuries, Traumatic/pathology , Cerebral Cortex/pathology , Adult , Alzheimer Disease/complications , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/genetics , Apolipoproteins E/genetics , Brain Injuries, Traumatic/complications , Brain Injuries, Traumatic/diagnostic imaging , Cerebral Cortex/diagnostic imaging , Cross-Sectional Studies , Disease Progression , Female , Genome-Wide Association Study , Genotype , Humans , Imaging, Three-Dimensional , Magnetic Resonance Imaging , Male , Middle Aged , Neuropsychological Tests , Polymorphism, Single Nucleotide/genetics , Psychiatric Status Rating Scales , Regression Analysis , Risk Factors , Veterans , Young AdultABSTRACT
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. METHODS: 196 white, non-Hispanic veterans of the wars in Iraq and Afghanistan underwent clinical diagnostic interviews, physiological assessments, and genome-wide genotyping; 168 also completed magnetic resonance imaging scans. Polygenic risk scores (PRSs) for obesity were calculated from results of a prior genome-wide association study (Speliotes et al., 2010) and PTSD and MetS severity factor scores were obtained. RESULTS: Obesity PRS (ß=0.15, p=0.009) and PTSD (ß=0.17, p=0.005) predicted MetS and interacted such that the association between PTSD and MetS was stronger in individuals with greater polygenic obesity risk (ß=0.13, p=0.02). Whole-brain vertex-wise analyses suggested that obesity PRS interacted with MetS to predict decreased cortical thickness in left rostral middle frontal gyrus (ß=-0.40, p<0.001). CONCLUSIONS: Results suggest that PTSD, genetic variability, and MetS are related in a transactional fashion wherein obesity genetic risk increases stress-related metabolic pathology, and compounds the ill health effects of MetS on the brain. Genetic proclivity towards MetS should be considered in PTSD patients when prescribing psychotropic medications with adverse metabolic profiles. Results are consistent with a growing literature suggestive of PTSD-related accelerated aging.
Subject(s)
Obesity/genetics , Stress Disorders, Post-Traumatic/complications , Adult , Brain/pathology , Female , Frontal Lobe/pathology , Genome-Wide Association Study , Genotype , Humans , Magnetic Resonance Imaging , Male , Metabolic Diseases/complications , Metabolic Diseases/genetics , Metabolic Syndrome/complications , Metabolic Syndrome/genetics , Metabolic Syndrome/metabolism , Middle Aged , Multifactorial Inheritance/genetics , Obesity/complications , Obesity/metabolism , Risk Factors , Stress Disorders, Post-Traumatic/genetics , Stress Disorders, Post-Traumatic/metabolism , Veterans , White PeopleABSTRACT
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. METHODS: Recent war veterans underwent structural MRI on a 3 T scanner. We extracted volumes of the right and left hippocampus using FreeSurfer and adjusted them for individual differences in intracranial volume. We assessed PTSD severity using the Clinician-Administered PTSD Scale. Hierarchical linear regression was used to model the genotype (Val158Met polymorphism) × PTSD severity interaction and its association with hippocampal volume. RESULTS: We included 146 white, non-Hispanic recent war veterans (90% male, 53% with diagnosed PTSD) in our analyses. A significant genotype × PTSD symptom severity interaction emerged such that individuals with greater current PTSD symptom severity who were homozygous for the Val allele showed significant reductions in left hippocampal volume. LIMITATIONS: The direction of proposed effects is unknown, thus precluding definitive assessment of whether differences in hippocampal volume reflect a consequence of PTSD, a pre-existing characteristic, or both. CONCLUSION: Our findings suggest that the COMT polymorphism moderates the association between PTSD and hippocampal volume. These results highlight the role that the dopaminergic system has in brain structure and suggest a possible mechanism for memory disturbance in individuals with PTSD.
Subject(s)
Catechol O-Methyltransferase/genetics , Genetic Predisposition to Disease , Hippocampus/diagnostic imaging , Polymorphism, Genetic , Stress Disorders, Post-Traumatic/diagnostic imaging , Stress Disorders, Post-Traumatic/genetics , Adult , Cross-Sectional Studies , Female , Genotyping Techniques , Humans , Imaging, Three-Dimensional , Linear Models , Magnetic Resonance Imaging , Male , Organ Size , Pattern Recognition, Automated , Psychiatric Status Rating Scales , Severity of Illness Index , TriazinesABSTRACT
BACKGROUND: Accumulating evidence suggests that posttraumatic stress disorder (PTSD) is associated with disrupted default mode network (DMN) connectivity, but findings across studies have not been uniform. Individual differences in relevant genes may account for some of the reported variability in the relationship between DMN connectivity and PTSD. In this study, we investigated this possibility using genome-wide association study (GWAS) derived polygenic risk scores (PRSs) for relevant psychiatric traits. We hypothesized that the association between PTSD and DMN connectivity would be moderated by genetic risk for one or more psychiatric traits such that individuals with elevated polygenic risk for psychopathology and severe PTSD would exhibit disrupted DMN connectivity. METHODS: Participants were 156 white, non-Hispanic veterans of the wars in Iraq and Afghanistan who were genotyped and underwent resting state functional magnetic resonance imaging and clinical assessment. PRSs for neuroticism, anxiety, major depressive disorder, and cross-disorder risk (based on five psychiatric disorders) were calculated using summary statistics from published large-scale consortia-based GWASs. RESULTS: Cross-disorder polygenic risk influenced the relationship between DMN connectivity and PTSD symptom severity such that individuals at greater genetic risk showed a significant negative association between PTSD symptom severity and connectivity between the posterior cingulate cortex and right middle temporal gyrus. Polygenic risk for neuroticism, anxiety, and major depressive disorder did not influence DMN connectivity directly or through an interaction with PTSD. CONCLUSIONS: Findings illustrate the potential power of genome-wide PRSs to advance understanding of the relationship between PTSD and DMN connectivity, a putative neural endophenotype of the disorder.
Subject(s)
Cerebral Cortex/physiopathology , Connectome/methods , Genome-Wide Association Study , Mental Disorders/genetics , Severity of Illness Index , Stress Disorders, Post-Traumatic/physiopathology , Veterans , Adult , Cerebral Cortex/diagnostic imaging , Female , Humans , Magnetic Resonance Imaging/methods , Male , Middle Aged , Multifactorial Inheritance , Risk Assessment , Stress Disorders, Post-Traumatic/diagnostic imaging , Young AdultABSTRACT
BACKGROUND: DNA methylation of the SKA2 gene has recently been implicated as a biomarker of suicide risk and posttraumatic stress disorder (PTSD). To examine the specificity and reliability of these findings, we examined associations between SKA2 DNA methylation, broad dimensions of psychiatric symptoms, and suicide phenotypes in adults with high levels of trauma exposure. METHODS: A total of 466 White, non-Hispanic veterans and their intimate partners (65% male) underwent clinical assessment and had blood drawn for genotyping and methylation analysis. DNA methylation of the CpG locus cg13989295 and genotype at the methylation-associated single-nucleotide polymorphism (SNP) rs7208505 were examined in relation to current and lifetime PTSD, internalizing and externalizing psychopathology, and suicide phenotypes (ideation, plans, and attempts). RESULTS: DNA methylation at the previously implicated SKA2 CpG locus (cg13989295) was associated with current and lifetime symptoms of internalizing (but not externalizing) disorders. SKA2 methylation levels also predicted higher rates of current suicidal thoughts and behaviors, even after including well-established psychiatric risk factors for suicide in the model. Associations between PTSD and SKA2 were not significant, and genetic variation at the methylation-associated SNP (rs7208505) was not related to any of the phenotypes examined. CONCLUSIONS: SKA2 methylation may index a general propensity to experience stress-related psychopathology, including internalizing disorders and suicidal thoughts and behaviors. This study demonstrates that SKA2 methylation levels explain unique variance in suicide risk not captured by clinical symptom interviews, providing further evidence of its potential utility as a biomarker of suicide risk and stress-related psychopathology.
Subject(s)
Chromosomal Proteins, Non-Histone/genetics , Genetic Predisposition to Disease/genetics , Genetic Variation/genetics , Mental Disorders/genetics , Mental Disorders/psychology , Suicide/psychology , DNA Methylation , Epigenesis, Genetic , Female , Genotype , Humans , Internal-External Control , Male , Middle Aged , Phenotype , Polymorphism, Single Nucleotide/genetics , Reproducibility of Results , Sensitivity and Specificity , Suicidal Ideation , Suicide, Attempted/psychology , Suicide, Attempted/statistics & numerical data , Veterans/psychology , Veterans/statistics & numerical dataABSTRACT
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. METHODS: Immunophenotyping was performed by immunohistochemistry and flow cytometry. Traditional G-band karyotyping was accompanied by fluorescence in-situ hybridization (FISH) using break-apart and dual fusion probes. Single nucleotide polymorphisms were assessed using a high-density DNA microarray. RESULTS: The karyotype of the blasts showed reciprocal translocation of chromosomes 4 and 18, reciprocal translocation of chromosomes 8 and 14 with two copies of the oncogenic translocation derivative(14)t(8;14), and no normal chromosome 14. FISH studies showed complex IGH-BCL2 and IGH-MYC fusion signals. CONCLUSIONS: A clonal evolution model involving multiple chromosomal translocations and mitotic recombination is postulated to account for the karyotype, FISH, and microarray results but leaves unresolved the exact order of the evolutionary changes.
Subject(s)
Lymphoma , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Humans , Clonal Evolution/genetics , Gene Rearrangement/genetics , Proto-Oncogene Proteins c-bcl-2/geneticsABSTRACT
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. Results showed that PTSD (ß = .199) and AUD (ß = .186) were associated with a quickened pace of epigenetic aging over time (ps < .021). Results replicate and extend prior work and offer foundational support for identifying interventions that slow the pace of biological aging among those with psychopathology.
ABSTRACT
This study examined the klotho (KL) longevity gene polymorphism rs9315202 and psychopathology, including posttraumatic stress disorder (PTSD), depression, and alcohol-use disorders, in association with advanced epigenetic age in three postmortem cortical tissue regions: dorsolateral and ventromedial prefrontal cortices and motor cortex. Using data from the VA National PTSD Brain Bank (n = 117), we found that rs9315202 interacted with PTSD to predict advanced epigenetic age in motor cortex among the subset of relatively older (>=45 years), white non-Hispanic decedents (corrected p = 0.014, n = 42). An evaluation of 211 additional common KL variants revealed that only variants in linkage disequilibrium with rs9315202 showed similarly high levels of significance. Alcohol abuse was nominally associated with advanced epigenetic age in motor cortex (p = 0.039, n = 114). The rs9315202 SNP interacted with PTSD to predict decreased KL expression via DNAm age residuals in motor cortex among older white non-Hispanics decedents (indirect ß = -0.198, p = 0.027). Finally, in dual-luciferase enhancer reporter system experiments, we found that inserting the minor allele of rs9315202 in a human kidney cell line HK-2 genomic DNA resulted in a change in KL transcriptional activities, likely operating via long noncoding RNA in this region. This was the first study to examine multiple forms of psychopathology in association with advanced DNA methylation age across several brain regions, to extend work concerning the association between rs9315202 and advanced epigenetic to brain tissue, and to identify the effects of rs9315202 on KL gene expression. KL augmentation holds promise as a therapeutic intervention to slow the pace of cellular aging, disease onset, and neuropathology, particularly in older, stressed populations.
Subject(s)
Glucuronidase/genetics , Stress Disorders, Post-Traumatic , Aged , Alleles , DNA Methylation , Epigenesis, Genetic , Epigenomics , Humans , Klotho Proteins , Middle Aged , Stress Disorders, Post-Traumatic/geneticsABSTRACT
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. The disorder later was diagnosed as AATP after bone marrow biopsy and was successfully treated with cyclosporine. DISCUSSION: The exact mechanism of AATP remains unclear; it is suspected to be an immune-mediated process. Patients with AATP present with severe bleeding and thrombocytopenia, which is usually unresponsive to high-dose corticosteroids. There are no standard treatment guidelines for AATP. Cyclosporine and antithymocyte globulin are found to be effective in some cases. The prompt diagnosis of AATP is vital because it carries high mortality because of excessive bleeding, and it can progress into aplastic anemia or myelodysplastic syndrome.
Subject(s)
Purpura, Thrombocytopenic, Idiopathic , Thrombocytopenia , Bone Marrow Diseases , Diagnostic Errors , Humans , Male , Megakaryocytes , Middle Aged , Purpura, Thrombocytopenic , Purpura, Thrombocytopenic, Idiopathic/diagnosis , Purpura, Thrombocytopenic, Idiopathic/drug therapy , Thrombocytopenia/diagnosisABSTRACT
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. We further examined KL DNA methylation as a predictor of longitudinal changes in a peripheral biomarker of inflammation (C-reactive protein; CRP). METHODS: The sample comprised 309 white non-Hispanic military veterans (93.5 % male; mean age: 32 years, range: 19-65; 30 % PTSD per structured diagnostic interview); 111 were reassessed approximately two years later. RESULTS: Analyses revealed a methylation quantitative trait locus at rs9527025 (C370S, previously implicated in numerous studies of aging) in association with a Cytosine-phosphate-Guanine site (cg00129557; B = -.65, p = 1.29 X 10-20), located within a DNase hypersensitivity site in the body of KL. There was also a rs9527025 x PTSD severity interaction (B = .004, p = .035) on methylation at this locus such that the minor allele was associated with reduced cg00129557 methylation in individuals with few or no PTSD symptoms while this effect was attenuated in those with elevated levels of PTSD. Path models revealed that methylation at cg00129557 was inversely associated with CRP over time (B = -.14, p = .005), controlling for baseline CRP. There was also an indirect effect of rs9527025 X PTSD on subsequent CRP via cg00129557 methylation (indirect B = -.002, p = .033). CONCLUSIONS: Results contribute to our understanding of the epigenetic correlates of inflammation in PTSD and suggest that KL methylation may be a mechanism by which KL genotype confers risk vs. resilience to accelerated aging in those experiencing traumatic stress.
Subject(s)
Aging, Premature , DNA Methylation/genetics , Epigenesis, Genetic/genetics , Glucuronidase/physiology , Inflammation , Longevity/genetics , Stress Disorders, Post-Traumatic , Adult , Aged , Aging, Premature/blood , Aging, Premature/etiology , Aging, Premature/genetics , Biomarkers/blood , C-Reactive Protein , Female , Gene-Environment Interaction , Genetic Predisposition to Disease , Glucuronidase/genetics , Humans , Inflammation/blood , Inflammation/etiology , Inflammation/genetics , Klotho Proteins , Longitudinal Studies , Male , Middle Aged , Stress Disorders, Post-Traumatic/complications , Stress Disorders, Post-Traumatic/genetics , Stress Disorders, Post-Traumatic/physiopathology , Veterans , Young AdultABSTRACT
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.S. Department of Veterans Affairs (VA) is preparing to implement a new electronic health records system. In this study, VA PGx test end users were surveyed about their preferences for how electronic test orders for PGx should be structured, including the nomenclature that should be used to search for and identify PGx-test orders, whether to offer single- versus multigene tests, and whether information about test methodology should be included in the order name. Responses were analyzed systematically to identify areas of agreement and disagreement with the survey options, and areas where respondents' opinions diverged. End users endorsed preferences for flexible ways to identify and order PGx tests and multigene panel tests; opinions on whether test methodology should be included in the test name were divergent. The results could be used for both informing the VA's new electronic health records implementation (including how PGx tests are searched for and ordered) and for providing insights for other health systems implementing PGx-testing programs.
Subject(s)
Choice Behavior , Electronic Health Records , Pharmacogenomic Testing , Humans , Surveys and QuestionnairesABSTRACT
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. We also examined in EPIC-based DNAm data generated from pre-frontal cortex (PFC) tissue from the National PTSD Brain Bank (n = 72). RESULTS: The analysis of blood samples yielded one genome-wide significant association with PTSD at cg19534438 in the gene G0S2 (p = 1.19 × 10-7, padj = 0.048). This association was replicated in an independent PGC-PTSD-EWAS consortium meta-analysis of military cohorts (p = 0.0024). We also observed association with the smoking-related locus cg05575921 in AHRR despite inclusion of a methylation-based smoking score covariate (p = 9.16 × 10-6), which replicates a previously observed PGC-PTSD-EWAS association (Smith et al. 2019), and yields evidence consistent with a smoking-independent effect. The top 100 EWAS loci were then examined in the PFC data. One of the blood-based PTSD loci, cg04130728 in CHST11, which was in the top 10 loci in blood, but which was not genome-wide significant, was significantly associated with PTSD in brain tissue (in blood p = 1.19 × 10-5, padj = 0.60, in brain, p = 0.00032 with the same direction of effect). Gene set enrichment analysis of the top 500 EWAS loci yielded several significant overlapping GO terms involved in pathogen response, including "Response to lipopolysaccharide" (p = 6.97 × 10-6, padj = 0.042). CONCLUSIONS: The cross replication observed in independent cohorts is evidence that DNA methylation in peripheral tissue can yield consistent and replicable PTSD associations, and our results also suggest that that some PTSD associations observed in peripheral tissue may mirror associations in the brain.