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Genetically regulated multi-omics study for symptom clusters of posttraumatic stress disorder highlights pleiotropy with hematologic and cardio-metabolic traits.

ABSTRACT: Posttraumatic stress disorder (PTSD) is a psychiatric disorder that may arise in response to severe traumatic event and is diagnosed based on three main symptom clusters (reexperiencing, avoidance, and hyperarousal) per the Diagnostic Manual of Mental Disorders (version DSM-IV-TR). In this study, we characterized the biological heterogeneity of PTSD symptom clusters by performing a multi-omics investigation integrating genetically regulated gene, splicing, and protein expression in dorsolateral prefrontal cortex tissue within a sample of US veterans enrolled in the Million Veteran Program (N _total = 186,689). We identified 30 genes in 19 regions across the three PTSD symptom clusters. We found nine genes to have cell-type specific expression, and over-representation of miRNA-families - miR-148, 30, and 8. Gene-drug target prioritization approach highlighted cyclooxygenase and acetylcholine compounds. Next, we tested molecular-profile based phenome-wide impact of identified genes with respect to 1678 phenotypes derived from the Electronic Health Records of the Vanderbilt University biorepository (N = 70,439). Lastly, we tested for local genetic correlation across PTSD symptom clusters which highlighted metabolic (e.g., obesity, diabetes, vascular health) and laboratory traits (e.g., neutrophil, eosinophil, tau protein, creatinine kinase). Overall, this study finds comprehensive genomic evidence including clinical and regulatory profiles between PTSD, hematologic and cardiometabolic traits, that support comorbidities observed in epidemiologic studies of PTSD.

SUBMITTER: Pathak GA

PROVIDER: S-EPMC9210390 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Genetically regulated multi-omics study for symptom clusters of posttraumatic stress disorder highlights pleiotropy with hematologic and cardio-metabolic traits.

Pathak Gita A GA Singh Kritika K Wendt Frank R FR Fleming Tyne W TW Overstreet Cassie C Koller Dora D Tylee Daniel S DS De Angelis Flavio F Cabrera Mendoza Brenda B Levey Daniel F DF Koenen Karestan C KC Krystal John H JH Pietrzak Robert H RH O' Donell Christopher C Gaziano J Michael JM Falcone Guido G Stein Murray B MB Gelernter Joel J Pasaniuc Bogdan B Mancuso Nicholas N Davis Lea K LK Polimanti Renato R

Molecular psychiatry 20220303 3

Posttraumatic stress disorder (PTSD) is a psychiatric disorder that may arise in response to severe traumatic event and is diagnosed based on three main symptom clusters (reexperiencing, avoidance, and hyperarousal) per the Diagnostic Manual of Mental Disorders (version DSM-IV-TR). In this study, we characterized the biological heterogeneity of PTSD symptom clusters by performing a multi-omics investigation integrating genetically regulated gene, splicing, and protein expression in dorsolateral ...[more]

PMID: 35241783

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Project description:Integrating findings from genome-wide association studies with molecular datasets can develop insight into the underlying functional mechanisms responsible for trait-associated genetic variants. We have applied the principles of Mendelian randomization (MR) to investigate whether brain-derived gene expression (n = 1194) may be responsible for mediating the effect of genetic variants on eight cognitive and psychological outcomes (attention deficit hyperactivity disorder (ADHD), Alzheimer's disease, bipolar disorder, depression, intelligence, insomnia, neuroticism and schizophrenia). Transcriptome-wide analyses identified 83 genes associated with at least one outcome (PBonferroni < 6.72 × 10-6), with multiple-trait colocalization also implicating changes to brain-derived DNA methylation at nine of these loci. Comparing effects between outcomes identified evidence of enrichment which may reflect putative causal relationships, such as an inverse relationship between genetic liability towards schizophrenia risk and cognitive ability in later life. Repeating these analyses in whole blood (n = 31 684), we replicated 58.2% of brain-derived effects (based on P < 0.05). Finally, we undertook phenome-wide evaluations at associated loci to investigate pleiotropic effects with 700 complex traits. This highlighted pleiotropic loci such as FURIN (initially implicated in schizophrenia risk (P = 1.05 × 10-7)) which had evidence of an effect on 28 other outcomes, as well as genes which may have a more specific role in disease pathogenesis (e.g. SLC12A5 which only provided evidence of an effect on depression (P = 7.13 × 10-10)). Our results support the utility of whole blood as a valuable proxy for informing initial target identification but also suggest that gene discovery in a tissue-specific manner may be more informative. Finally, non-pleiotropic loci highlighted by our study may be of use for therapeutic translational endeavours.

Project description:[Correction Notice: An Erratum for this article was reported online in Psychological Assessment on Nov 19 2018 (see record 2018-60122-001). In the article, the affiliations of multiple authors were incorrectly listed in the author byline and author note. For Daniel J. Lee, Michelle J. Bovin, Denise M. Sloan, Terence M. Keane, and Brian P. Marx, the affiliations should have read "National Center for PTSD, Boston, Massachusetts; VA Boston Healthcare System, Boston, Massachusetts; and Department of Psychiatry, Boston University School of Medicine." For author Paula P. Schnurr, the affiliations should have read "National Center for PTSD, White River Junction, Vermont; Department of Psychiatry, Geisel School of Medicine at Dartmouth." All versions of this article have been corrected.] The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) 4-factor model of posttraumatic stress disorder (PTSD) has demonstrated adequate fit in several confirmatory factor analysis (CFA) studies. Although several alternative measurement models have demonstrated better fit, there is no consensus yet on the best model, and newly proposed models lack sufficient construct validation. Notably, these studies have relied exclusively on questionnaire data, and thus their findings may be attributable to a method effect. This study examined the factor structure of DSM-5 PTSD symptoms using both questionnaire and interview data to determine the impact of assessment method on factor structure and construct validity of alternative model symptom clusters. Participants (N = 380) were veterans who completed the PTSD Checklist for DSM-5 (PCL-5; Weathers et al., 2013) and the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5; Weathers et al., 2013). Fit was similar across models. However, the seven-factor Hybrid model (Armour et al., 2015) fit best. Limited evidence of a method effect was observed. Results of construct validity analyses were mixed; some of the newly proposed symptom clusters demonstrated hypothesized differential associations with external correlates, but others did not. These findings suggest that results of previous DSM-5 PTSD CFAs supporting the Hybrid model are not attributable to a method effect. However, observed limited difference in model fit and mixed construct validity evidence raise concerns regarding the value of parsing DSM-5 symptom clusters. Constructs implied by the new factors in the more complex measurement models of PTSD require greater explication and construct validation. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Project description:BackgroundPsychological distress due to the ongoing war, violence, and persecution is particularly common among Afghan asylum seekers and refugees. In addition, individuals face a variety of post-migration living difficulties (PMLDs). Complex posttraumatic stress symptoms are among the most common mental health problems in this population, and were associated with the overall burden of PMLDs. The complex interplay of posttraumatic symptoms has been investigated from a network perspective in previous studies. However, individuals are embedded in and constantly react to the environment, which makes it important to include external factors in network models to better understand the etiology and maintaining factors of posttraumatic mental health problems. PMLDs are a major risk factor for posttraumatic distress and considering their impact in interventions might improve response rates. However, the interaction of these external factors with posttraumatic psychopathological distress is not yet fully understood. Thus, we aimed to illuminate the complex interaction between PMLDs and CPTSD symptom clusters.ObjectiveThe main objective is the exploration of the network structure and the complex interplay of ICD-11 CPTSD symptom clusters and distinct forms of PMLDs.MethodThe symptom clusters of CPTSD and PMLDs were collected within a randomised controlled trial among 93 treatment-seeking Afghan asylum seekers and refugees via a fully structured face-to-face and interpreter assisted interview. Using a network analytical approach, we explored the complex associations and network centrality of the CPTSD symptom clusters and the PMLD factors: discrimination & socio-economical living conditions, language acquisition & barriers, family concerns, and residence insecurity.ResultsThe results suggest direct links within and between the constructs (CPTSD, PMLD). Almost all PMLD factors were interrelated and associated to CPTSD, family concerns was the only isolated variable. The CPTSD symptom cluster re-experiencing and the PMLD factor language acquisition & barriers connected the two constructs. Affective dysregulation had the highest and avoidance the lowest centrality.ConclusionsRe-experiencing and affective dysregulation have the strongest ties to PMLDs. Thus, these domains might explain the strong association of posttraumatic psychopathology with PLMDs and, consequently, prioritization of these domains in treatment approaches might both facilitate treatment response and reduce burden caused by PMLDs.

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Genetically regulated multi-omics study for symptom clusters of posttraumatic stress disorder highlights pleiotropy with hematologic and cardio-metabolic traits.

Publications

Genetically regulated multi-omics study for symptom clusters of posttraumatic stress disorder highlights pleiotropy with hematologic and cardio-metabolic traits.

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