Genomewide Analyses of Psychological Resilience in US Army Soldiers

Stein, Murray B.; Choi, Karmel W.; Jain, Sonia; Campbell‐Sills, Laura; Chen, Chia‐Yen; Gelernter, Joel; He, Feng; Heeringa, Steven G.; Maihofer, Adam X.; Nievergelt, Caroline M.; Nock, Matthew K.; Ripke, Stephan; Sun, Xiaoying; Kessler, Ronald C.; Smoller, Jordan W.; Ursano, Robert J.

doi:10.1101/516716

Cited by 8 publications

(13 citation statements)

References 60 publications

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“…This is because, in particular, recent genome-wide studies have reported several loci to significantly contribute to coping and resilience phenotypes. 34,35 Along these lines, future studies will have to disentangle the individual and interactive genetic effects on risk and resilience, respectively, given that resilience towards stress-related mental disorders has been reported to show a heritability of up to 40% 36 and to display distinct biological underpinnings which do not simply constitute a reversal of mechanisms leading to disease risk. 37,38 In addition, given increasing evidence for a role of temporally dynamic epigenetic processes in the modulation of gene function partly mediating adaptation to environmental influences in the context of anxiety disorders and anxiety-related phenotypes, 39 future G × E × C models would benefit from the inclusion of epigenetic markers such as DNA methylation towards the formulation of a comprehensive multidimensional model of anxiety risk.…”

Section: Discussionmentioning

confidence: 99%

Extending the vulnerability–stress model of mental disorders: three-dimensional NPSR1 × environment × coping interaction study in anxiety

et al. 2020

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Background The general understanding of the ‘vulnerability–stress model’ of mental disorders neglects the modifying impact of resilience-increasing factors such as coping ability. Aims Probing a conceptual framework integrating both adverse events and coping factors in an extended ‘vulnerability–stress–coping model’ of mental disorders, the effects of functional neuropeptide S receptor gene (NPSR1) variation (G), early adversity (E) and coping factors (C) on anxiety were addressed in a three-dimensional G × E × C model. Method In two independent samples of healthy probands (discovery: n = 1403; replication: n = 630), the interaction of NPSR1 rs324981, childhood trauma (Childhood Trauma Questionnaire, CTQ) and general self-efficacy as a measure of coping ability (General Self-Efficacy Scale, GSE) on trait anxiety (State-Trait Anxiety Inventory) was investigated via hierarchical multiple regression analyses. Results In both samples, trait anxiety differed as a function of NPSR1 genotype, CTQ and GSE score (discovery: β = 0.129, P = 3.938 × 10−8; replication: β = 0.102, P = 0.020). In A allele carriers, the relationship between childhood trauma and anxiety was moderated by general self-efficacy: higher self-efficacy and childhood trauma resulted in low anxiety scores, and lower self-efficacy and childhood trauma in higher anxiety levels. In turn, TT homozygotes displayed increased anxiety as a function of childhood adversity unaffected by general self-efficacy. Conclusions Functional NPSR1 variation and childhood trauma are suggested as prime moderators in the vulnerability–stress model of anxiety, further modified by the protective effect of self-efficacy. This G × E × C approach – introducing coping as an additional dimension further shaping a G × E risk constellation, thus suggesting a three-dimensional ‘vulnerability–stress–coping model’ of mental disorders – might inform targeted preventive or therapeutic interventions strengthening coping ability to promote resilient functioning.

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Section: Discussionmentioning

confidence: 99%

Extending the vulnerability–stress model of mental disorders: three-dimensional NPSR1 × environment × coping interaction study in anxiety

et al. 2020

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“…Although the biological functions of its product, hexosaminidase D, remain largely unknown, it is believed to be a glycosidase and previous studies found associations with rheumatoid arthritis [37,38]. Interestingly, recent studies found significant pleiotropy between rheumatoid arthritis and PTSD [39], and rheumatoid arthritis and schizophrenia [40]. Other studies found associations between PTSD symptoms and rheumatoid arthritis in a twin population [41] and in an epidemiological study of military veterans [42].…”

Section: Discussionmentioning

confidence: 99%

Longitudinal epigenome-wide association studies of three male military cohorts reveal multiple CpG sites associated with post-traumatic stress disorder

et al. 2020

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Background: Epigenetic mechanisms have been suggested to play a role in the development of post-traumatic stress disorder (PTSD). Here, blood-derived DNA methylation data (HumanMethylation450 BeadChip) collected prior to and following combat exposure in three cohorts of male military members were analyzed to assess whether DNA methylation profiles are associated with the development of PTSD. A total of 123 PTSD cases and 143 traumaexposed controls were included in the analyses. The Psychiatric Genomics Consortium (PGC) PTSD EWAS QC pipeline was used on all cohorts, and results were combined using a sample size weighted meta-analysis in a twostage design. In stage one, we jointly analyzed data of two new cohorts (N = 126 and 78) for gene discovery, and sought to replicate significant findings in a third, previously published cohort (N = 62) to assess the robustness of our results. In stage 2, we aimed at maximizing power for gene discovery by combining all three cohorts in a metaanalysis. Results: Stage 1 analyses identified four CpG sites in which, conditional on pre-deployment DNA methylation, postdeployment DNA methylation was significantly associated with PTSD status after epigenome-wide adjustment for multiple comparisons. The most significant (intergenic) CpG cg05656210 (p = 1.0 × 10 −08) was located on 5q31 and significantly replicated in the third cohort. In addition, 19 differentially methylated regions (DMRs) were identified, but failed replication. Stage 2 analyses identified three epigenome-wide significant CpGs, the intergenic CpG cg05656210 and two additional CpGs located in MAD1L1 (cg12169700) and HEXDC (cg20756026). Interestingly, cg12169700 had an underlying single nucleotide polymorphism (SNP) which was located within the same LD block as a recently identified PTSD-associated SNP in MAD1L1. Stage 2 analyses further identified 12 significant differential methylated regions (DMRs), 1 of which was located in MAD1L1 and 4 were situated in the human leukocyte antigen (HLA) region.

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“…Aggressive behaviour in humans is defined as a multi-factorial and complex functional behavioural act [3], which can lead to a plethora of problems, such as gangsterism, criminal activities, and the development of mental health disorders (e.g., psychotic disorders, conduct disorders, and PTSD) [4,5]. PTSD carries a significant heritability of PTSD risk [6] and a high polygenicity [7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

“…Research in physiological genomics has also revolutionised the understanding of the pathophysiology of complex diseases, including psychiatric diseases [14,15]. Several studies have investigated the effect of molecular genetic variants in search of causative genetic variants of mental health disorders, such as aggressive behaviours, anxiety disorders, post-traumatic stress disorder (PTSD), and depression [9,15,21,22]. The current review will summarise previously studied genes in different types of aggression and PTSD.…”

Section: Introductionmentioning

confidence: 99%

Physiological Genomics Plays a Crucial Role in Response to Stressful Life Events, the Development of Aggressive Behaviours, and Post-Traumatic Stress Disorder (PTSD)

Magwai

Xulu

2022

Genes

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Physiological genomics plays a crucial role in responding to stressful life events, such as violence and traumatic stress. This exposure to traumatic stress can trigger several physiological pathways, which are associated with genetic variability. Exposure to traumatic stress can result in the development of behavioural and psychiatric disorders, such as aggressive behaviour and anxiety disorders. Several genes play a crucial role in the neurophysiological response to chronic stress and trauma. These essential genes include monoamine oxidase A (MAOA), solute carrier family 6 member 4 (SLC6A4), brain-derived neurotrophic factor (BDNF), catechol-O-methyltransferase (COMT), dopamine receptor 2 and 4 (DRD2 and DRD4), and FK506 binding protein 5 (FKBP5). Genetic variations in several genes have been found to have altered physiological response, which associates with the development of several behavioural traits. Interestingly, previous studies show that there is an interplay between aggressive behaviour and anxiety disorders, which may be associated with physiological genomics structure. The physiological responses are based on genetic architecture and its molecular reaction. Understanding physiological genomics may show underpinnings related to the development of aggressive behaviours and their interaction with anxiety disorders. This review aims to discuss the association between different physiological genes and the development of psychiatric disorders related to aggressive behaviours and anxiety disorders, such as post-traumatic stress disorder.

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Genomewide Analyses of Psychological Resilience in US Army Soldiers

Cited by 8 publications

References 60 publications

Extending the vulnerability–stress model of mental disorders: three-dimensional NPSR1 × environment × coping interaction study in anxiety

Extending the vulnerability–stress model of mental disorders: three-dimensional NPSR1 × environment × coping interaction study in anxiety

Longitudinal epigenome-wide association studies of three male military cohorts reveal multiple CpG sites associated with post-traumatic stress disorder

Physiological Genomics Plays a Crucial Role in Response to Stressful Life Events, the Development of Aggressive Behaviours, and Post-Traumatic Stress Disorder (PTSD)

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