ABSTRACT
Background: The occurrence of post-traumatic stress disorder (PTSD) following a traumatic event is associated with biological differences that can represent the susceptibility to PTSD, the impact of trauma, or the sequelae of PTSD itself. These effects include differences in DNA methylation (DNAm), an important form of epigenetic gene regulation, at multiple CpG loci across the genome. Moreover, these effects can be shared or specific to both central and peripheral tissues. Here, we aim to identify blood DNAm differences associated with PTSD and characterize the underlying biological mechanisms by examining the extent to which they mirror associations across multiple brain regions. Methods: As the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup, we conducted the largest cross-sectional meta-analysis of epigenome-wide association studies (EWASs) of PTSD to date, involving 5077 participants (2156 PTSD cases and 2921 trauma-exposed controls) from 23 civilian and military studies. PTSD diagnosis assessments were harmonized following the standardized guidelines established by the PGC-PTSD Workgroup. DNAm was assayed from blood using either Illumina HumanMethylation450 or MethylationEPIC (850K) BeadChips. A common QC pipeline was applied. Within each cohort, DNA methylation was regressed on PTSD, sex (if applicable), age, blood cell proportions, and ancestry. An inverse variance-weighted meta-analysis was performed. We conducted replication analyses in tissue from multiple brain regions, neuronal nuclei, and a cellular model of prolonged stress. Results: We identified 11 CpG sites associated with PTSD in the overall meta-analysis (1.44e-09 < p < 5.30e-08), as well as 14 associated in analyses of specific strata (military vs civilian cohort, sex, and ancestry), including CpGs in AHRR and CDC42BPB. Many of these loci exhibit blood-brain correlation in methylation levels and cross-tissue associations with PTSD in multiple brain regions. Methylation at most CpGs correlated with their annotated gene expression levels. Conclusions: This study identifies 11 PTSD-associated CpGs, also leverages data from postmortem brain samples, GWAS, and genome-wide expression data to interpret the biology underlying these associations and prioritize genes whose regulation differs in those with PTSD.
ABSTRACT
Bipolar disorder (BD) is characterized by disrupted circadian rhythms and neuronal loss. Lithium is neuroprotective and used to treat BD, but outcomes are variable. Past research identified that circadian rhythms in BD patient neurons are associated with lithium response (Li-R) or non-response (Li-NR). However, the underlying cellular mechanisms remain unknown. To study interactions among circadian clock genes and cell survival, and their role in BD and predicting lithium response, we tested selected genes (PER1, BMAL1 and REV-ERBα) and small molecule modulators of ROR/REV-ERB nuclear receptors in models of cell survival using mouse neurons and stem-cell derived neuronal progenitor cells (NPC) from BD patients and controls. In apoptosis assays using staurosporine (STS), lithium was neuroprotective. Knockdown of PER1, BMAL1 and REV-ERBα modified cell survival across models. In NPCs, reduced expression of PER1 and BMAL1 led to more extensive cell death in Li-NR vs. Li-R. Reduced REV-ERBα expression caused more extensive cell death in BD vs. control NPCs, without distinguishing Li-R and Li-NR. In IMHN, The REV-ERB agonist GSK4112 had strong effects on circadian rhythm amplitude, and was neuroprotective in mouse neurons and control NPCs, but not in BD NPCs. Expression of cell survival genes following STS and GSK4112 treatments revealed BD-associated, and Li-R associated differences in expression profiles. We conclude that the neuroprotective response to lithium is similar in NPCs from Li-R and Li-NR. However, knockdown of circadian clock genes or stimulation of REV-ERBs reveal distinct contributions to cell death in BD patient NPCs, some of which distinguish Li-R and Li-NR.
ABSTRACT
The molecular pathology of stress-related disorders remains elusive. Our brain multiregion, multiomic study of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) included the central nucleus of the amygdala, hippocampal dentate gyrus, and medial prefrontal cortex (mPFC). Genes and exons within the mPFC carried most disease signals replicated across two independent cohorts. Pathways pointed to immune function, neuronal and synaptic regulation, and stress hormones. Multiomic factor and gene network analyses provided the underlying genomic structure. Single nucleus RNA sequencing in dorsolateral PFC revealed dysregulated (stress-related) signals in neuronal and non-neuronal cell types. Analyses of brain-blood intersections in >50,000 UK Biobank participants were conducted along with fine-mapping of the results of PTSD and MDD genome-wide association studies to distinguish risk from disease processes. Our data suggest shared and distinct molecular pathology in both disorders and propose potential therapeutic targets and biomarkers.
Subject(s)
Brain , Depressive Disorder, Major , Genetic Loci , Stress Disorders, Post-Traumatic , Female , Humans , Male , Amygdala/metabolism , Biomarkers/metabolism , Brain/metabolism , Depressive Disorder, Major/genetics , Gene Regulatory Networks , Genome-Wide Association Study , Neurons/metabolism , Prefrontal Cortex/metabolism , Stress Disorders, Post-Traumatic/genetics , Systems Biology , Single-Cell Gene Expression Analysis , Chromosome MappingABSTRACT
Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.
Subject(s)
Genetic Predisposition to Disease , Genome-Wide Association Study , Polymorphism, Single Nucleotide , Stress Disorders, Post-Traumatic , Humans , Stress Disorders, Post-Traumatic/genetics , White People/genetics , Neurobiology , Genetic LociABSTRACT
Females are twice as likely to experience PTSD as compared to males. Although sex differences in prevalence are well-established, little is known about why such sex differences occur. Biological factors that vary with sex, including sex hormone production, may contribute to these differences. Considerable evidence links sex hormones, such as testosterone, to PTSD risk though less is known about the shared genetic underpinnings. The objective of the present study was to test for genetic relationships between testosterone and PTSD. To do so, we used summary statistics from large, publicly available genetic consortia to conduct linkage disequilibrium score regression to estimate the genetic correlations between PTSD and testosterone in males and females, and two-sample, bi-directional Mendelian randomization to examine potential causal relationships of testosterone on PTSD and the reverse. Heritability estimates of testosterone were significantly higher in males (0.17, SE = 0.02) than females (0.11, SE = 0.01; z = 2.46, p = 00.01). The correlation between testosterone and PTSD was negative in males (rg = -0.11, SE = 0.02, p = 6.7 x 10-6), but not significant in females (rg = 0.002, SE = 0.03, p = 0.95). MR analyses found no evidence of a causal effect of testosterone on PTSD or the reverse. Findings are consistent with phenotypic literature suggesting a relationship between testosterone and PTSD that may be sex-specific. This work provides early evidence of a relationship between testosterone and PTSD genotypically and suggests an avenue for future research that will enable a better understanding of disparities in PTSD.
Subject(s)
Stress Disorders, Post-Traumatic , Testosterone , Humans , Stress Disorders, Post-Traumatic/genetics , Stress Disorders, Post-Traumatic/blood , Male , Testosterone/blood , Female , Sex Characteristics , Linkage Disequilibrium , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Mendelian Randomization AnalysisABSTRACT
Observational studies suggest that posttraumatic stress disorder (PTSD) increases risk for various autoimmune diseases. Insights into shared biology and causal relationships between these diseases may inform intervention approaches to PTSD and co-morbid autoimmune conditions. We investigated the shared genetic contributions and causal relationships between PTSD, 18 autoimmune diseases, and 3 immune/inflammatory biomarkers. Univariate MiXeR was used to contrast the genetic architectures of phenotypes. Genetic correlations were estimated using linkage disequilibrium score regression. Bi-directional, two-sample Mendelian randomization (MR) was performed using independent, genome-wide significant single nucleotide polymorphisms; inverse variance weighted and weighted median MR estimates were evaluated. Sensitivity analyses for uncorrelated (MR PRESSO) and correlated horizontal pleiotropy (CAUSE) were also performed. PTSD was considerably more polygenic (10,863 influential variants) than autoimmune diseases (median 255 influential variants). However, PTSD evidenced significant genetic correlation with nine autoimmune diseases and three inflammatory biomarkers. PTSD had putative causal effects on autoimmune thyroid disease (p = 0.00009) and C-reactive protein (CRP) (p = 4.3 × 10-7). Inferences were not substantially altered by sensitivity analyses. Additionally, the PTSD-autoimmune thyroid disease association remained significant in multivariable MR analysis adjusted for genetically predicted inflammatory biomarkers as potential mechanistic pathway variables. No autoimmune disease had a significant causal effect on PTSD (all p values > 0.05). Although causal effect models were supported for associations of PTSD with CRP, shared pleiotropy was adequate to explain a putative causal effect of CRP on PTSD (p = 0.18). In summary, our results suggest a significant genetic overlap between PTSD, autoimmune diseases, and biomarkers of inflammation. PTSD has a putative causal effect on autoimmune thyroid disease, consistent with existing epidemiologic evidence. A previously reported causal effect of CRP on PTSD is potentially confounded by shared genetics. Together, results highlight the nuanced links between PTSD, autoimmune disorders, and associated inflammatory signatures, and suggest the importance of targeting related pathways to protect against disease and disability.
Subject(s)
Autoimmune Diseases , Hashimoto Disease , Stress Disorders, Post-Traumatic , Humans , Stress Disorders, Post-Traumatic/genetics , Phenotype , C-Reactive Protein , Autoimmune Diseases/genetics , Biomarkers , Genome-Wide Association StudyABSTRACT
Background: Incorporating genomic data into risk prediction has become an increasingly useful approach for rapid identification of individuals most at risk for complex disorders such as PTSD. Our goal was to develop and validate Methylation Risk Scores (MRS) using machine learning to distinguish individuals who have PTSD from those who do not. Methods: Elastic Net was used to develop three risk score models using a discovery dataset (n = 1226; 314 cases, 912 controls) comprised of 5 diverse cohorts with available blood-derived DNA methylation (DNAm) measured on the Illumina Epic BeadChip. The first risk score, exposure and methylation risk score (eMRS) used cumulative and childhood trauma exposure and DNAm variables; the second, methylation-only risk score (MoRS) was based solely on DNAm data; the third, methylation-only risk scores with adjusted exposure variables (MoRSAE) utilized DNAm data adjusted for the two exposure variables. The potential of these risk scores to predict future PTSD based on pre-deployment data was also assessed. External validation of risk scores was conducted in four independent cohorts. Results: The eMRS model showed the highest accuracy (92%), precision (91%), recall (87%), and f1-score (89%) in classifying PTSD using 3730 features. While still highly accurate, the MoRS (accuracy = 89%) using 3728 features and MoRSAE (accuracy = 84%) using 4150 features showed a decline in classification power. eMRS significantly predicted PTSD in one of the four independent cohorts, the BEAR cohort (beta = 0.6839, p-0.003), but not in the remaining three cohorts. Pre-deployment risk scores from all models (eMRS, beta = 1.92; MoRS, beta = 1.99 and MoRSAE, beta = 1.77) displayed a significant (p < 0.001) predictive power for post-deployment PTSD. Conclusion: Results, especially those from the eMRS, reinforce earlier findings that methylation and trauma are interconnected and can be leveraged to increase the correct classification of those with vs. without PTSD. Moreover, our models can potentially be a valuable tool in predicting the future risk of developing PTSD. As more data become available, including additional molecular, environmental, and psychosocial factors in these scores may enhance their accuracy in predicting the condition and, relatedly, improve their performance in independent cohorts.
ABSTRACT
Tinnitus is a heritable, highly prevalent auditory disorder treated by multiple medical specialties. Previous GWAS indicated high genetic correlations between tinnitus and hearing loss, with little indication of differentiating signals. We present a GWAS meta-analysis, triple previous sample sizes, and expand to non-European ancestries. GWAS in 596,905 Million Veteran Program subjects identified 39 tinnitus loci, and identified genes related to neuronal synapses and cochlear structural support. Applying state-of-the-art analytic tools, we confirm a large number of shared variants, but also a distinct genetic architecture of tinnitus, with higher polygenicity and large proportion of variants not shared with hearing difficulty. Tissue-expression analysis for tinnitus infers broad enrichment across most brain tissues, in contrast to hearing difficulty. Finally, tinnitus is not only correlated with hearing loss, but also with a spectrum of psychiatric disorders, providing potential new avenues for treatment. This study establishes tinnitus as a distinct disorder separate from hearing difficulties.
Subject(s)
Deafness , Hearing Loss, Noise-Induced , Tinnitus , Humans , Tinnitus/diagnosis , Tinnitus/genetics , CochleaABSTRACT
Genetic contributions to human cortical structure manifest pervasive pleiotropy. This pleiotropy may be harnessed to identify unique genetically-informed parcellations of the cortex that are neurobiologically distinct from functional, cytoarchitectural, or other cortical parcellation schemes. We investigated genetic pleiotropy by applying genomic structural equation modeling (SEM) to map the genetic architecture of cortical surface area (SA) and cortical thickness (CT) for the 34 brain regions recently reported in the ENIGMA cortical GWAS. Genomic SEM uses the empirical genetic covariance estimated from GWAS summary statistics with LD score regression (LDSC) to discover factors underlying genetic covariance, which we are denoting genetically informed brain networks (GIBNs). Genomic SEM can fit a multivariate GWAS from summary statistics for each of the GIBNs, which can subsequently be used for LD score regression (LDSC). We found the best-fitting model of cortical SA identified 6 GIBNs and CT identified 4 GIBNs. The multivariate GWASs of these GIBNs identified 74 genome-wide significant (GWS) loci (p<5×10-8), including many previously implicated in neuroimaging phenotypes, behavioral traits, and psychiatric conditions. LDSC of GIBN GWASs found that SA-derived GIBNs had a positive genetic correlation with bipolar disorder (BPD), and cannabis use disorder, indicating genetic predisposition to a larger SA in the specific GIBN is associated with greater genetic risk of these disorders. A negative genetic correlation was observed with attention deficit hyperactivity disorder (ADHD), major depressive disorder (MDD), and insomnia, indicating genetic predisposition to a larger SA in the specific GIBN is associated with lower genetic risk of these disorders. CT GIBNs displayed a negative genetic correlation with alcohol dependence. Jointly modeling the genetic architecture of complex traits and investigating multivariate genetic links across phenotypes offers a new vantage point for mapping the cortex into genetically informed networks.
ABSTRACT
Large-scale genetic studies of traumatic brain injury (TBI) are lacking; thus, our understanding of the influence of genetic factors on TBI risk and recovery is incomplete. This study aimed to conduct a genome-wide association study (GWAS) of TBI in VA Million Veteran Program (MVP) enrollees. Participants included a multi-ancestry cohort (European, African, and Hispanic ancestries; N = 304,485; 111,494 TBI cases, 192,991 controls). TBI was assessed using MVP survey data and International Classification of Diseases (ICD) codes from the Veterans Health Administration's electronic health record. GWAS was performed using logistic regression in PLINK, and meta-analyzed in METAL. FUMA was used for post-GWAS analysis. Genomic structural equation modeling (gSEM) was conducted to investigate underlying genetic associations with TBI, and bivariate MiXeR was used to estimate phenotype specific and shared polygenicity. SNP-based heritability was 0.060 (SE = 0.004, p = 7.83×10-66). GWAS analysis identified 15 genome-wide significant (GWS) loci at p < 5×10-8. Gene-based analyses revealed 14 gene-wide significant genes; top genes included NCAM1, APOE, FTO, and FOXP2. Gene tissue expression analysis identified the brain as significantly enriched, particularly in the frontal cortex, anterior cingulate cortex, and nucleus accumbens. Genetic correlations with TBI were significant for risk-taking behaviors and psychiatric disorders, but generally not significant for the neurocognitive variables investigated. gSEM analysis revealed stronger associations with risk-taking traits than with psychiatric traits. Finally, the genetic architecture of TBI was similar to polygenic psychiatric disorders. Neurodegenerative disorders including Alzheimer's and Parkinson's disease showed much less polygenicity, however, the proportion of shared variance with TBI was high. This first well-powered GWAS of TBI identified 15 loci including genes relevant to TBI biology, and showed that TBI is a heritable trait with comparable genetic architecture and high genetic correlation with psychiatric traits. Our findings set the stage for future TBI GWASs that focus on injury severity and diversity and chronicity of symptom sequelae.
ABSTRACT
Posttraumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 novel). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (e.g., GRIA1, GRM8, CACNA1E ), developmental, axon guidance, and transcription factors (e.g., FOXP2, EFNA5, DCC ), synaptic structure and function genes (e.g., PCLO, NCAM1, PDE4B ), and endocrine or immune regulators (e.g., ESR1, TRAF3, TANK ). Additional top genes influence stress, immune, fear, and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.
ABSTRACT
Observational studies suggest that physical activity can reduce the risk of mental health and substance use disorders. However, it is unclear whether this relationship is causal or explained by confounding bias (e.g., common underlying causes or reverse causality). We investigated the bidirectional causal relationship of physical activity (PA) and sedentary behaviour (SB) with ten mental health and substance use disorders, applying two-sample Mendelian Randomisation (MR). Genetic instruments for the exposures and outcomes were derived from the largest available, non-overlapping genome-wide association studies (GWAS). Summary-level data for objectively assessed PA (accelerometer-based average activity, moderate activity, and walking) and SB and self-reported moderate-to-vigorous PA were obtained from the UK Biobank. Data for mental health/substance use disorders were obtained from the Psychiatric Genomics Consortium and the GWAS and Sequencing Consortium of Alcohol and Nicotine Use. MR estimates were combined using inverse variance weighted meta-analysis (IVW). Sensitivity analyses were conducted to assess the robustness of the results. Accelerometer-based average PA was associated with a lower risk of depression (b = -0.043, 95% CI: -0.071 to -0.016, effect size[OR] = 0.957) and cigarette smoking (b = -0.026; 95% CI: -0.035 to -0.017, effect size[ß] = -0.022). Accelerometer-based SB decreased the risk of anorexia (b = -0.341, 95% CI: -0.530 to -0.152, effect size[OR] = 0.711) and schizophrenia (b = -0.230; 95% CI: -0.285 to -0.175, effect size[OR] = 0.795). However, we found evidence of reverse causality in the relationship between SB and schizophrenia. Further, PTSD, bipolar disorder, anorexia, and ADHD were all associated with increased PA. This study provides evidence consistent with a causal protective effect of objectively assessed but not self-reported PA on reduced depression and cigarette smoking. Objectively assessed SB had a protective relationship with anorexia. Enhancing PA may be an effective intervention strategy to reduce depressive symptoms and addictive behaviours, while promoting sedentary or light physical activities may help to reduce the risk of anorexia in at-risk individuals.
Subject(s)
Mental Health , Substance-Related Disorders , Humans , Sedentary Behavior , Anorexia , Genome-Wide Association Study , Exercise , Substance-Related Disorders/genetics , Polymorphism, Single NucleotideABSTRACT
OBJECTIVE: Multidisciplinary studies of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) implicate the dorsolateral prefrontal cortex (DLPFC) in disease risk and pathophysiology. Postmortem brain studies have relied on bulk-tissue RNA sequencing (RNA-seq), but single-cell RNA-seq is needed to dissect cell-type-specific mechanisms. The authors conducted the first single-nucleus RNA-seq postmortem brain study in PTSD to elucidate disease transcriptomic pathology with cell-type-specific resolution. METHOD: Profiling of 32 DLPFC samples from 11 individuals with PTSD, 10 with MDD, and 11 control subjects was conducted (â¼415K nuclei; >13K cells per sample). A replication sample included 15 DLPFC samples (â¼160K nuclei; >11K cells per sample). RESULTS: Differential gene expression analyses identified significant single-nucleus RNA-seq differentially expressed genes (snDEGs) in excitatory (EX) and inhibitory (IN) neurons and astrocytes, but not in other cell types or bulk tissue. MDD samples had more false discovery rate-corrected significant snDEGs, and PTSD samples had a greater replication rate. In EX and IN neurons, biological pathways that were differentially enriched in PTSD compared with MDD included glucocorticoid signaling. Furthermore, glucocorticoid signaling in induced pluripotent stem cell (iPSC)-derived cortical neurons demonstrated greater relevance in PTSD and opposite direction of regulation compared with MDD, especially in EX neurons. Many snDEGs were from the 17q21.31 locus and are particularly interesting given causal roles in disease pathogenesis and DLPFC-based neuroimaging (PTSD: ARL17B, LINC02210-CRHR1, and LRRC37A2; MDD: LRRC37A and LRP4), while others were regulated by glucocorticoids in iPSC-derived neurons (PTSD: SLC16A6, TAF1C; MDD: CDH3). CONCLUSIONS: The study findings point to cell-type-specific mechanisms of brain stress response in PTSD and MDD, highlighting the importance of examining cell-type-specific gene expression and indicating promising novel biomarkers and therapeutic targets.
Subject(s)
Depressive Disorder, Major , Stress Disorders, Post-Traumatic , Humans , Dorsolateral Prefrontal Cortex , Depressive Disorder, Major/genetics , Depressive Disorder, Major/metabolism , Stress Disorders, Post-Traumatic/genetics , Glucocorticoids/metabolism , Gene Expression Profiling , Transcriptome/genetics , Neurons/metabolism , Prefrontal Cortex/metabolismABSTRACT
BACKGROUND: Hearing problems (HP) in adults are common and are associated with several comorbid conditions. Its prevalence increases with age, reflecting the cumulative effect of environmental factors and genetic predisposition. Although several risk loci have been already identified, HP biology and epidemiology are still insufficiently investigated by large-scale genetic studies. METHODS: Leveraging the UK Biobank, the Nurses' Health Studies (I and II), the Health Professionals Follow-up Study, and the Million Veteran Program, we conducted a comprehensive genome-wide investigation of HP in 748,668 adult participants (discovery N = 501,825; replication N = 226,043; cross-ancestry replication N = 20,800). We leveraged the GWAS findings to characterize HP polygenic architecture, exploring sex differences, polygenic risk across ancestries, tissue-specific transcriptomic regulation, cause-effect relationships with genetically correlated traits, and gene interactions with HP environmental risk factors. RESULTS: We identified 54 risk loci and demonstrated that HP polygenic risk is shared across ancestry groups. Our transcriptomic regulation analysis highlighted the potential role of the central nervous system in HP pathogenesis. The sex-stratified analyses showed several additional associations related to peripheral hormonally regulated tissues reflecting a potential role of estrogen in hearing function. This evidence was supported by the multivariate interaction analysis that showed how genes involved in brain development interact with sex, noise pollution, and tobacco smoking in relation to their HP associations. Additionally, the genetically informed causal inference analysis showed that HP is linked to many physical and mental health outcomes. CONCLUSIONS: The results provide many novel insights into the biology and epidemiology of HP in adults. Our sex-specific analyses and transcriptomic associations highlighted molecular pathways that may be targeted for drug development or repurposing. Additionally, the potential causal relationships identified may support novel preventive screening programs to identify individuals at risk.
Subject(s)
Genetic Predisposition to Disease , Sex Characteristics , Humans , Adult , Male , Female , Follow-Up Studies , Multifactorial Inheritance , Hearing , Genome-Wide Association Study/methodsABSTRACT
Bipolar disorder (BD) is characterized by mood episodes, disrupted circadian rhythms and gray matter reduction in the brain. Lithium is an effective pharmacotherapy for BD, but not all patients respond to treatment. Lithium has neuroprotective properties and beneficial effects on circadian rhythms that may distinguish lithium responders (Li-R) from non-responders (Li-NR). The circadian clock regulates molecular pathways involved in apoptosis and cell survival, but how this overlap impacts BD and/or lithium responsiveness is unknown. In primary fibroblasts from Li-R/Li-NR BD patients and controls, we found patterns of co-expression among circadian clock and cell survival genes that distinguished BD vs. control, and Li-R vs. Li-NR cells. In cellular models of apoptosis using staurosporine (STS), lithium preferentially protected fibroblasts against apoptosis in BD vs. control samples, regardless of Li-R/Li-NR status. When examining the effects of lithium treatment of cells in vitro, caspase activation by lithium correlated with period alteration, but the relationship differed in control, Li-R and Li-NR samples. Knockdown of Per1 and Per3 in mouse fibroblasts altered caspase activity, cell death and circadian rhythms in an opposite manner. In BD cells, genetic variation in PER1 and PER3 predicted sensitivity to apoptosis in a manner consistent with knockdown studies. We conclude that distinct patterns of coordination between circadian clock and cell survival genes in BD may help predict lithium response.
Subject(s)
Bipolar Disorder , Circadian Clocks , Mice , Animals , Lithium/pharmacology , Lithium/therapeutic use , Bipolar Disorder/drug therapy , Bipolar Disorder/genetics , Bipolar Disorder/metabolism , Circadian Clocks/genetics , Cell Survival , Circadian Rhythm , Fibroblasts , Caspases/pharmacology , Caspases/therapeutic useABSTRACT
Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E-09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.
ABSTRACT
Bipolar disorder (BD) is characterized by manic and depressive mood episodes and loss of brain gray matter. Lithium has antimanic and neuroprotective properties, but only 30% BD patients respond to lithium pharmacotherapy. Dopamine signaling has been implicated in BD and may contribute to lithium response. Methamphetamine (METH) stimulates dopamine release and models the clinical features of mania but has never been used to study cell death in BD patient neurons. We used BD patient derived neuronal progenitor cells (NPCs) to determine whether the vulnerability to cell death differed in samples from lithium responder (Li-R) and non-responder (Li-NR) BD patients and healthy controls following METH exposure in vitro. We hypothesized that NPCs from Li-R and Li-NR would differ in vulnerability to METH, dopamine signaling and neuroprotection from lithium. Following METH, NPCs from controls and Li-NR showed significantly greater cell loss compared to Li-R. Pre-treatment of NPCs with the D1 dopamine receptor antagonist SCH 23390 reversed the neurotoxic effects of METH. In Li-R NPCs, expression of phosho-ERK1/2 was significantly increased. In Li-NR NPCs, phospho-AKT, D1 and D2 dopamine receptor proteins were significantly increased. Pre-treatment of NPCs with lithium before METH reversed the neurotoxic effects of METH in control NPCs, whereas Li-NR showed less protective benefit. Li-R cells showed decreased levels of cell death after METH and comparatively high viability, and lithium treatment did not increase viability any further. This novel NPC model of mania reveals differences in cell death that could help identify mechanisms of lithium response in BD.
Subject(s)
Bipolar Disorder , Methamphetamine , Neural Stem Cells , Humans , Lithium/pharmacology , Bipolar Disorder/drug therapy , Lithium Compounds/pharmacology , Mania/drug therapy , Methamphetamine/pharmacology , Dopamine/pharmacology , Antimanic Agents/pharmacologyABSTRACT
Many patients with mild traumatic brain injury (mTBI) are at risk for mental health problems such as posttraumatic stress disorder (PTSD). The objective of this study was to determine whether the polygenic risk for PTSD (or for related mental health disorders or traits including major depressive disorder [MDD] and neuroticism [NEU]) was associated with an increased likelihood of PTSD in the aftermath of mTBI. We used data from individuals of European ancestry with mTBI enrolled in TRACK-TBI (n = 714), a prospective longitudinal study of level 1 trauma center patients. One hundred and sixteen mTBI patients (16.3%) had probable PTSD (PCL-5 score ≥33) at 6 months post-injury. We used summary statistics from recent GWAS studies of PTSD, MDD, and NEU to generate polygenic risk scores (PRS) for individuals in our sample. A multivariable model that included age, sex, pre-injury history of mental disorder, and cause of injury explained 7% of the variance in the PTSD outcome; the addition of the PTSD-PRS (and five ancestral principal components) significantly increased the variance explained to 11%. The adjusted odds of PTSD in the uppermost PTSD-PRS quintile was nearly four times higher (aOR = 3.71, 95% CI 1.80-7.65) than in the lowest PTSD-PRS quintile. There was no evidence of a statistically significant interaction between PTSD-PRS and prior history of mental disorder, indicating that PTSD-PRS had similar predictive utility among those with and without pre-injury psychiatric illness. When added to the model, neither MDD-PRS nor NEU-PRS were significantly associated with the PTSD outcome. These findings show that the risk for PTSD in the context of mTBI is, in part, genetically influenced. They also raise the possibility that an individual's PRS could be clinically actionable if used-possibly with other non-genetic predictors-to signal the need for enhanced follow-up and early intervention; this precision medicine approach needs to be prospectively studied.
Subject(s)
Brain Concussion , Depressive Disorder, Major , Stress Disorders, Post-Traumatic , Humans , Brain Concussion/complications , Stress Disorders, Post-Traumatic/psychology , Prospective Studies , Longitudinal Studies , Depressive Disorder, Major/genetics , Depressive Disorder, Major/complicationsABSTRACT
BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD) are associated, but it is unclear if this is a causal relationship or confounding. We used genetic analyses and sibling comparisons to clarify the direction of this relationship. METHODS: Linkage disequilibrium score regression and 2-sample Mendelian randomization were used to test for genetic correlation (rg) and bidirectional causal effects using European ancestry genome-wide association studies of ADHD (20,183 cases and 35,191 controls) and 6 PTSD definitions (up to 320,369 individuals). Several additional variables were included in the analysis to verify the independence of the ADHD-PTSD relationship. In a population-based sibling comparison (N = 2,082,118 individuals), Cox regression models were fitted to account for time at risk, a range of sociodemographic factors, and unmeasured familial confounders (via sibling comparisons). RESULTS: ADHD and PTSD had consistent rg (rg range, 0.43-0.52; p < .001). ADHD genetic liability was causally linked with increased risk for PTSD (ß = 0.367; 95% CI, 0.186-0.552; p = 7.68 × 10-5). This result was not affected by heterogeneity, horizontal pleiotropy (Mendelian randomization Egger intercept = 4.34 × 10-4, p = .961), or other phenotypes and was consistent across PTSD datasets. However, we found no consistent associations between PTSD genetic liability and ADHD risk. Individuals diagnosed with ADHD were at a higher risk for developing PTSD than their undiagnosed sibling (hazard ratio = 2.37; 95% CI, 1.98-3.53). CONCLUSIONS: Our findings add novel evidence supporting the need for early and effective treatment of ADHD, as patients with this diagnosis are at significantly higher risk to develop PTSD later in life.
Subject(s)
Attention Deficit Disorder with Hyperactivity , Stress Disorders, Post-Traumatic , Humans , Stress Disorders, Post-Traumatic/genetics , Attention Deficit Disorder with Hyperactivity/epidemiology , Attention Deficit Disorder with Hyperactivity/genetics , Attention Deficit Disorder with Hyperactivity/diagnosis , Siblings , Genome-Wide Association Study , Mendelian Randomization AnalysisABSTRACT
Posttraumatic stress disorder (PTSD) is a heritable (h2 = 24-71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (beta = 0.029, SE = 0.005, P = 6.3 × 10-8). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (beta = 0.0206, SE = 0.0056, P = 0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR q < 0.05), but these associations were not significant once NDD regions were removed. A larger sample size, better detection methods, and annotated resources of CNV are needed to explore this relationship further.