No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Epigenetic Variation at SKA2 Predicts Suicide Phenotypes and Internalizing Psychopathology
Abstract
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.
... with ACE-induced demethylation to affect gene transcription [30]. Genotyping and methylation analysis [35] Genotyping and methylation analysis [36] Differential methylation: Methylation at CpG locus cg13989295 associated with higher levels of internalizing disorders [35]. ...
... with ACE-induced demethylation to affect gene transcription [30]. Genotyping and methylation analysis [35] Genotyping and methylation analysis [36] Differential methylation: Methylation at CpG locus cg13989295 associated with higher levels of internalizing disorders [35]. ...
... The gene SKA2 encodes a component of the microtubule-binding complex involved in mitosis. A study of military veterans exposed to at least one lifetime trauma found that methylation at cg13989295 of SKA2 was associated with higher rates of internalizing disorders (depression, dysthymia, generalized anxiety, phobia, obsessive-compulsive disorder, and panic disorder) and current suicidal ideation and suicidal behaviors [35]. It was not associated with high rates of externalizing disorders (substance use disorders and antisocial personality disorder) or PTSD. ...
Post-traumatic stress disorder (PTSD) is an acquired psychiatric disorder with functionally impairing physiological and psychological symptoms following a traumatic exposure. Genetic, epigenetic, and environmental factors act together to determine both an individual’s susceptibility to PTSD and its clinical phenotype. In this literature review, we briefly review the candidate genes that have been implicated in the development and severity of the PTSD phenotype. We discuss the importance of the epigenetic regulation of these candidate genes. We review the general epigenetic mechanisms that are currently understood, with examples of each in the PTSD phenotype. Our focus then turns to studies that have examined PTSD in the context of comorbid psychiatric disorders or associated social and behavioral stressors. We examine the epigenetic variation in cases or models of PTSD with comorbid depressive disorders, anxiety disorders, psychotic disorders, and substance use disorders. We reviewed the literature that has explored epigenetic regulation in PTSD in adverse childhood experiences and suicide phenotypes. Finally, we review some of the information available from studies of the transgenerational transmission of epigenetic variation in maternal cases of PTSD. We discuss areas pertinent for future study to further elucidate the complex interactions between epigenetic modifications and this complex psychiatric disorder.
... In this regard, a gene named SKA2 (spindle and kinetochore (KT)-associated protein 2). involved in anaphasic movement of mitotic chromosome (Hanisch et al., 2006), has been identified as a molecular escort to help translocate glucocorticoid receptor (GR) from cytosol to nucleus where GR acts as a transcription factor (Rice et al., 2008;Sadeh et al., 2016).). A study conducted by Guintivano and colleagues (Guintivano et al., 2014) showed DNA methylation-mediated epigenetic mode of gene regulation with a polymorphic nucleotide rs7208505 at cg13989295 locus of SKA2 gene in neuronal population of autopsy brain. ...
... One of them was a continuation (Kaminsky et al., 2015) of the study of epigenetic profiling of SKA2 gene which was discussed earlier in the postmortem brain section. The same group had taken initiative to predict the biomarker value of a DNA methylation associated polymorphic locus (rs7208505) in SKA2 gene in a study population of 466 individuals following a noninvasive approach of analyzing their peripheral blood tissue (Sadeh et al., 2016). The study was aimed to ascertain the reliability of this specific SNP linked epigenetic signature on SKA2 3′UTR and its association with suicide risk where high degree of mental trauma was involved as a precipitating factor. ...
... The study was aimed to ascertain the reliability of this specific SNP linked epigenetic signature on SKA2 3′UTR and its association with suicide risk where high degree of mental trauma was involved as a precipitating factor. With an attempt to associate the epigenetic variation at 'C' allele of (rs7208505) SKA2 locus (CpG cg13989295) with suicidal thoughts and behaviors, the study was found to be successful in establishing a strong relationship between SKA2 and suicidal behavior in the living cohort of military individuals (Sadeh et al., 2016). This finding happened to be congruent with an earlier report from an independent study cohort of civilians where the subjects experienced major trauma in their lifetime before going through the investigational procedure (Niculescu et al., 2015a;Niculescu et al., 2015b). ...
Current understanding of environmental cross-talk with genetic makeup is found to be mediated through an epigenetic interface which is associated with prominent reversible and heritable changes at gene expression level. Recent emergence of epigenetic modulation in shaping the genetic information has become a key regulatory factor in answering the underlying complexities associated with several mental disorders. A comprehensive understanding of the pertinent changes in the epigenetic makeup of suicide phenotype exhibits a characteristic signature with the possibility of using it as a biomarker to help predict the risk factors associated with suicide. Within the scope of this current review, the most sought after epigenetic changes of DNA methylation and histone modification are thoroughly scrutinized to understand their close functional association with the broad spectrum of suicide phenotype.
... As such, in recent years, epigenetic mechanisms have been suggested to play a role in "quantifying the missing heritability" of suicide in schizophrenia [9]. DNA methylation and suicide have been well-studied in relation to the dysfunction of the adaptive stress response by the hypothalamic-pituitary-adrenal (HPA) axis, particularly in the NR3C1 and SKA2 genes [10][11][12][13][14]. Therefore, the evidence suggests that these epigenetic markers can prove valuable in investigating suicide attempts and completed suicides. ...
... The present study will investigate genome-wide methylation status in association with suicidal ideation severity. Based on previous studies investigating DNA methylation and suicide [10][11][12][13][14], we further predict that suicide ideation will be associated with genome-wide methylation. ...
There is a multitude of factors that makes difficult to identify those at risk for suicide, especially among schizophrenia patients. Suicide cannot be explained by genetics alone, therefore epigenetic mechanisms including DNA methylation are thought to play a role. DNA methylation could be a valuable tool in helping predict those at-risk individuals. This cross-sectional study comprised 112 subjects diagnosed with schizophrenia spectrum disorders, and were grouped according to the current suicidal ideation severity. DNA methylation across the genome was measured with the Infinium® MethylationEPIC BeadChip. We utilized the dmpFinder and bumphunter functions within the Bioconductor minfi package to identify differentially methylated positions (DMPs) and differentially methylated regions (DMRs), respectively. Following quality control, we removed one sample from the analysis and reported the most significant DMPs and DMRs associated with suicidal ideation severity. All positions and regions identified in this analysis were only found to have suggestive levels of significance at the genome-wide level. The present study was one of the first to investigate genome-wide methylation and suicidal ideation severity. While there were many strengths of our study, including investigating both differentially methylated positions and regions, further larger-scale studies are necessary to replicate, support, and validate our findings presented here.
... On this note, studies have used human structural and functional neuroimaging data in tandem with epigenetic measures but have primarily utilized candidate gene approaches. Measuring peripheral 5mC of the SLC6A4 [43][44][45], NR3C1 [46,47], FKBP5 [48], and SKA2 [49,50] genes, these studies have investigated associations between peripheral 5mC and variability in the structure and function of the frontal cortex, hippocampus, and amygdala. Findings suggest that locus-specific peripheral 5mC can index CNS structural alterations [43][44][45][46][47][48][49][50], and may statistically mediate ASE-induced CNS structural alterations [50]. ...
... Measuring peripheral 5mC of the SLC6A4 [43][44][45], NR3C1 [46,47], FKBP5 [48], and SKA2 [49,50] genes, these studies have investigated associations between peripheral 5mC and variability in the structure and function of the frontal cortex, hippocampus, and amygdala. Findings suggest that locus-specific peripheral 5mC can index CNS structural alterations [43][44][45][46][47][48][49][50], and may statistically mediate ASE-induced CNS structural alterations [50]. ...
Background
Poor family emotional health (FEH) during childhood is prevalent and impactful, and likely confers similar neurodevelopmental risks as other adverse social environments. Pointed FEH study efforts are underdeveloped, and the mechanisms by which poor FEH are biologically embedded are unclear. The current exploratory study examined whether variability in 5-methyl-cytosine (5mC) and fronto-limbic grey matter volume may represent pathways through which FEH may become biologically embedded.
Results
In 98 university students aged 18–22 years, retrospective self-reported childhood FEH was associated with right hemisphere hippocampus (b = 10.4, p = 0.005), left hemisphere amygdala (b = 5.3, p = 0.009), and right hemisphere amygdala (b = 5.8, p = 0.016) volumes. After pre-processing and filtering to 5mC probes correlated between saliva and brain, analyses showed that childhood FEH was associated with 49 5mC principal components (module eigengenes; MEs) (prange = 3 × 10–6 to 0.047). Saliva-derived 5mC MEs partially mediated the association between FEH and right hippocampal volume (Burlywood ME indirect effect b = − 111, p = 0.014), and fully mediated the FEH and right amygdala volume relationship (Pink4 ME indirect effect b = − 48, p = 0.026). Modules were enriched with probes falling in genes with immune, central nervous system (CNS), cellular development/differentiation, and metabolic functions.
Conclusions
Findings extend work highlighting neurodevelopmental variability associated with adverse social environment exposure during childhood by specifically implicating poor FEH, while informing a mechanism of biological embedding. FEH-associated epigenetic signatures could function as proxies of altered fronto-limbic grey matter volume associated with poor childhood FEH and inform further investigation into primarily affected tissues such as endocrine, immune, and CNS cell types.
... SKA2 rs7208505 is located in the 3′ untranslated region (UTR) of the gene and is followed by a guanine nucleotide that makes it a polymorphic CpG site [46]. Recently, SKA2 genomic variation and its DNA methylation status has been the focus of several studies associating it with suicide across various cohorts, as well as HPA axis dysregulation, and internalizing symptoms in PTSD [46][47][48][49]. In addition, Pandey et al. [50], found decreased SKA2 gene expression in prefrontal cortex of suicide completers. ...
... Furthermore, DNA methylation did not appear to play a role in OCD symptom severity, when corrected for rs7208505 genotype. According to the findings of Sadeh et al. [49], SKA2 methylation was associated with the broad dimension of internalizing psychopathology, i.e., vulnerability for symptoms involving depression, fear, and anxiety that occur at a high rate in OCD. Internalizing disorders have themselves been associated with stressful life events and HPA axis dysregulation [75]. ...
Background
Obsessive-Compulsive Disorder (OCD) has a complex genetic component and may be preceded by environmental stressors. The spindle and kinetochore associated complex subunit 2 (SKA2) gene interacts with the glucocorticoid receptor and is implicated in mediating hypothalamic–pituitary-adrenal (HPA) axis function but has yet to be examined in OCD. We hypothesized that genetic and epigenetic variation of SKA2 may be involved in OCD disease risk and symptom severity.
Methods
OCD patients (n = 54) were rated for disease severity using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Genotyping of SKA2 rs7208505 was performed using Taqman TM, while DNA methylation levels were quantified using bisulfite pyrosequencing. OCD genotype frequencies were compared to the general population (n = 379, 1000 Genomes Project Consortium) using Pearson’s chi-square test. The relationships among the rs7208505 variant, methylation density, and symptom severity were modeled using linear regression.
Results
Genotype distributions significantly differed between OCD patients and the 1000 Genomes sample (χ² (2, n = 433) = 8.66, p = 0.013). The odds of having OCD was 1.66 times more likely for individuals carrying a C allele (OR 1.66 [95% CI: 1.09–2.55]; p = 0 0.02). Specifically, the odds of having the CC genotype was 2.58 times more likely for OCD patients (OR 2.58 [95% CI: 1.23–5.23]; p = 0.007). When examining symptom severity there was no effect of genotype (p > 0.05). Finally, epigenetic variation was not significantly associated with symptom severity in our statistical models.
Conclusions
These results provide preliminary evidence that SKA2 genetic variation may be associated with OCD disease status, while no association was detected when examining symptom severity, or methylation density at this locus. The rs7208505 minor allele occurs more frequently in OCD patients than in the general population, suggesting that there is merit in pursing further studies of this marker in larger sample sizes.
... There is increasing evidence that epigenetic processes can play an essential role in the lifelong regulation of gene expression that mediates stress vulnerability. Several studies have demonstrated that post-and prenatal stressors can produce long-term changes in an offspring's neuroendocrine function, neuroepigenetic regulation, and behaviour, and these changes could persist into adulthood and can be heritable (Sadeh et al. 2016 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 8 maternal stress endured during the early-life produced a stronger effect on the offspring's adult phenotypes than the offspring's own early-life experiences at all phenotypic levels. ...
... Moreover, epigenetic mechanisms can play crucial roles in the lifelong regulation of gene expression and neuroendocrine function (Sadeh et al. 2016;Cunliffe 2016;Vaiserman 2015;Grundwald and Brunton 2015;Gapp et al. 2014aGapp et al. , 2014bKlengel et al. 2016;Ressler 2014a, 2014b;Alyamani and Murgatroyd 2018;Zannas and West 2014), which can mediate stress vulnerability/resilience. Several studies have demonstrated that postand prenatal stressors can produce long-term changes in the offspring's neuroendocrine function, neuroepigenetic regulation, and behaviour, which could persist into adulthood (Glover 2014;Merlot et al. 2008;Császár and Bókkon 2017;Juruena 2014;Morris et al. 2010;Glover et al. 2010). ...
Spontaneous loss of a twin most often occurs in the first trimester. This phenomenon is called vanishing twin. Foetuses are especially vulnerable to various stress-related factors. As a result, twin loss in the uterus can produce deep and long-lasting consequences on mental health and may increase the risk of a variety of disease states in the surviving twin. In addition, twin loss may generate strong non-conscious stress that creates epigenetic alterations that impair the brain’s development endocrine and inflammatory substances produced by perturbed signalling pathways. These altered signalling pathways may generate lasting dysfunctions in various areas of the limbic system, predisposing the surviving twin to psychological and emotional problems later in life. We also hypothesise that specific cfDNA and other substances from the dead twin during its reabsorption may affect the surviving twin’s neurodevelopmental and emotional (e.g. resilience) development.
... The genome-wide DNA methylation studies demonstrated significant site-specific differences in the methylation patterns of the promoter regions of the polyamine system genes including OAZ1 (ornithine decarboxylase antienzyme 1), OAZ2 (ornithine decarboxylase antizyme 2), AMD1 (S-adenosylmethionine decarboxylase 2), ARG2 (arginase 2) (Gross et al., 2013), and SKA2 (spindle and kinetochore associated complex subunit 2) (Guintivano et al., 2014;Pandey et al., 2016;Olie, Gourtet, 2017) in the brain of individuals with completed suicide compared to the control. The methylation pattern of the SKA2 gene is specific to SB and can be used as a biomarker for determining suicidal risk (Sadeh et al., 2016). ...
... The analysis of the methylation pattern of BDNF (Kang et al., 2013;Kim et al., 2014) and the SKA2 genes (Sadeh et al., 2016) made it possible to propose them as epigenetic biomarkers of SB. For SB therapy it was suggested to use the histone deacetylase inhibitor tetrapeptide FK228, which is able to enhance transcription of the Rap1 and ERK1/2 genes known to be reduced in the hippocampus of SB individuals. ...
Suicide is the second leading cause of death among young people and therefore being a serious global problem worldwide. The study of genetic and epigenetic factors in the development of suicidal behavior plays an important role in the development of advanced methods of diagnosis and treatment of this pathology. The role of hereditary factors in the development of suicidal behavior is estimated at 30–55 %, with a pronounced comorbidity with other psychopathologies. The study of genetic liability to suicidal behavior is based on molecular-genetic methods including association and linkage analyses, chip gene expression arrays, and genome-wide association studies. Published data identified multiple genes including those involved in the functioning of serotonergic ( SLC6A4 , TPH , 5-HT1A ), hypothalamic-pituitary-adrenal systems ( FKBP5 ) and polyamines ( SAT and OATL1 ) associated with suicidal behavior. However, the diversity of interacting genetic loci complicates the interpretation of the development of a complex phenotype of pathology and prevents the association from being detected. To solve this problem and interpret the missing relationship between the environment and the genome, promising results were obtained from a study of epigenetic factors, which affected the expression of a number of candidate genes involved in brain functioning in suicidal behavior. The analysis of a brain obtained from suicide victims, representing a unique tool for the analysis of modified genomic processes, revealed a wide range of reprogramming patterns of DNA methylation in promoters of the genes of polyamine ( OAZ1 , OAZ2 , AMD1 , ARG2 , SKA2 ), serotonergic ( SLC6A4 ) and GABAergic ( GABRA1 ) systems, HPA-axis ( GR , NR3C1 ), tyrosine kinase ( TrkB ) receptors, brain-derived neurotrophic factor ( BDNF ). The role of histone modifications in distinct genes ( Cx30 , Cx43 , TrkB.T1 ) and the expression of specific long noncoding RNAs and microRNAs in the development of suicidal behavior, which is promising for the development of diagnostic algorithms and target therapy, is discussed.
... [ [60][61][62][63] H P A -a x i s Double-stranded RNA-specific endoribonuclease ...
... In a recent study of trauma-exposed veterans, Sadeh and colleagues (2016) [60] investigated 5mC of SKA2 in whole blood. Differential 5mC methylation of SKA2 predicts suicidal behavior and PTSD status [61], the development of PTSD after military deployment [62], as well as aberrant internalizing psychopathology [63]. In the current study, investigators found that an increase of SKA2 5mC at cg13989295, located in the fourth exon, was associated with decreased PFC thickness bilaterally at the frontal pole and superior frontal gyrus, and in the right hemisphere at the orbitofrontal cortex (OBFC) and inferior frontal gyrus. ...
Purpose of Review
Traumatic stress has profound impacts on many domains of life, yet the mechanisms that confer risk for or resilience to the development of traumatic stress-related psychopathologies are still very much under investigation. The current review highlights recent developments in the field of traumatic stress epigenetics in humans.
Recent Findings
Recent results reveal traumatic stress-related epigenetic dysregulation in neural, endocrine, and immune system genes and associated networks. Emerging work combining imaging with epigenetic measures holds promise for addressing the correspondence between peripheral and central effects of traumatic stress. A growing literature is also documenting the transgenerational effects of prenatal stress exposures in humans.
Summary
Moving forward, increasing focus on epigenetic marks of traumatic stress in CNS tissue will create a clearer picture of the relevance of peripheral measures; PTSD brain banks will help in this regard. Similarly, leveraging multigenerational birth cohort data will do much to clarify the extent of transgenerational epigenetic effects of traumatic stress. Greater efforts should be made towards developing prospective studies with longitudinal design.
... Another promising research area focuses on epigenetic alterations linked to suicidal behavior (Le-Niculescu et al., 2013;Turecki, Ota, Belangero, Jackowski, & Kaufman, 2014)-most notably expression of the spindle and kinetochore-associated protein 2 (SKA2) gene, which may be important for modulating the hypothalamicpituitary-adrenal axis (Clive et al., 2016;Guintivano et al., 2014;Kaminsky et al., 2015;Pandey, Rizavi, Zhang, Bhaumik, & Ren, 2016;Sadeh et al., 2016). Epigenetic variation of SKA2 may help explain how early life adversities disrupt stress-response systems to confer risk for later suicidal behavior (Guintivano et al., 2014;Kaminsky et al., 2015). ...
... Epigenetic variation of SKA2 may help explain how early life adversities disrupt stress-response systems to confer risk for later suicidal behavior (Guintivano et al., 2014;Kaminsky et al., 2015). Some have suggested that SKA2 methylation levels may uniquely predict suicidal thoughts and behaviors independent of psychiatric symptomatology, supporting its consideration as a biomarker for suicide risk (Pandey et al., 2016;Sadeh et al., 2016). ...
Suicide is a leading cause of death worldwide. Prior research has focused primarily on sociodemographic and psychiatric risk factors with little improvement in the prediction or prevention of suicidal behavior over time. The Research Domain Criteria (RDoC) may be an especially useful framework for advancing research in this area. This article provides a brief and broad overview of research on suicidal behavior relating to each of the RDoC domains—highlighting the RDoC construct(s) where research has focused, the construct(s) where research is lacking, and suggestions for future research directions. We also discuss major challenges for suicide research within the RDoC framework, including the intersection of RDoC domains, interaction of domains with the environment, incorporation of developmental stage, integration of distal and proximal processes, and inclusion of suicide-specific constructs. We conclude by underscoring important considerations for future research aimed at using the RDoC framework to study suicidal behavior and other forms of psychopathology.
... The scales vary by study cohort and include the Child Trauma Questionnaire (CTQ), the Perceived Stress Scale, waking salivary cortisol levels, and various metrics of anxiety including self-reported binary estimates and those quantified by the Self-Report for Childhood Anxiety Related Disorders (SCARED) [4,8,9]. Furthermore, our work and others have noted an increased model efficacy in subgroups of individuals having experienced childhood trauma [8,9,12,13]. It is possible that high values in the stress metrics represent a biological state that may be related to HPA axis function. ...
... Boks et al. showed that development of PTSD symptoms was associated with longitudinal decreases in SKA2 methylation after military deployment, which is the opposite of the positive association between SKA2 methylation and suicide risk [4,8]. Furthermore, Sadeh et al. observed a positive association between genotype-adjusted SKA2 methylation and PTSD symptom severity in one military cohort, while this PTSD association was not replicated in a second military cohort [13], adding to the complexity that is the interaction between SKA2 methylation, PTSD, and suicidal behavior [12]. One biological explanation for this interaction is altered HPA axis function in PTSD, as shown by increased clearance of dexamethasone in the DST [45]. ...
Background
Suicide is the second leading cause of death among adolescents in the USA, and rates are rising. Methods to identify individuals at risk are essential for implementing prevention strategies, and the development of a biomarker can potentially improve prediction of suicidal behaviors. Prediction of our previously reported SKA2 biomarker for suicide and PTSD is substantially improved by questionnaires assessing perceived stress or anxiety and is therefore reliant on psychological assessment. However, such stress-related states may also leave a biosignature that could equally improve suicide prediction. In genome-wide DNA methylation data, we observed significant overlap between waking cortisol-associated and suicide-associated DNA methylation in blood and the brain, respectively.
Results
Using a custom bioinformatic brain to blood discovery algorithm, we derived a DNA methylation biosignature that interacts with SKA2 methylation to improve the prediction of suicidal ideation in our existing suicide prediction model across both blood and saliva data sets. This biosignature was independently validated in the Grady Trauma Project cohort and interacted with HPA axis metrics in the same cohort. The biosignature showed a relationship with immune status by its correlation with myeloid-derived cell proportions in all data sets and with IL-6 measures in a prospective postpartum depression cohort. Three probes showed significant correlations with the biosignature: cg08469255 (DDR1), cg22029879 (ARHGEF10), and cg24437859 (SHP1), of which SHP1 methylation correlated with immune measures.
Conclusions
We conclude that this biosignature interacts with SKA2 methylation to improve suicide prediction and may represent a biological state of immune and HPA axis modulation that mediates suicidal behavior.
Electronic supplementary material
The online version of this article (doi:10.1186/s13148-016-0279-1) contains supplementary material, which is available to authorized users.
... In general, findings on methylation of the HPA axis related genes are sparse as few genes have been extensively studied. Four studies(Clive et al., 2016;Kaminsky et al., 2015;Kouter et al., 2022;Sadeh et al., 2016) implicate methylation in the SKA2 gene, first identified in EWAS, to be important in SI and SA, with prospective predictive capability and possible interaction with lifetime trauma history. However, other HPA axis candidate genes such as CRH and NR3C1 have not been extensively studied by independent teams in the context of methylation and SITB.Only two of the candidate methylation studies focused on adolescents (POMC, SIRT1;Zheng et al., 2020;Wang et al., 2021), and both ...
Suicide is a multifaceted and poorly understood clinical outcome, and there is an urgent need to advance research on its phenomenology and etiology. Epidemiological studies have demonstrated that suicidal behavior is heritable, suggesting that genetic and epigenetic information may serve as biomarkers for suicide risk. Here we systematically review the literature on genetic and epigenetic alterations observed in phenotypes across the full range of self‐injurious thoughts and behaviors (SITB). We included 577 studies focused on genome‐wide and epigenome‐wide associations, candidate genes (SNP and methylation), noncoding RNAs, and histones. Convergence of specific genes is limited across units of analysis, although pathway‐based analyses do indicate nervous system development and function and immunity/inflammation as potential underlying mechanisms of SITB. We provide suggestions for future work on the genetic and epigenetic correlates of SITB with a specific focus on measurement issues.
... Similarly, secure attachment (assessed by means of the CamiR) was revealed as a protective factor for suicide. This was also found in the study by McLaughlin and colleagues, which showed that a greater secure attachment predicted lower rates of internalizing disorders in both genders [75], from which we can infer that this would reduce suicidal behavior, as internalizing disorders are a risk factor for suicidal behavior [76,77]. Additionally, childhood trauma appears repeatedly as a risk factor in different studies of suicide behaviors in adolescents [78,79] and can be related to the stressful life events as observed in the present research. ...
Objective:
This research aims to investigate what type of family patterns (specifically attachment, bonding and family functioning) and stressful life events can trigger or protect adolescents from developing suicidal behavior.
Methods:
For these purposes, a case-control study (adolescents with suicidal behavior vs. paired adolescents with no suicidal behavior) was conducted with one hundred 12 to 17-year-old adolescents (50 controls, 50 cases, 74% females), assessed between 2018 and 2020.
Results:
Negligent (p < 0.001) or affection-less control bonding (p < 0.001), insecure attachment (p = 0.001) and stressful life events (p < 0.001) revealed to be significant risk factors for suicidal behavior. On the contrary, parents' care (p < 0.001) and security (p < 0.001) were revealed as protective factors for suicidal behavior.
Conclusions:
Considering these results, family interventions and improving coping skills seem to be two essential targets for any suicide prevention intervention in adolescents.
... As for NR3C1, findings on FKBP5 DNAm are different across disorder, suggesting a divergent transdiagnostic mechanism involving in HPA related genes (see Fig. 2). The SKA2 interacts with adversity scores in predicting lifetime suicide attempt (Kaminsky et al., 2015), and mediated the association between reduced cortical thickness and PTSD (Sadeh et al., 2016a) and suicide phenotypes (Sadeh et al., 2016b). ...
A significant proportion of the global burden of disease can be attributed to mental illness. Despite important advances in identifying risk factors for mental health conditions, the biological processing underlying causal pathways to disease onset remain poorly understood. This represents a limitation to implement effective prevention and the development of novel pharmacological treatments. Epigenetic mechanisms have emerged as mediators of environmental and genetic risk factors which might play a role in disease onset, including childhood adversity (CA) and cannabis use (CU). Particularly, human research exploring DNA methylation has provided new and promising insights into the role of biological pathways implicated in the aetio-pathogenesis of psychiatric conditions, including: monoaminergic (Serotonin and Dopamine), GABAergic, glutamatergic, neurogenesis, inflammatory and immune response and oxidative stress. While these epigenetic changes have been often studied as disease-specific, similarly to the investigation of environmental risk factors, they are often transdiagnostic. Therefore, we aim to review the existing literature on DNA methylation from human studies of psychiatric diseases (i) to identify epigenetic modifications mapping onto biological pathways either transdiagnostically or specifically related to psychiatric diseases such as Eating Disorders, Post-traumatic Stress Disorder, Bipolar and Psychotic Disorder, Depression, Autism Spectrum Disorder and Anxiety Disorder, and (ii) to investigate a convergence between some of these epigenetic modifications and the exposure to known risk factors for psychiatric disorders such as CA and CU, as well as to other epigenetic confounders in psychiatry research.
... As for NR3C1, findings on FKBP5 DNAm are different across disorder, suggesting a divergent transdiagnostic mechanism involving in HPA related genes (see Fig. 2). The SKA2 interacts with adversity scores in predicting lifetime suicide attempt (Kaminsky et al., 2015), and mediated the association between reduced cortical thickness and PTSD (Sadeh et al., 2016a) and suicide phenotypes (Sadeh et al., 2016b). ...
Background
Considerable evidence on general population suggests that an “Affective pathway to psychosis”, involving depression and anxiety dimensions, mediates the abuse-psychosis association. However, this has never been tested in Early Psychosis (EP) patients. We aim at testing whether severity of depressive and anxiety mediates the abuse-positive symptoms dyad in an EP prospective sample.
Methods
330 EP subjects aged 18–35 were assessed for psychopathology after 2, 6, 12, 18, 24, 30, and 36 months of treatment. Abuse was considered as facing at least one experience of physical, sexual, or emotional abuse before age 16. Positive psychotic symptoms and anxiety were measured with the Positive and Negative Syndrome Scale and depressive symptoms with the Montgomery-Asberg Depression Rating Scale. Mediation analyses were performed to study whether the abuse-positive symptom's link was mediated by depressive, anxiety, and a combination of anxiety/mood symptoms.
Results
Among the 330 EP patient included, 104 (31.5% of the total) were exposed to abuse. Analyses across the 36 months of follow-up showed that depression and anxiety partially mediated 26.7% of the total effect of the abuse-positive symptoms association (indirect effects (IE) = 0.392 and 0.421 respectively), while the combined anxiety/mood model mediated 28.9% (IE = 0.475). Subanalyses at two and 36 months revealed a consistent role of depression, while that of anxiety was only present at baseline.
Conclusion
Our work confirms a mediating role of mood and anxiety in the association between abuse and positive symptoms during the first three years of treatment.
Evidence of Mediation of Anxiety and Depression Between Abuse and Positive symptoms of Psychosis.
... Four studies [25,41,44,52] examined the association between SKA2 SNPs and SB in 1675 cases and 1320 controls. rs8082544 and rs7502947 showed an association with CS [41] as well as significant interactions for SKA2 3 -UTR DNA methylation, while the rs7208505 SNP was associated with SI and SA [25]. ...
Background:
Suicide behavior (SB) has been highly associated with the response to stress and the hypothalamic-pituitary-adrenal (HPA) axis. The aim of this study was to summarize the results obtained in genetic studies that analyzed the HPA axis-stress pathway and SB through a systematic review.
Methods:
We performed an online search in PubMed, EBSCO, Web of Science, Scopus, and PsycoInfo databases up to May 2021. We followed the PRISMA guidelines for systematic reviews. We included case-control and expression studies that provided data on mRNA expression and single-nucleotide polymorphisms of genes associated with SB.
Results:
A total of 21,926 individuals participated across 41 studies (not repeats); 34 studies provided data on single-nucleotide polymorphisms in 21,284 participants and 11 studies reported data on mRNA expression in 1034 participants. Ten genes were identified: FKBP5, CRH, CRHBP, CRHR1, CRHR2, NR3C1, NR3C2, SKA2, MC2R, and POMC.
Conclusions:
Our findings suggest that key stress pathway genes are significantly associated with SB and show potential as biomarkers for SB.
... Kaminsky et al. (2015) tested the rs7208505 DNA methylation and genotype as a possible biomarker for predict suicidal behavior, finding low predictive accuracy but significant for suicide attempt; stronger associations were detected in participants who reported emotional but not physical or sexual abuse. Additionally, a study on peripheral blood cells from military veterans determined that the SKA2 methylation levels at CpG locus cg13989295 (where polymorphic variant rs7208505 is found) are associated with current suicidal thoughts and behaviors (Sadeh et al., 2016). It is important to emphasize that Kaminsky et al. and Sadeh et al. performed the analysis in posttraumatic stress disorder cohorts; therefore, it is necessary to evaluate the reproducibility of results in another suicide-associated mental disorder population. ...
Suicide is a complex phenomenon and a global public health problem that involves several biological factors that could contribute to the pathophysiology of suicide. There is evidence that epigenetic factors influence some psychiatric disorders, suggesting a predisposition to suicide or suicidal behavior. Here, we review studies of molecular mechanisms of suicide in an epigenetic perspective in the postmortem brain of suicide completers and peripheral blood cells of suicide attempters. Besides, we include studies of gene-specific DNA methylation, epigenome-wide association, histone modification, and interfering RNAs as epigenetic factors. This review provides an overview of the epigenetic mechanisms described in different biological systems related to suicide, contributing to an understanding of the genetic regulation in suicide. We conclude that epigenetic marks are potential biomarkers in suicide, and they could become attractive therapeutic targets due to their reversibility and importance in regulating gene expression.
... Third, due to the cross-sectional nature of the study, it was not possible to differentiate between Li-induced differences in DNA methylation in LiERs and LiNRs from pre-existing differences due to the genetic background and/or to other environmental factors that might be linked to non-response to Li, such as exposure to childhood maltreatment for example 39 . In addition, the level of disease progression and related characteristics (frequency of mood episodes or suicide attempts) are likely to influence the methylation status 40,41 and may differ between LiERs and LiNRs participants. Third, this signature is identified in blood, which makes the extrapolation of the biological significance at the brain level uncertain. ...
... Another gene participating in the HPA axis activity encodes the Spindle and Kinetochore Associated Complex Subunit 2 (SKA2), responsible for the production of a protein that transports the GR into the cell nucleus (Chmielewska et al., 2019). Methylation at the CpG locus cg13989295 within the SKA2 gene was related to general susceptibility to experience stress-related psychopathology, including internalizing disorders and suicidal thoughts and behaviors in adults with high levels of trauma exposure, including ELS (Sadeh et al., 2016). ...
Major depressive disorder (MDD) is the most common psychiatric disorder and responds for important psychosocial consequences. Stressful life events, especially early life stress (ELS), contribute to an increased probability to develop MDD, leading in particular to severe and chronic manifestation and unfavorable treatment outcome. The association between ELS and MDD seems to have biological bases, consisting in dysregulations occurring at different levels. The aim of this narrative review is to propose an overview of the literature ranging from genetic, epigenetic, expression and protein to neuroimaging correlates underlying this relationship. A search on Pubmed of studies assessing biological correlates of ELS in MDD development, focusing on human studies conducted in both peripheral and brain tissues, was performed. Evidence indicated that the hypothalamic-pituitary-adrenal (HPA) axis and the serotonergic, dopaminergic, neurotrophin and oxytocin systems might play a role in the mediation between ELS and MDD. The most consistent results were found for genetic and epigenetic studies and indicated a joint involvement of the systems mentioned. Expression studies are less numerous and point to an involvement of stress-related systems. Concerning protein studies, the main mediators are markers related to the inflammatory and immune systems. Neuroimaging studies aiming at evaluating brain alterations connecting ELS and MDD in relation to biomarkers indicated the hippocampus, the amygdala and the frontal cortex as important anatomical mediators. These findings can build the bases for future research and clinical interventions; indeed, the clarification of biological mechanisms mediating the relationship between ELS and MDD can lead to new and individualized preventive and therapeutic possibilities.
... Third, due to the cross-sectional nature of the study, it was not possible to differentiate between Li-induced differences in DNA methylation in LiERs and LiNRs from pre-existing differences due to the genetic background and/or to other environmental factors that might be linked to non-response to Li, such as exposure to childhood maltreatment for example 39 . In addition, the level of disease progression and related characteristics (frequency of mood episodes or suicide attempts) are likely to influence the methylation status 40,41 and may differ between LiERs and LiNRs participants. Third, this signature is identified in blood, which makes the extrapolation of the biological significance at the brain level uncertain. ...
Lithium (Li) is the cornerstone maintenance treatment for bipolar disorders (BD), but response rates are highly variable. To date, no clinical or biological marker is available to reliably define eligibility criteria for a maintenance treatment with Li. We examined whether the prophylactic response to Li (assessed retrospectively) is associated with distinct blood DNA methylation profiles. Bisulfite-treated total blood DNA samples from individuals with BD type 1 (15 excellent-responders (LiERs) versus 11 non-responders (LiNRs)) were used for targeted enrichment of CpG rich genomic regions followed by high-resolution next-generation sequencing to identify differentially methylated regions (DMRs). After controlling for potential confounders we identified 111 DMRs that significantly differ between LiERs and LiNRs with a significant enrichment in neuronal cell components. Logistic regression and receiver operating curves identified a combination of 7 DMRs with a good discriminatory power for response to Li (Area Under the Curve 0.806). Annotated genes associated with these DMRs include Eukaryotic Translation Initiation Factor 2B Subunit Epsilon (EIF2B5), Von Willebrand Factor A Domain Containing 5B2 (VWA5B2), Ral GTPase Activating Protein Catalytic Alpha Subunit 1 (RALGAPA1). Although preliminary and deserving replication, these results suggest that biomarkers of response to Li may be identified through peripheral epigenetic measures.
... In addition, future studies could also examine the transcriptional consequences of the observed DNA methylation changes at the PSORS1C3 DMR on additional nearby genes and/or novel splice variants in the region. There is considerable interest in using DNA methylation-based biomarkers as predictors for suicide risk and previous studies 30, [80][81][82][83][84] have identified polymorphic CpGs that can act as a unique molecular signature for suicide prediction. The data from this study provide many more candidate regions as potential biomarkers for suicide risk and also identifies genes/networks potentially dysregulated in suicidal brain. ...
Suicide is the second leading cause of death globally among young people representing a significant global health burden. Although the molecular correlates of suicide remains poorly understood, it has been hypothesised that epigenomic processes may play a role. The objective of this study was to identify suicide-associated DNA methylation changes in the human brain by utilising previously published and unpublished methylomic datasets. We analysed prefrontal cortex (PFC, n = 211) and cerebellum (CER, n = 114) DNA methylation profiles from suicide completers and non-psychiatric, sudden-death controls, meta-analysing data from independent cohorts for each brain region separately. We report evidence for altered DNA methylation at several genetic loci in suicide cases compared to controls in both brain regions with suicide-associated differentially methylated positions enriched among functional pathways relevant to psychiatric phenotypes and suicidality, including nervous system development (PFC) and regulation of long-term synaptic depression (CER). In addition, we examined the functional consequences of variable DNA methylation within a PFC suicide-associated differentially methylated region (PSORS1C3 DMR) using a dual luciferase assay and examined expression of nearby genes. DNA methylation within this region was associated with decreased expression of firefly luciferase but was not associated with expression of nearby genes, PSORS1C3 and POU5F1. Our data suggest that suicide is associated with DNA methylation, offering novel insights into the molecular pathology associated with suicidality.
... Moreover, in the same study, greater DNA methylation at SKA2 and less expression were found in suicide decedents compared with controls. Finally, SKA2 methylation was found to be associated not only with SI and SA but also with current and lifetime symptoms of internalizing disorders (Sadeh et al., 2016). ...
Background:
There has been increasing interest in both suicide-specific diagnoses within the psychiatric nomenclature and related biomarkers. Because the Suicide Crisis Syndrome (SCS)--an emotional crescendo of several interrelated symptoms--seems to be promising for the identification of individuals at risk of suicide, the aim of the present paper is to review the putative biological underpinnings of the SCS symptoms (entrapment, affective disturbance, loss of cognitive control, hyperarousal, social withdrawal).
Methods:
A PubMed literature search was performed to identify studies reporting a link between each of the 5 SCS symptoms and biomarkers previously reported to be associated with suicidal outcomes.
Results:
Disturbances in the hypothalamic-pituitary-adrenal axis, with dysregulated corticotropin-releasing hormone and cortisol levels, may be linked to a sense of entrapment. Affective disturbance is likely mediated by alterations in dopaminergic circuits involved in reward and anti-reward systems, as well as endogenous opioids. Loss of cognitive control is linked to altered neurocognitive function in the areas of executive function, attention, and decision-making. Hyperarousal is linked to autonomic dysregulation, which may be characterized by a reduction in both heart rate variability and electrodermal activity. Social withdrawal has been associated with oxytocin availability. There is also evidence that inflammatory processes may contribute to individual SCS symptoms.
Conclusion:
The SCS is a complex syndrome that is likely the consequence of distinct changes in interconnected neural, neuroendocrine and autonomic systems. Available clinical and research data allow for development of empirically testable hypotheses and experimental paradigms to scrutinize the biological substrates of the SCS.
... For this dataset, methylation in blood was assessed with 450K BeadChips. The cleaning and processing of the 450K data for the NCPTSD cohort is described in detail elsewhere [22] and followed the same pipeline used for the TRACTS cohort. We also examined the performance of these methods using multiple publicly available datasets from the Gene Expression Omnibus (GEO; https://www.ncbi.nlm.nih.gov/geo/) ( Table 1). ...
Aim: 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 et al. (GEA), and Li and Ji methods. Materials & methods: The experiment-wide type 1 error rate was examined in simulations based on Illumina EPIC and 450K data. Results: For high-correlation genes, Sidak and false-discovery rate corrections were conservative while the Li and Ji method was liberal. The GEA method tended to be conservative unless a threshold parameter was adjusted. The ETT yielded an appropriate type 1 error rate. Conclusion: For genes with substantial correlation across measured CpGs, GEA and ETT can appropriately correct for multiple testing in candidate gene methylation studies.
... In contrast, in a subsequent study, Sadeh et al. (2016b) reported no association between PTSD diagnosis and SKA2 methylation, but a positive association between suicidal phenotype (i.e., ideations, plans, attempts) and internalizing psychopathology-both important features of depression--and SKA2 methylation (n=466). The authors acknowledged that differences in the chronicity of PTSD may have contributed to the observed discrepancy (i.e., the length of time since PTSD diagnosis averaged 4.5 years in the first study and 28 years in the second study). ...
Environmental stressors, such as childhood maltreatment, have been recognized to contribute to the development of depression. Growing evidence suggests that epigenetic changes are a key mechanism by which stressors interact with the genome leading to stable changes in DNA structure, gene expression, and behaviour. The current review aimed to evaluate the relationship between stress-associated epigenetic changes and depression. Human studies were identified via systematic searching of PubMed/Medline from inception to February 2018. Seventeen articles were identified. Stress-associated epigenetic changes in the following genes were correlated with depression: NRC31, SLCA4, BDNF, FKBP5, SKA2, OXTR, LINGO3, POU3F1 and ITGB1. Epigenetic changes in glucocorticoid signaling (e.g., NR3C1, FKBP5), serotonergic signaling (e.g. SLC6A4), and neurotrophin (e.g., BDNF) genes appear to be the most promising therapeutic targets for future research. However, continued research is warranted due to inconsistent findings regarding the directionality of epigenetic modification. Future studies should also aim to control for the use of psychotropic agents due to their widespread use in depressed populations and established effects on DNA methylation.
... Une première étude menée par Guintivano et al. a montré que les variations génétiques et épigénétiques de SKA2 étaient associées avec les conduites suicidaires . Par la suite, plusieurs autres études ont corroboré cette hypothèse en montrant que la méthylation du gène SKA2 était associée à des TS et IS actuelles ainsi qu'à une diminution de l'expression de la protéine SKA2, associée à une diminution de l'épaisseur du cortex préfrontal chez des victimes de suicides (Kaminsky et al., 2015;Naomi Sadeh et al., 2016;N. Sadeh et al., 2016b). ...
Les troubles des conduites alimentaires (TCA) et les troubles des conduites suicidaires (TCS) sont des pathologies mentales graves. Ces deux troubles représentent un problème de santé publique majeur. En effet, il s’agit de pathologies pour lesquelles les pronostics sont médiocres, ayant un impact lourd sur la vie des patients et de leur entourage et représentant un coût élevé pour la société. Il n’existe actuellement aucun biomarqueur validé dans l’une ou l’autre de ces pathologies. L’objectif de ce travail est de réussir à identifier de potentiels biomarqueurs dans ces deux troubles. L’identification de biomarqueurs potentiels pourrait être utile dans divers domaines : faciliter le diagnostic des patients, améliorer la prise en charge des patients et enfin servir de cibles thérapeutiques dans le but d’élaborer de nouveaux traitements plus efficaces. Nous présenterons dans ce travail l’intérêt et l’utilisation des biomarqueurs en psychiatrie puis deux axes d’exploration des TCA ainsi qu’un axe d’exploration des TCS: l’approche neuropsychologique ainsi que l’approche biologique pour les TCA et l’approche génétique pour les TCS. Concernant les TCA, nos résultats suggèrent un intérêt potentiel des oestro-progestatifs dans l’amélioration des fonctions cognitives des patientes. Au sujet des TCS, il semblerait que deux des polymorphismes génétiques que nous avons étudiés (l’un du gène MOR et l’autre du gène SKA2) soient associés avec le risque d’émergence d’idées suicidaires au cours de l’initiation d’un traitement antidépresseur. Si ces études étaient répliquées, ces divers éléments pourraient s’avérer être des outils diagnostics et thérapeutiques.
... N Sadeh et al analyzed the rs7208505 genotype, cg13989295 methylation, and methylation adjusted for genotype in 200 white non-Hispanic veterans, and they found that SKA2 methylation is associated with decreased prefrontal cortical thickness and increased PTSD severity among trauma-exposed veterans, in another collection of 466 white non-Hispanic blood sample of veterans, SKA2 methylation (at CpG locus cg13989295) was found to be associated with lifetime suicidal risk, although the association between PTSD and SKA2 were not significant. 29,30 A follow-up study of blood samples from trauma-exposed veterans and neuroimaging revealed that DNA methylation was associated with bilateral reductions of cortical thickness in frontal pole and superior frontal gyrus, and similar effects were found in the right orbitofrontal cortex and right inferior frontal gyrus. PTSD symptom severity was positively correlated with SKA2 DNA methylation and negatively correlated with cortical thickness in these regions. ...
SKA2 (spindle and KT associated 2), also referred to as FAM33A (family with sequence similarity 33, member A), is a recently identified gene involved in cell cycle regulation, and growing evidence is implicating its roles in tumorigenesis and psychiatric disorders. It has been demonstrated that SKA2, along with its coworkers SKA1 and SKA3, constitutes the SKA complex which plays a critical role in the maintenance of the metaphase plate and/or spindle checkpoint silencing during mitosis. SKA2 is over-expressed both in cancer cell lines and clinical samples including small cell lung cancer and breast cancer, whereas downregulation of SKA2 is associated with depression and suicidal ideation. The expression of SKA2 is regulated by transcription factors including NF-κΒ and CREB, miRNAs as well as DNA methylation. In this review, we provide an overview of studies that reveal SKA2 gene and protein characteristics as well as physiological function, with a special focus on its transcription regulatory mechanisms, and also provide a summary regarding the translational opportunity of the SKA2 gene as a clinical biomarker for cancers and psychiatric disorders.
... Since the expression of this miRNA is tied to SKA2 expression, it was suggested as a proxy of suicideassociated SKA2 decreases [55,72]. Further support to these preliminary findings has been provided by more recent studies suggesting the influence of trauma exposure on SKA2 DNA methylation as well as DNA methylation of the SKA2 gene as a biomarker of suicide risk and stressrelated psychopathology [74,75]. ...
... Cortisol and glucocorticoid receptor (GR) levels and dynamics vary across individuals and subpopulations with PTSD, and likely reflect the impact of multiple factors: genetic predisposition, developmental timing of trauma, cumulative stress and trauma, sex, menstrual state, comorbid conditions such as depression or chronic pain, acute or chronic use of exogenous agents such as nicotine, alcohol, and a variety of pharmaceuticals including those often used to treat PTSD, experimental design, and study specific assay techniques [15,122]. Despite the intrinsic complexity of the glucocorticoid system, and the wide variety of factors that may perturb it, including factors not typically considered in studies of glucocorticoid system dynamics [e.g., 123,124], coherent glucocorticoid system endophenotypes associated with PTSD are b e g i n n i ng t o t a ke s h a pe . R e c o g n i t i o n o f t h e s e endophenotypes may, in turn, guide development and targeting of more effective individualized treatments for PTSD. ...
Purpose of review:
This review summarizes neurotransmitter, peptide, and other neurohormone abnormalities associated with posttraumatic stress disorder (PTSD) and relevant to development of precision medicine therapeutics for PTSD.
Recent findings:
As the number of molecular abnormalities associated with PTSD across a variety of subpopulations continues to grow, it becomes clear that no single abnormality characterizes all individuals with PTSD. Instead, individually variable points of molecular dysfunction occur within several different stress-responsive systems that interact to produce the clinical PTSD phenotype. Future work should focus on critical interactions among the systems that influence PTSD risk, severity, chronicity, comorbidity, and response to treatment. Effort also should be directed toward development of clinical procedures by which points of molecular dysfunction within these systems can be identified in individual patients. Some molecular abnormalities are more common than others and may serve as subpopulation biological endophenotypes for targeting of currently available and novel treatments.
... Future PTSD brain bank studies could use a similar methodology to evaluate mechanisms of PTSD-related accelerated aging in the brain. Specifically, using in situ hybridization and immunohistochemistry, RNA and protein expression of candidate genes implicated in PTSD-and HPA-axis functioning (e.g., CRF, FKBP5, NR3C1, SKA2) [87][88][89][90][91], oxidative stress (RORA, ALOX12) [30••, 92••, 93], and inflammation (TNFα, CRP) [32, 74, 75, 76•, 77] could be compared across brain regions (in both neurons and glia) and the periphery. To discern which cellular elements drive the hypothesized effects on DNAm age, fluorescence-activated cell sorting (FACS) could be used to interrogate differential methylation status of the loci in the age algorithms, and reactive oxygen species (ROS) levels, in glia compared to neurons across brain regions. ...
Purpose of review: The aim of this paper is to review the recent literature on traumatic stress-related accelerated aging, including a focus on cellular mechanisms and biomarkers of cellular aging and on the clinical manifestations of accelerated biological aging.
Recent findings: Multiple lines of research converge to suggest that PTSD is associated with accelerated aging in the epigenome, and the immune and inflammation systems, and this may be reflected in premature onset of cardiometabolic and cardiovascular disease.
Summary: The current state of research paves the way for future work focused on identifying the peripheral and central biological mechanisms linking traumatic stress to accelerated biological aging and medical morbidity, with an emphasis on processes involved in inflammation, immune functioning, oxidative stress, autonomic arousal, and stress responding. Ultimately, such work could help reduce the pace of biological aging and improve health and wellness.
Stress is associated with contextual memory deficits, which may mediate avoidance of trauma-associated contexts in posttraumatic stress disorder. These deficits may emerge from impaired pattern separation, the independent representation of similar experiences by the dentate gyrus-Cornu Ammonis 3 (DG-CA3) circuit of the dorsal hippocampus, which allows for appropriate behavioral responses to specific environmental stimuli. Neurogenesis in the DG is controlled by mitochondrial reactive oxygen species (ROS) production, and may contribute to pattern separation. In Experiment 1, we performed RNA sequencing of the dorsal hippocampus 16 days after stress in rats that either develop conditioned place avoidance to a predator urine-associated context (Avoiders), or do not (Non-Avoiders). Weighted genome correlational network analysis showed that increased expression of oxidative phosphorylation-associated gene transcripts and decreased expression of gene transcripts for axon guidance and insulin signal-ing were associated with avoidance behavior. Based on these data, in Experiment 2, we hypothesized that Avoiders would exhibit elevated hippocampal (HPC) ROS production and degraded object pattern separation (OPS) compared with Non-Avoiders. Stress impaired pattern separation performance in Non-Avoider and Avoider rats compared with nonstressed Controls, but surprisingly, Avoiders exhibited partly preserved pattern separation performance and significantly lower
ROS production compared with Non-Avoiders. Lower ROS production was associ-
ated with better OPS performance in Stressed rats, but ROS production was not
associated with OPS performance in Controls. These results suggest a strong neg-
ative association between HPC ROS production and pattern separation after
stress, and that stress effects on these outcome variables may be associated with
avoidance of a stress-paired context.
Adverse social exposures (ASEs) such as low income, low educational attainment, and childhood/adult trauma exposure are associated with variability in brain region measurements of gray matter volume (GMV), surface area (SA), and cortical thickness (CT). These CNS morphometries are associated with stress-related psychiatric illnesses and represent endophenotypes of stress-related psychiatric illness development. Epigenetic mechanisms, such as 5-methyl-cytosine (5mC), may contribute to the biological embedding of the environment but are understudied and not well understood. How 5mC relates to CNS endophenotypes of psychiatric illness is also unclear. In 97 female, African American, trauma-exposed participants from the Grady Trauma Project, we examined the associations of childhood trauma burden (CTQ), adult trauma burden, low income, and low education with blood-derived 5mC clusters and variability in brain region measurements in the amygdala, hippocampus, and frontal cortex subregions. To elucidate whether peripheral 5mC indexes central nervous system (CNS) endophenotypes of psychiatric illness, we tested whether 73 brain/blood correlated 5mC clusters, defined by networks of correlated 5mC probes measured on Illumina’s HumanMethylation Epic Beadchip, mediated the relationship between ASEs and brain measurements. CTQ was negatively associated with rostral middle frontal gyrus (RMFG) SA (β =−0.231, p = 0.041). Low income and low education were also associated with SA or CT in a number of brain regions. Seven 5mC clusters were associated with CTQ (pmin = 0.002), two with low education (pmin = 0.010), and three with low income (pmin = 0.007). Two clusters fully mediated the relation between CTQ and RMFG SA, accounting for 47 and 35% of variability, respectively. These clusters were enriched for probes falling in DNA regulatory regions, as well as signal transduction and immune signaling gene ontology functions. Methylome-network analyses showed enrichment of macrophage migration ( p = 9 × 10 –8 ), T cell receptor complex ( p = 6 × 10 –6 ), and chemokine-mediated signaling ( p = 7 × 10 –4 ) pathway enrichment in association with CTQ. Our results support prior work highlighting brain region variability associated with ASEs, while informing a peripheral inflammation-based epigenetic mechanism of biological embedding of such exposures. These findings could also serve to potentiate increased investigation of understudied populations at elevated risk for stress-related psychiatric illness development.
Differentially methylated regions (DMRs) are genomic regions with specific methylation patterns across multiple loci that are associated with a phenotype. We examined the genome-wide false positive (GFP) rates of five widely used DMR methods: comb-p, Bumphunter, DMRcate, mCSEA and coMethDMR using both Illumina HumanMethylation450 (450 K) and MethylationEPIC (EPIC) data and simulated continuous and dichotomous null phenotypes (i.e., generated independently of methylation data). coMethDMR provided well-controlled GFP rates (~5%) except when analysing skewed continuous phenotypes. DMRcate generally had well-controlled GFP rates when applied to 450 K data except for the skewed continuous phenotype and EPIC data only for the normally distributed continuous phenotype. GFP rates for mCSEA were at least 0.096 and comb-p yielded GFP rates above 0.34. Bumphunter had high GFP rates of at least 0.35 across conditions, reaching as high as 0.95. Analysis of the performance of these methods in specific regions of the genome found that regions with higher correlation across loci had higher regional false positive rates on average across methods. Based on the false positive rates, coMethDMR is the most recommended analysis method, and DMRcate had acceptable performance when analysing 450 K data. However, as both could display higher levels of FPs for skewed continuous distributions, a normalizing transformation of skewed continuous phenotypes is suggested. This study highlights the importance of genome-wide simulations when evaluating the performance of DMR-analysis methods.
Suicide is a problem resulting from the interaction between several factors. Among these, early-life adversity, characterized by child sexual, physical abuse or parental neglect, is one of the strongest risk factors for depression and suicidal behaviors. While it is clear that child abuse increases the risk for depression and suicide, the mechanisms mediating these effects are still under deep investigation. A growing body of literature suggests that epigenetic mechanisms may be involved in mediating the effects of early-life adversity (ELA) on behavior. In both human and animal models, ELA has been shown to alter DNA methylation in genes regulatory regions which, in turn, has been associated with changes in gene expression and behavioral modifications. However, although epigenetic modifications have been found in several genes, the extent of epigenetic changes induced by ELA is still unknown, and their impact on increasing suicide risk are unclear. This chapter aims at identifying and describing the molecular mechanisms by which ELA induces behavioral changes conferring vulnerability toward mood disorders and suicidal behaviors.
Post-traumatic stress disorder (PTSD) is one of the prevalent neurological disorder which is drawing increased attention over the past few decades. Major risk factors for PTSD can be categorized into environmental and genetic factors. Among the genetic risk factors, polymorphisms in the catechol-O-methyltransferase (COMT) gene is known to be associated with the risk for PTSD. In the present study, we analysed the impact of deleterious single nucleotide polymorphisms (SNPs) in the COMT gene conferring risk to PTSD using computational based approaches followed by molecular dynamic simulations. The data on COMT gene associated with PTSD were collected from several databases including Online Mendelian Inheritance in Man (OMIM) search. Datasets related to SNP were downloaded from the dbSNP database. To study the structural and dynamic effects of COMT wild type and mutant forms, we performed molecular dynamics simulations (MD simulations) at a time scale of 300 ns.Results from screening the SNPs using the computational tools SIFT and Polyphen-2 demonstrated that the SNP, rs4680 (V158M) in COMT has a deleterious effect with phenotype in PTSD . Results from the MD simulations showed that there is some major fluctuations in the structural features including root mean square deviation (RMSD), radius of gyration (Rg), root mean square fluctuation (RMSF) and secondary structural elements including α-helices, sheets and turns between wild-type (WT) and mutant forms of COMT protein. In conclusion, our study provides novel insights into the deleterious effects and impact of V158M mutation on COMT protein structure which plays a key role in PTSD.
Suicidal behaviors have been associated with both heritable genetic variables and environmental risk factors. Epigenetic processes, such as DNA methylation, have important roles in mediating the effects of the environment on behavior. Dysregulation of these processes has been observed in many psychiatric disorders, and evidence suggests that they may also be involved in suicidal behaviors. Herein, we have summarized candidate gene and epigenome-wide studies which have investigated DNA methylation in relation to suicidal behaviors, as well as discussed some of the limitations of the field to date.
Most people will experience a traumatic event within their lifetime. One commonly recognized response to trauma exposure is posttraumatic stress disorder (PTSD). The biological underpinnings of PTSD, including epigenetic mechanisms of DNA methylation and gene expression, have been studied intensively. However, psychological posttrauma responses vary widely and can include positive outcomes, such as posttraumatic growth (PTG) and, more commonly, resilience. The aim of this systematic review was to summarize the current DNA methylation and gene expression data with respect to three potential posttrauma responses: PTSD, PTG, and resilience. A literature search identified 486 studies, 51 of which were deemed eligible for inclusion (total N = 10,633). All included studies examined PTSD and consistently implicated DNA methylation and gene expression changes in hypothalamic-pituitary-adrenal axis and inflammatory genes. Ten studies acknowledged resilience as a posttrauma response, but only two studies examined epigenetics and gene expression using a scale to measure resilience. Low resilience was associated with gene expression patterns in immune and dopamine genes, and high resilience was associated with a blunted inflammatory response. No studies examined epigenetic or gene expression changes associated with PTG. These findings highlight a focus on pathogenic research, which has failed to adequately acknowledge and measure positive posttrauma outcomes of PTG and resilience. Future research should examine DNA methylation and gene expression changes associated with PTG and resilience in addition to PTSD in order to gain a more comprehensive picture of an individual's well-being following exposure to trauma.
Background:
Suicide results in over 800,000 deaths every year, making it a major public health concern worldwide. It is highly complex, with genetic and environmental influences. Epigenetic mechanisms, including DNA methylation, miRNA, and histone modifications, could explain the complex interplay of environmental risk factors with genetic risk factors in the emergence of suicidal behavior.
Methods:
Here, we review the literature on suicide epigenetics over the past 10 years.
Results:
There has been significant progress in the field of suicide epigenetics, with emerging findings in the brain-derived neurotrophic factor and hypothalamic-pituitary-adrenal axis genes.
Limitations:
Studying patient subgroups is needed in order to extract more comparable and reproducible epigenetic findings in suicide.
Conclusions:
It is crucial to consider suicidal patients or suicide victims' distal and proximal past history e.g., early-life adversity and psychiatric disorder in epigenetic studies of suicidality.
Nearly one million people take their own lives each year world-wide - however, contrary to popular belief, suicide can be prevented. While suicide is commonly thought to be an understandable reaction to severe stress, it is actually an abnormal reaction to regular situations. Something more than unbearable stress is needed to explain suicide, and neuroscience shows what this is, how it is caused and how it can be treated. Professor Kees van Heeringen describes findings from neuroscientific research on suicide, using various approaches from population genetics to brain imaging. Compelling evidence is reviewed that shows how and why genetic characteristics or early traumatic experiences may lead to a specific predisposition that makes people vulnerable to triggering life events. Neuroscientific studies are yielding results that provide insight into how the risk of suicide may develop; ultimately demonstrating how suicide can be prevented.
Background:
There is a relationship between preterm birth (PTB) and anxiety. Spindle and Kinetochore Associated Complex Subunit 2 (SKA2) gene polymorphism (NC_000017.11: g.59110368 G > A) has also been associated with the development of anxiety. The current study was designed to evaluate the relationship between SKA2 gene SNP (NC_000017.11: g.59110368 G > A) with the occurrence of anxiety and PTB which might be considered a predictive biomarker for the prediction of preterm delivery.
Methods:
SKA2 gene (SNP rs7208505) genotyping was performed in 300 women with term birth (TB) and 293 women with PTB using PCR-RFLP method and then followed by DNA sequencing. Cortisol level was analyzed with ELISA method and the presence of anxiety was detected using Spielberg Inventory.
Results:
The AA genotype of SKA2 gene significantly increased the risk of PTB compared to the GG genotype by 9.6 fold ([CI] 4.5-20.2, P < 0.001) according to codominant model. Also, the frequency of A allele was significantly higher in PTB group (χ2 = 20.4, df = 1, P < 0.001) in comparison with the control group that increased the risk of PTB by 1.703 fold ([CI] 1.39-2.23, P < 0.001). Women with higher cortisol level with average 343.7 ± 3 nmol/L had AA genotype, while, the concentrations of cortisol in women with AG, and GG genotypes were 244.2 ± 3.1 nmol/L and 192.6 ± 2.5 nmol/L, respectively (P < 0.001). The score of apparent and latent anxiety in women with the AA genotype was higher compared to the AG and GG genotypes and also this score in women with the AG genotype was higher than the GG genotypes (P < 0.001). The history of preterm delivery was higher in women with the AA genotype (42.1%) in comparison with the GG (14.9%) and AG (22%) genotypes (P < 0.05).
Conclusion:
The results of the current study suggest that prognosis of women with the AA genotype are more susceptible to be spontaneous preterm birth. Therefore, the A allele of SKA2 gene (NC_000017.11:g.59110368 G > A) could be as a predictive biomarker for the risk of PTB.
While diagnosis of PTSD is based on behavioral symptom clusters that are most directly associated with brain function, epigenetic studies of PTSD in humans to date have been limited to peripheral tissues. Animal models of PTSD have been key for understanding the epigenetic alterations in the brain most directly relevant to endophenotypes of PTSD, in particular those pertaining to fear memory and stress response. This chapter provides an overview of neuroepigenetic studies based on animal models of PTSD, with an emphasis on the effect of stress on fear memory. Where relevant, we also describe human-based studies with relevance to neuroepigenetic insights gleaned from animal work and suggest promising directions for future studies of PTSD neuroepigenetics in living humans that combine peripheral epigenetic measures with measures of central nervous system activity, structure and function.
Stressful life incidents often cause a predisposition for developing mental disorders such as major depressive disorder (MDD). Impaired neurocognitive and neuro-vegetative functions of the central nervous system are the hallmarks of this mental illness. Blunted responses from emotionally salient regions of the brain including cortex, hippocampus, and amygdala have been associated with MDD-related behavioral changes. Moreover, improper signal processing and neuronal atrophy were held responsible for the overall dysfunctionality of these vulnerable regions in the MDD brain. The prevalence of genetic susceptibility along with adverse environmental stimuli often makes the situation worse for MDD patients, leading to an increased risk of suicidal behavior and eventually death by suicide. Despite considerable efforts to understand the complex neurobiology associated with MDD and suicidal behavior, their pathological determinants remain mostly elusive. Recent research, however, has shown that epigenetic perturbations have a formidable impact on the etiopathogenesis of MDD. Understanding the neuroepigenetic nature of this mental disorder may provide opportunities to devise more effective treatment strategies. Moreover, this can potentially lead to identifying predictive biomarkers associated with suicide risk. The present chapter critically reviews studies pertaining to epigenetic signatures of MDD and suicide brain.
The use of structured interviews that yield continuous measures of symptom severity has become increasingly widespread in the assessment of posttraumatic stress disorder (PTSD). To date, however, few scoring rules have been developed for converting continuous severity scores into dichotomous PTSD diagnoses. In this article, we describe and evaluate 9 such rules for the Clinician-Administered PTSD Scale (CAPS). Overall, these rules demonstrated good to excellent reliability and good correspondence with a PTSD diagnosis based on the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (3rd ed., rev.; DSM-III—R ; American Psychiatric Association, 1987). However, the rules yielded widely varying prevalence estimates in 2 samples of male Vietnam veterans. Also, the use of DSM-III—R versus DSM-IV criteria had negligible impact on PTSD diagnostic status. The selection of CAPS scoring rules for different assessment tasks is discussed. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
This report presents 2014 U.S. final mortality data on deaths and death rates by demographic and medical characteristics. These data provide information on mortality patterns among U.S. residents by such variables as sex, race and ethnicity, and cause of death. Information on mortality patterns is key to understanding changes in the health and well-being of the U.S. population. Life expectancy estimates, age-adjusted death rates by race and ethnicity and sex, the 10 leading causes of death, and the 10 leading causes of infant death were analyzed by comparing 2014 final data with 2013 final data. All material appearing in this report is in the public domain and may be reproduced or copied without permission; citation as to source, however, is appreciated.
Genomic variation in the SKA2 gene has recently been identified as a promising suicide biomarker. In light of its role in glucocorticoid receptor transactivation, we investigated whether SKA2 DNA methylation influences cortisol stress reactivity and is involved in the development of post traumatic stress disorder (PTSD). Increased SKA2 methylation was significantly associated with lower cortisol stress reactivity in 85 healthy individuals exposed to the Trier Social Stress Test (B=-173.40, t=-2.324, p=0.023). Next, we observed that longitudinal decreases in SKA2 methylation after deployment were associated with the emergence of post-deployment PTSD symptoms in a Dutch military cohort (N=93) (B=-0.054, t=-3.706, p=3.66 × 10(-4)). In contrast, exposure to traumatic stress during deployment by itself resulted in longitudinal increases in SKA2 methylation (B=0.037, t=4.173, p=6.98 × 10(-5)). Using pre-deployment SKA2 methylation levels and childhood trauma exposure, we found that the previously published suicide prediction rule significantly predicted post-deployment PTSD symptoms (AUC=0.66, 95%CI: 0.53-0.79) with an optimal sensitivity of 0.81 and specificity of 0.91. Permutation analysis using random methylation loci supported these findings. Together, these data establish the importance of SKA2 for cortisol stress responsivity and the development of PTSD and provide further evidence that SKA2 is a promising biomarker for stress-related disorders including PTSD.Neuropsychopharmacology accepted article preview online, 11 September 2015. doi:10.1038/npp.2015.286.
Traumatic stress results in hypothalamic pituitary adrenal (HPA) axis abnormalities and an increased risk to both suicidal behaviors and post-traumatic stress disorder (PTSD). Previous work out of our laboratory identified SKA2 DNA methylation associations with suicidal behavior in the blood and brain of multiple cohorts. Interaction of SKA2 with stress predicted suicidal behavior with ~80% accuracy. SKA2 is hypothesized to reduce the ability to suppress cortisol following stress, which is of potentially high relevance in traumatized populations. Our objective was to investigate the interaction of SKA2 and trauma exposure on HPA axis function, suicide attempt and PTSD. SKA2 DNA methylation at Illumina HM450 probe cg13989295 was assessed for association with suicidal behavior and PTSD metrics in the context of Child Trauma Questionnaire (CTQ) scores in 421 blood and 61 saliva samples from the Grady Trauma Project (GTP) cohort. Dexamethasone suppression test (DST) data were evaluated for a subset of 209 GTP subjects. SKA2 methylation interacted with CTQ scores to predict lifetime suicide attempt in saliva and blood with areas under the receiver operator characteristic curve (AUCs) of 0.76 and 0.73 (95% confidence interval (CI): 0.6-0.92, P=0.003, and CI: 0.65-0.78, P<0.0001) and to mediate the suppression of cortisol following DST (β=0.5±0.19, F=1.51, degrees of freedom (df)=12/167, P=0.0096). Cumulatively, the data suggest that epigenetic variation at SKA2 mediates vulnerability to suicidal behaviors and PTSD through dysregulation of the HPA axis in response to stress.
Blood biomarkers may provide a scientifically useful and clinically usable peripheral signal in psychiatry, as they have been doing for other fields of medicine. Jumping to premature conclusions, negative or positive, can create confusion in this field. Reproducibility is a hallmark of good science. We discuss some recent examples from this dynamic field, and show some new data in support of previously published biomarkers for suicidality (SAT1, MARCKS and SKA2). Methodological clarity and rigor in terms of biomarker discovery, validation and testing is needed. We propose a set of principles for what constitutes a good biomarker, similar in spirit to the Koch postulates used at the birth of the field of infectious diseases.Molecular Psychiatry advance online publication, 13 January 2015; doi:10.1038/mp.2014.180.
We conducted a retrospective cohort mortality study to determine the postservice suicide risk of recent wartime veterans comparing them with the US general population as well as comparing deployed veterans to nondeployed veterans.
Veterans were identified from the Defense Manpower Data Center records, and deployment to Iraq or Afghanistan war zone was determined from the Contingency Tracking System. Vital status of 317,581 deployed and 964,493 nondeployed veterans was followed from the time of discharge to December 31, 2009. Underlying causes of death were obtained from the National Death Index Plus.
Based on 9353 deaths (deployed, 1650; nondeployed, 7703), of which 1868 were suicide deaths (351; 1517), both veteran cohorts had 24% to 25% lower mortality risk from all causes combined but had 41% to 61% higher risk of suicide relative to the US general population. However, the suicide risk was not associated with a history of deployment to the war zone. After controlling for age, sex, race, marital status, branch of service, and rank, deployed veterans showed a lower risk of suicide compared with nondeployed veterans (hazard ratio, 0.84; 95% confidence interval, 0.75-0.95). Multiple deployments were not associated with the excess suicide risk among deployed veterans (hazard ratio, 1.00; 95% confidence interval, 0.79-1.28).
Veterans exhibit significantly higher suicide risk compared with the US general population. However, deployment to the Iraq or Afghanistan war, by itself, was not associated with the excess suicide risk.
Published by Elsevier Inc.
Key findings:
Data from the National Vital Statistics System, Mortality. Life expectancy at birth for the U.S. population reached a record high of 78.8 years in 2012. The age-adjusted death rate for the United States decreased 1.1% from 2011 to 2012 to a record low of 732.8 per 100,000 standard population. The 10 leading causes of death in 2012 remained the same as in 2011. Age-adjusted death rates decreased significantly from 2011 to 2012 for 8 of the 10 leading causes and increased significantly for one leading cause (suicide). The infant mortality rate decreased 1.5% from 2011 to 2012 to a historic low of 597.8 infant deaths per 100,000 live births. The 10 leading causes of infant death in 2012 remained the same as in 2011. This report presents 2012 U.S. final mortality data on deaths and death rates by demographic and medical characteristics. These data provide information on mortality patterns among residents of the United States by such variables as sex, race and ethnicity, and cause of death. Information on mortality patterns is key to understanding changes in the health and well-being of the U.S. population (1). Life expectancy estimates, age-adjusted death rates by race and ethnicity and sex, 10 leading causes of death, and 10 leading causes of infant death were analyzed by comparing 2012 final data with 2011 final data.
Background
Recent evidence has emerged suggesting that multiple mood and anxiety disorders may be better assessed using a single dimension representing internalizing liability. The current study seeks to demonstrate the validity and utility of internalizing liability when accounting for suicidality, treatment seeking, and disability over and above any disorder specific relationship.
Methods
Data were from the 2007 Australian National Survey of Mental Health and Wellbeing. A model containing a single factor was fit to the data as a means of explaining the shared relationship across seven DSM-IV mood and anxiety disorders. The shared and specific relationships between lifetime and past 12 months internalizing and mental health consultations, suicidality, and disability were examined using Multiple Indicators, Multiple Causes models.
Results
General levels of latent internalizing were significantly related to all covariates of interest across both lifetime and past 12 months diagnoses. Models that included the specific relationship between various internalizing disorders and the clinical correlates failed to significantly improve model fit over and above a model that already included the general relationship between latent internalizing and the covariates.
Limitations
Limitations include the use of cross-sectional data and diagnostic assessments based on self-report lay-administered interviews.
Conclusions
The overall internalizing latent variable sufficiently explains the majority of the relationship between multiple mood and anxiety disorders and suicidality, treatment seeking, and disability. Researchers should focus on investigating the shared or common components across all mood and anxiety disorders particularly with respect to individuals presenting with higher rates of suicidality, treatment seeking behavior, and disability.
Objective: Reliable identification of individuals at high risk for suicide is a priority for suicide prevention. This study was conducted to identify genes exhibiting epigenetic variation associated with suicide and suicidal behaviors. Method: Genome-wide DNA methylation profiling was employed separately on neuronal and glial nuclei in a discovery set of postmortem brains from the National Institute of Child Health and Human Development to identify associations with suicide. Pyrosequencing-based validation was conducted in prefrontal cortical tissue in cohorts from the Stanley Medical Research Institute and Harvard Brain Bank at McLean Hospital and peripheral blood from three living groups. Functional associations with gene expression, stress and anxiety, and salivary cortisol were assessed. Results: The DNA methylation scan identified an additive epigenetic and genetic association with suicide at rs7208505 within the 3' untranslated region of the SKA2 gene independently in the three brain cohorts. This finding was replicated with suicidal ideation in blood from three live cohorts. SKA2 gene expression was significantly lower in suicide decedents and Was associated with genetic and epigenetic variation of rs7208505, possibly mediated by interaction with an intronic microRNA, miR-301a. Analysis of salivary cortisol measurements suggested that SKA2 epigenetic and genetic variation may modulate cortisol suppression, consistent with its implicated role in glucocorticoid receptor transactivation. SKA2 significantly interacted with anxiety and stress to explain about 80% of suicidal behavior and progression from suicidal ideation to suicide attempt. Conclusions: These findings implicate SKA2 as a novel genetic and epigenetic target involved in the etiology of suicide and suicidal behaviors.
By characterizing the geographic and functional spectrum of human genetic variation, the 1000 Genomes Project aims to build a resource to help to understand the genetic contribution to disease. Here we describe the genomes of 1,092 individuals from 14 populations, constructed using a combination of low-coverage whole-genome and exome sequencing. By developing methods to integrate information across several algorithms and diverse data sources, we provide a validated haplotype map of 38 million single nucleotide polymorphisms, 1.4 million short insertions and deletions, and more than 14,000 larger deletions. We show that individuals from different populations carry different profiles of rare and common variants, and that low-frequency variants show substantial geographic differentiation, which is further increased by the action of purifying selection. We show that evolutionary conservation and coding consequence are key determinants of the strength of purifying selection, that rare-variant load varies substantially across biological pathways, and that each individual contains hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites. This resource, which captures up to 98% of accessible single nucleotide polymorphisms at a frequency of 1% in related populations, enables analysis of common and low-frequency variants in individuals from diverse, including admixed, populations.
The use of structured interviews that yield continuous measures of symptom severity has become increasingly widespread in the assessment of posttraumatic stress disorder (PTSD). To date, however, few scoring rules have been developed for converting continuous severity scores into dichotomous PTSD diagnoses. In this article, we describe and evaluate 9 such rules for the Clinician-Administered PTSD Scale (CAPS). Overall, these rules demonstrated good to excellent reliability and good correspondence with a PTSD diagnosis based on the Structured Clinical Interview for
Diagnostic and Statistical Manual of Mental Disorders (3rd ed., rev.;
DSM-III—R; American Psychiatric Association, 1987). However, the rules yielded widely varying prevalence estimates in 2 samples of male Vietnam veterans. Also, the use of
DSM-III—R versus
DSM-IV criteria had negligible impact on PTSD diagnostic status. The selection of CAPS scoring rules for different assessment tasks is discussed. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Multivariate comorbidity research indicates mood and anxiety (internalizing) disorders share one or more common liabilities, but categorical, dimensional, and hybrid accounts of these liabilities have not been directly compared. We modeled seven internalizing disorders in a nationally representative sample of 43,093 individuals via confirmatory factor, latent class, exploratory factor mixture, and exploratory structural equation modeling analyses. A two-dimensional (distress-fear) liability structure fit best and replicated across gender, assessment waves, and lifetime/12-month diagnoses. These liabilities, not disorder-specific variation, predicted future internalizing pathology, suicide attempts, angina, and ulcer. (PsycINFO Database Record (c) 2012 APA, all rights reserved).
This study replicated and extended prior findings of internalizing and externalizing subtypes of posttraumatic response (M. W. Miller, J. L. Greif, & A. A. Smith, 2003). Cluster analyses of the Minnesota Multiphasic Personality Inventory--2 Personality Psychopathology--Five (MMPI-2 PSY-5; A. R. Harkness, J. L. McNulty, Y. S. Ben-Porath, 1995) profiles obtained from 736 veterans with posttraumatic stress disorder (PTSD) partitioned the sample into a low pathology cluster defined by personality scores in the normal range, an externalizing cluster characterized by low constraint and high negative emotionality, and an internalizing cluster with high negative emotionality and low positive emotionality. Externalizers showed the highest rates of alcohol-related and antisocial personality disorders; internalizers, the highest rates of panic and major depressive disorder. These findings support the development of a personality-based typology of posttraumatic response designed to account for heterogeneity in the expression of PTSD and associated psychopathology.
Prior research using the Brief Form of the Multidimensional Personality Questionnaire (MPQ-BF; Patrick, Curtin, & Tellegen, 2002) has shown evidence of 3 temperament-based subtypes--termed internalizing, externalizing, and simple PTSD--among individuals with symptoms of posttraumatic stress disorder (PTSD; Miller, Greif, & Smith, 2003). This study sought to replicate and extend research in this area by conducting a latent profile analysis of higher order temperament scales from the MPQ-BF using a new sample of 208 veterans with symptoms of PTSD. Results suggest that a 3-class solution reflecting internalizing, externalizing, and simple subtypes of posttraumatic psychopathology provided the best fit to the data. The externalizing subtype was characterized by features of antisocial, borderline, histrionic, and narcissistic personality disorders on the International Personality Disorder Examination (Loranger, 1999) as well as low levels of constraint and high levels of negative emotionality on the MPQ-BF. In contrast, individuals in the internalizing class exhibited features of schizoid and avoidant personality disorders, low levels of positive emotionality, and high levels of negative emotionality. The simple subtype was defined by low levels of comorbid personality disorder features and relatively normal personality profiles. Findings support the reliability of this typology and support the relevance of the internalizing and externalizing model to the structure of personality disorders.
All organisms must maintain a complex dynamic equilibrium, or homeostasis, which is constantly challenged by internal or external adverse forces termed stressors. Stress occurs when homeostasis is threatened or perceived to be so; homeostasis is re-established by various physiological and behavioral adaptive responses. Neuroendocrine hormones have major roles in the regulation of both basal homeostasis and responses to threats, and are involved in the pathogenesis of diseases characterized by dyshomeostasis or cacostasis. The stress response is mediated by the stress system, partly located in the central nervous system and partly in peripheral organs. The central, greatly interconnected effectors of this system include the hypothalamic hormones arginine vasopressin, corticotropin-releasing hormone and pro-opiomelanocortin-derived peptides, and the locus ceruleus and autonomic norepinephrine centers in the brainstem. Targets of these effectors include the executive and/or cognitive, reward and fear systems, the wake-sleep centers of the brain, the growth, reproductive and thyroid hormone axes, and the gastrointestinal, cardiorespiratory, metabolic, and immune systems. Optimal basal activity and responsiveness of the stress system is essential for a sense of well-being, successful performance of tasks, and appropriate social interactions. By contrast, excessive or inadequate basal activity and responsiveness of this system might impair development, growth and body composition, and lead to a host of behavioral and somatic pathological conditions.
Stressful life events are associated with the onset of episodes of major depression. However, exposure to stressful life events is influenced by genetic factors, and these factors are correlated with those that predispose to major depression. The aim of this study was to clarify the degree to which stressful life events cause major depression.
The authors assessed the occurrence of 15 classes of stressful life events and the onset of DSM-III-R major depression over a 1-year period in female twins ascertained from a population-based registry. The sample contained 24,648 person-months and 316 onsets of major depression. Stressful life events were individually rated on contextual threat and dependence (the degree to which the stressful life event could have resulted from the respondent's behavior). The nature of the relationship between stressful life events and major depression was tested by 1) discrete-time survival analysis examining the relationship between dependence and the depressogenic effect of stressful life events and 2) a co-twin control analysis.
While independent stressful life events were significantly associated with onsets of depression, when level of threat was controlled, the association was significantly stronger for dependent events. The odds ratio for onset of major depression in the month of a stressful life event was 5.64 in all subjects, 4.52 within dizygotic pairs, and 3.58 within monozygotic pairs.
Stressful life events have a substantial causal relationship with the onset of episodes of major depression. However, about one-third of the association between stressful life events and onsets of depression is noncausal, since individuals predisposed to major depression select themselves into high-risk environments.
Suicide is most often associated with internalizing disorders such as depression; however, recent evidence suggests that externalizing psychopathology (substance dependence disorders, antisocial personality disorder) may have an independent relationship with suicidal behavior. The aim in the present study was to examine the relationship between lifetime suicide attempts and lifetime externalizing psychopathology in the US National Comorbidity Survey data set (n = 5877). First, hierarchical regression was performed to explore the associations between internalizing and externalizing disorders and suicide attempts. Externalizing psychopathology was significantly associated with lifetime suicide attempts (adjusted odds ratio = 3.47; P < .001) and significantly improved the model beyond that including only the sociodemographic variables and internalizing psychopathology (chi(2) difference = 73.12; df = 1; P < .001). A second logistic regression was used to investigate the association between specific patterns of psychopathology and suicidality. Externalizing disorders were significantly associated with suicide attempts even in the absence of internalizing disorders (adjusted odds ratio = 5.98; 95% confidence interval = 3.07-11.67; P < .001). These findings add to the growing literature that suggests that externalizing psychopathology is an important psychiatric correlate of suicidal behavior.
Glucocorticoid (GC) receptors (GRs) have profound anti-survival effects on human small cell lung cancer (SCLC). To explore the basis of these effects, protein partners for GRs were sought using a yeast two-hybrid screen. We discovered a novel gene, FAM33A, subsequently identified as a SKA1 partner and involved in mitosis, and so renamed Ska2. We produced an anti-peptide antibody that specifically recognized full-length human SKA2 to measure expression in human cell lines and tissues. There was a wide variation in expression across multiple cell lines, but none was detected in the liver cell line HepG2. A xenograft model of human SCLC had intense staining and archival tissue revealed SKA2 in several human lung and breast tumours. SKA2 was found in the cytoplasm, where it co-localized with GR, but nuclear expression of SKA2 was seen in breast tumours. SKA2 overexpression increased GC transactivation in HepG2 cells while SKA2 knockdown in A549 human lung epithelial cells decreased transactivation and prevented dexamethasone inhibition of proliferation. GC treatment decreased SKA2 protein levels in A549 cells, as did Staurosporine, phorbol ester and trichostatin A; all agents that inhibit cell proliferation. Overexpression of SKA2 potentiated the proliferative response to IGF-I exposure, and knockdown with shRNA caused cells to arrest in mitosis. SKA2 has recently been identified in HeLa S3 cells as part of a complex, which is critical for spindle checkpoint silencing and exit from mitosis. Our new data show involvement in cell proliferation and GC signalling, with implications for understanding how GCs impact on cell fate.
This report presents final 2018 U.S. mortality data on deaths and death rates by demographic and medical characteristics. These data provide information on mortality patterns among U.S. residents by variables such as sex, age, race and Hispanic origin, and cause of death. Life expectancy estimates, 10 leading causes of death, age-specific death rates, and 10 leading causes of infant death were analyzed by comparing 2018 and 2017 final data.
Methylation of the SKA2 (spindle and kinetochore-associated complex subunit 2) gene has recently been identified as a promising biomarker of suicide risk. Based on this finding, we examined associations between SKA2 methylation, cortical thickness and psychiatric phenotypes linked to suicide in trauma-exposed veterans. About 200 trauma-exposed white non-Hispanic veterans of the recent conflicts in Iraq and Afghanistan (91% male) underwent clinical assessment and had blood drawn for genotyping and methylation analysis. Of all, 145 participants also had neuroimaging data available. Based on previous research, we examined DNA methylation at the cytosine–guanine locus cg13989295 as well as DNA methylation adjusted for genotype at the methylation-associated single nucleotide polymorphism (rs7208505) in relationship to whole-brain cortical thickness, posttraumatic stress disorder symptoms (PTSD) and depression symptoms. Whole-brain vertex-wise analyses identified three clusters in prefrontal cortex that were associated with genotype-adjusted SKA2 DNA methylation (methylation adj). Specifically, DNA methylation adj was associated with bilateral reductions of cortical thickness in frontal pole and superior frontal gyrus, and similar effects were found in the right orbitofrontal cortex and right inferior frontal gyrus. PTSD symptom severity was positively correlated with SKA2 DNA methylation adj and negatively correlated with cortical thickness in these regions. Mediation analyses showed a significant indirect effect of PTSD on cortical thickness via SKA2 methylation status. Results suggest that DNA methylation adj of SKA2 in blood indexes stress-related psychiatric phenotypes and neurobiology, pointing to its potential value as a biomarker of stress exposure and susceptibility.
Worldwide, one person dies every 40 seconds by suicide, a potentially preventable tragedy. A limiting step in our ability to intervene is the lack of objective, reliable predictors. We have previously provided proof of principle for the use of blood gene expression biomarkers to predict future hospitalizations due to suicidality, in male bipolar disorder participants. We now generalize the discovery, prioritization, validation, and testing of such markers across major psychiatric disorders (bipolar disorder, major depressive disorder, schizoaffective disorder, and schizophrenia) in male participants, to understand commonalities and differences. We used a powerful within-participant discovery approach to identify genes that change in expression between no suicidal ideation and high suicidal ideation states (n=37 participants out of a cohort of 217 psychiatric participants followed longitudinally). We then used a convergent functional genomics (CFG) approach with existing prior evidence in the field to prioritize the candidate biomarkers identified in the discovery step. Next, we validated the top biomarkers from the prioritization step for relevance to suicidal behavior, in a demographically matched cohort of suicide completers from the coroner's office (n=26). The biomarkers for suicidal ideation only are enriched for genes involved in neuronal connectivity and schizophrenia, the biomarkers also validated for suicidal behavior are enriched for genes involved in neuronal activity and mood. The 76 biomarkers that survived Bonferroni correction after validation for suicidal behavior map to biological pathways involved in immune and inflammatory response, mTOR signaling and growth factor regulation. mTOR signaling is necessary for the effects of the rapid-acting antidepressant agent ketamine, providing a novel biological rationale for its possible use in treating acute suicidality. Similarly, MAOB, a target of antidepressant inhibitors, was one of the increased biomarkers for suicidality. We also identified other potential therapeutic targets or biomarkers for drugs known to mitigate suicidality, such as omega-3 fatty acids, lithium and clozapine. Overall, 14% of the top candidate biomarkers also had evidence for involvement in psychological stress response, and 19% for involvement in programmed cell death/cellular suicide (apoptosis). It may be that in the face of adversity (stress), death mechanisms are turned on at a cellular (apoptosis) and organismal level. Finally, we tested the top increased and decreased biomarkers from the discovery for suicidal ideation (CADM1, CLIP4, DTNA, KIF2C), prioritization with CFG for prior evidence (SAT1, SKA2, SLC4A4), and validation for behavior in suicide completers (IL6, MBP, JUN, KLHDC3) steps in a completely independent test cohort of psychiatric participants for prediction of suicidal ideation (n=108), and in a future follow-up cohort of psychiatric participants (n=157) for prediction of psychiatric hospitalizations due to suicidality. The best individual biomarker across psychiatric diagnoses for predicting suicidal ideation was SLC4A4, with a receiver operating characteristic (ROC) area under the curve (AUC) of 72%. For bipolar disorder in particular, SLC4A4 predicted suicidal ideation with an AUC of 93%, and future hospitalizations with an AUC of 70%. SLC4A4 is involved in brain extracellular space pH regulation. Brain pH has been implicated in the pathophysiology of acute panic attacks. We also describe two new clinical information apps, one for affective state (simplified affective state scale, SASS) and one for suicide risk factors (Convergent Functional Information for Suicide, CFI-S), and how well they predict suicidal ideation across psychiatric diagnoses (AUC of 85% for SASS, AUC of 89% for CFI-S). We hypothesized a priori, based on our previous work, that the integration of the top biomarkers and the clinical information into a universal predictive measure (UP-Suicide) would show broad-spectrum predictive ability across psychiatric diagnoses. Indeed, the UP-Suicide was able to predict suicidal ideation across psychiatric diagnoses with an AUC of 92%. For bipolar disorder, it predicted suicidal ideation with an AUC of 98%, and future hospitalizations with an AUC of 94%. Of note, both types of tests we developed (blood biomarkers and clinical information apps) do not require asking the individual assessed if they have thoughts of suicide, as individuals who are truly suicidal often do not share that information with clinicians. We propose that the widespread use of such risk prediction tests as part of routine or targeted healthcare assessments will lead to early disease interception followed by preventive lifestyle modifications and proactive treatment.Molecular Psychiatry advance online publication, 18 August 2015; doi:10.1038/mp.2015.112.
This study followed on findings from a recent genome-wide association study of PTSD that implicated the retinoid-related orphan receptor alpha (RORA) gene (Logue et al., 2012) by examining its relationship to broader array of disorders.
Using data from the same cohort (N=540), we analyzed patterns of association between 606 single nucleotide polymorphisms (SNPs) spanning the RORA gene and comorbidity factors termed fear, distress (i.e., internalizing factors) and externalizing.
Results showed that rs17303244 was associated with the fear component of internalizing (i.e., defined by symptoms of panic, agoraphobia, specific phobia, and obsessive-compulsive disorder) at a level of significance that withstood correction for gene-wide multiple testing.
The primary limitations were the modest size of the cohort and the absence of a replication sample.
Results add to a growing literature implicating the RORA gene in a wide range of neuropsychiatric disorders and offer new insight into possible molecular mechanisms of the effects of traumatic stress on the brain and the role of genetic factors in those processes.
Suicide is difficult to predict and prevent and remains a leading cause of death worldwide. Although soldiers historically have had a suicide rate well below that of the general population, the suicide rate among members of the U.S. Army has increased markedly over the past several years and now exceeds that of the general population. This paper reviews psychosocial factors known to be associated with the increased risk of suicidal behavior in general and describes how some of these factors may be especially important in understanding suicide among soldiers. Moving forward, the prevention of suicide requires additional research aimed at: (a) better describing when, where, and among whom suicidal behavior occurs, (b) using exploratory studies to discover new risk and protective factors, (c) developing new methods of predicting suicidal behavior that synthesize information about modifiable risk and protective factors from multiple domains, and (d) understanding the mechanisms and pathways through which suicidal behavior develops. Although the scope and severity of this problem is daunting, the increasing attention and dedication to this issue by the Armed Forces, scientists, and society provide hope for our ability to better predict and prevent these tragic outcomes in the future.
We describe the results of the first genome-wide association study (GWAS) of post-traumatic stress disorder (PTSD) performed using trauma-exposed white non-Hispanic participants from a cohort of veterans and their intimate partners (295 cases and 196 controls). Several single-nucleotide polymorphisms (SNPs) yielded evidence of association. One SNP (rs8042149), located in the retinoid-related orphan receptor alpha gene (RORA), reached genome-wide significance. Nominally significant associations were observed for other RORA SNPs in two African-American replication samples-one from the veteran cohort (43 cases and 41 controls) and another independent cohort (100 cases and 421 controls). However, only the associated SNP from the veteran African-American replication sample survived gene-level multiple-testing correction. RORA has been implicated in prior GWAS studies of psychiatric disorders and is known to have an important role in neuroprotection and other behaviorally relevant processes. This study represents an important step toward identifying the genetic underpinnings of PTSD.Molecular Psychiatry advance online publication, 7 August 2012; doi:10.1038/mp.2012.113.
Research examining cortisol dysregulation is seemingly contradictory with studies showing that both internalizing and externalizing behaviors are related to high and low cortisol. One extant theory to explain divergent findings in the stress literature is that both hypo- and hyper-arousal of the hypothalamic-pituitary-adrenal (HPA) axis may be present depending on time since onset of the stressor. This theory may extend to the onset of internalizing and externalizing behaviors. Data from 96 youth participating in a longitudinal project were used to examine this possibility. Composite measures of internalizing and externalizing behaviors at both childhood and early adolescence were formed using mother and teacher reports. Multiple salivary cortisol samples were also collected over two consecutive days during early adolescence. Problematic behaviors were associated with cortisol and the direction of the association was dependent on amount of time passed since onset of the behaviors. When examined concurrently in adolescence, youth with more internalizing behaviors had higher morning cortisol; however, when examined longitudinally, youth with more internalizing behaviors in childhood had lower morning cortisol levels as adolescents. Youth with more externalizing behaviors in childhood had flattened diurnal cortisol rhythms as adolescents, and this finding persisted when examined in adolescence. Cortisol dysregulation was greatest in children with the most severe behavior problems. Findings support the theoretical model of blunting of the HPA axis over time. While the HPA axis may show hyper-arousal when youth first display behaviors, long-term exposure may lead to a hypo-arousal of the HPA axis which culminates in a dysregulated diurnal rhythm.
Anxiety confers increased risk for inflammatory diseases, and elevated inflammatory activity in anxious individuals may contribute to this increased risk. One complication, however, is that anxiety could be associated with inflammatory activity either through a specific anxiety pathway or through a more general negative emotionality pathway. To investigate, we measured levels of the stress hormone cortisol, the pro-inflammatory cytokine interleukin-6 (IL-6), and the systemic inflammatory marker C-reactive protein (CRP), as well as depression and neuroticism, in clinically anxious and non-anxious adults. Compared with non-anxious participants, clinically anxious participants exhibited significantly lower levels of morning cortisol and significantly higher levels of IL-6, independent of age, sex, and depressive symptoms. These group differences were robust when controlling for neuroticism. Conversely, the groups had equivalent levels of CRP in all analyses. Results are indicative of anxiety-specific effects on inflammatory activity, and highlight a pathway by which anxiety may increase risk for inflammatory diseases.
Childhood adversity (CA) is associated with adult mental disorders, but the mechanisms underlying this association remain inadequately understood. Stress sensitization, whereby CA increases vulnerability to mental disorders following adult stressful life events, has been proposed as a potential mechanism. We provide a test of the stress sensitization hypothesis in a national sample.
We investigated whether the association between past-year stressful life events and the 12-month prevalence of major depression, post-traumatic stress disorder (PTSD), other anxiety disorders, and perceived stress varies according to exposure to CA. We used data from the National Epidemiological Survey of Alcohol and Related Conditions (NESARC) (n=34 653).
Past-year stressful life events were associated with an increased risk of major depression, PTSD, anxiety disorders, and perceived stress. However, the magnitude of the increased risk varied according to respondents' history of CA. For example, past-year major stressors were associated with a 27.3% increase in the 12-month risk of depression among individuals with 3 CAs and a 14.8% increased risk among individuals without CAs. Stress sensitization effects were present for depression, PTSD, and other anxiety disorders in women and men, although gender differences were found in the threshold of past-year stress needed to trigger such effects. Stress sensitization was most evident among individuals with 3 CAs.
CA is associated with increased vulnerability to the deleterious mental health effects of adult stressors in both men and women. High levels of CA may represent a general diathesis for multiple types of psychopathology that persists throughout the life course.
The latent structure and stability of 10 common mental disorders were examined in a birth cohort at ages 18 and 21. A 2-factor model, in which some disorders were presumed to reflect internalizing problems and others were presumed to reflect externalizing problems, provided a more optimal fit to the data than either a 1- or a 4-factor model. To a significant extent, persons in the sample retained their relative positions on the latent factors across the 3-year period from age 18 to age 21. Results offer potential clarification of the meaning of comorbidity in psychopathology research by suggesting that comorbidity may results from common mental disorders being reliable, covariant indicators of stable, underlying "core psychopathological processes."
This report presents the results of confirmatory factor analyses of patterns of comorbidity among 10 common mental disorders in the National Comorbidity Survey, a national probability sample of US civilians who completed structured diagnostic interviews.
Patterns of comorbidity among DSM-III-R mental disorders were analyzed via confirmatory factor analyses for the entire National Comorbidity Survey sample (N = 8098; age range, 15-54 years), for random halves of the sample, for men and women separately, and for a subsample of participants who were seeing a professional about their mental health problems. Four models were compared: a 1-factor model, a 2-factor model in which some disorders represented internalizing problems and others represented externalizing problems, a 3-factor variant of the 2-factor model in which internalizing was modeled as having 2 subfactors (anxious-misery and fear), and a 4-factor model in which the disorders represented separate affective, anxiety, substance dependence, and antisocial factors.
The 3-factor model provided the best fit in the entire sample. This result was replicated across random halves of the sample as well as across women and men. The substantial empirical intercorrelation between anxious-misery and fear (0.73) suggested that these factors were most appropriately conceived as subfactors of a higher-order internalizing factor. In the treatment sample, the 2-factor model fit best.
The results offer a novel perspective on comorbidity, suggesting that comorbidity results from common, underlying core psychopathological processes. The results thereby argue for focusing research on these core processes themselves, rather than on their varied manifestations as separate disorders.
This study used the Multidimensional Personality Questionnaire (MPQ; A. Tellegen, in press) to identify personality-based subtypes of posttraumatic response. Cluster analyses of MPQs completed by combat veterans revealed subgroups that differed on measures relating to the externalization versus internalization of distress. The MPQ profile of the externalizing cluster was defined by low Constraint and Harmavoidance coupled with high Alienation and Aggression. Individuals in this cluster also had histories of delinquency and high rates of substance-related disorder. In comparison, the MPQ profile of the internalizing cluster was characterized by lower Positive Emotionality, Alienation, and Aggression and higher Constraint, and individuals in this cluster showed high rates of depressive disorder. These findings suggest that dispositions toward externalizing versus internalizing psychopathology may account for heterogeneity in the expression of posttraumatic responses, including patterns of comorbidity.
Borrowing from recent dimensional models of psychopathology, the authors conducted analyses that optimized the common variance shared by internalizing (depression, anxiety) and externalizing (antisocial personality, substance dependence) disorders in statistically predicting suicidal behaviors. These relationships were analyzed in a large epidemiological sample, thus allowing for the examination of gender differences in risk for suicide attempts associated with psychopathology.
The data were obtained from the Colorado Social Health Survey. Participants (N=4,745) were a community sample recruited by household address. Structured clinical interviews were used to obtain lifetime diagnostic and symptom count information. Symptom counts were included in a factor analysis that yielded two main dimensions of psychopathology: internalizing and externalizing. These factors were used in hierarchical logistic regression analyses to predict history of suicide attempts associated with the presence of internalizing symptoms, externalizing symptoms, and comorbid internalizing and externalizing symptoms.
After the investigators controlled for the presence of internalizing symptoms and the comorbidity of internalizing and externalizing symptoms, externalizing symptoms were related to suicidal behavior in both men and women, although comorbidity was most predictive of suicide attempts among women, compared to men.
Suicidal behavior among individuals with externalizing symptoms is not necessarily a result of comorbid depressive or other internalizing disorder. Thus, persons exhibiting antisocial behaviors should receive rigorous assessment for suicidal ideation and behavior.
Disease and injury regional mortality estimates for Available at: http://www.who. int/healthinfo/global_burden_disease
WHO (World Health Organization). Disease and injury regional
mortality estimates for 2004–2008. Available at: http://www.who.
int/healthinfo/global_burden_disease/estimates_regional_2004_
2008/en.
Multidimensional personality questionnaire profiles of veterans with traumatic combat exposure: externalizing and internalizing subtypes
- Mw Miller
- Jl Grief
- Aa Smith
Miller MW, Grief JL, Smith AA. Multidimensional personality questionnaire profiles of veterans with traumatic combat exposure: externalizing and internalizing subtypes. Psychol Assess
2003;15(2):205–215.
IPDE: international personality disorder examination: DSM-IV and ICD-10 interviews. PARS Psychological Assessment Resources
- A W Loranger
Loranger AW. IPDE: international personality disorder examination: DSM-IV and ICD-10 interviews. PARS Psychological
Assessment Resources; 1999.
An integrated map of genetic variation from 1,092 human genomes
- Gr Abecasis
- A Auton
- Ld Brooks
Abecasis GR, Auton A, Brooks LD, et al. An integrated map of genetic variation from 1,092 human genomes. Nature 2012;491:56–
65.