Twin studies of posttraumatic stress disorder: Differentiating vulnerability factors from sequelae

Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA.
Neuropharmacology (Impact Factor: 5.11). 03/2011; 62(2):647-53. DOI: 10.1016/j.neuropharm.2011.03.012
Source: PubMed


Posttraumatic stress disorder (PTSD) is defined by one's response to an environmental event. However, genetic factors are important in determining people's response to that event, and even their likelihood of being exposed to particular traumatic events in the first place. Classical twin designs can decompose genetic and environmental sources of variance. Such studies are reviewed extensively elsewhere, and we cover them only briefly in this review. Instead, we focus primarily on the identical co-twin control design. This design makes it possible to resolve the "chicken-egg" dilemma inherent in standard case-control designs, namely, distinguishing risk from sequelae. Abnormalities that are present in both the twin with PTSD and the unaffected co-twin suggest pre-existing vulnerability indicators. These include smaller hippocampal volume, large cavum septum pellucidum, more neurological soft signs, lower general intellectual ability, and poorer performance in the specific cognitive abilities of executive function, attention, declarative memory, and processing of contextual cues. In contrast, abnormalities in a twin with PTSD that are not present in the identical co-twin suggest consequences of PTSD or trauma exposure. These include psychophysiological responding, higher resting anterior cingulate metabolism, event-related potential abnormalities associated with attentional processes, recall intrusions, and possibly some types of chronic pain. Most co-twin control studies of PTSD have been small and come from the same twin registry of middle-aged male veterans. Consequently, there is a great need for replication and extension of the findings, particularly in women and younger individuals. The creation of new twin registries would do much toward accomplishing this goal. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

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    • "The additional variability in PTSD risk is expected to arise from genetic susceptibility. Indeed, between 30% and 70% of the variance for PTSD risk is estimated to be attributed to genetic factors by family and twin heritability studies (Kremen et al., 2012; Lyons et al., 1993; Sack et al., 1995; Sartor et al., 2011; Stein et al., 2002; True et al., 1993; Yehuda et al., 2001). To identify the specific genetic risk factors contributing to PTSD, many candidate gene association studies have been performed in human cohorts on genes in neurobiological pathways, including the hypothalamic-pituitary-adrenal (HPA) axis, the locus coeruleus-noradrenergic system, monoamine and neuroendocrine metabolism, and the limbic-frontal system (Cornelis et al., 2010; Kim et al., 2013; Logue et al., 2013b; Lu et al., 2008; Lyons et al., 2013; Norrholm and Ressler, 2009; Pitman et al., 2012; Uddin et al., 2011; Valente et al., 2011; Wang et al., 2011; Wolf et al., 2013; Yehuda et al., 2011). "
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    ABSTRACT: Posttraumatic stress disorder (PTSD) is a psychiatric disorder that can develop after experiencing traumatic events. A genome-wide association study (GWAS) design was used to identify genetic risk factors for PTSD within a multi-racial sample primarily composed of U.S. veterans. Participants were recruited at multiple medical centers, and structured interviews were used to establish diagnoses. Genotypes were generated using three Illumina platforms and imputed with global reference data to create a common set of SNPs. SNPs that increased risk for PTSD were identified with logistic regression, while controlling for gender, trauma severity, and population substructure. Analyses were run separately in non-Hispanic black (NHB; n=949) and non-Hispanic white (NHW; n=759) participants. Meta-analysis was used to combine results from the two subsets. SNPs within several interesting candidate genes were nominally significant. Within the NHB subset, the most significant genes were UNC13C and DSCAM. Within the NHW subset, the most significant genes were TBC1D2, SDC2 and PCDH7. In addition, PRKG1 and DDX60L were identified through meta-analysis. The top genes for the three analyses have been previously implicated in neurologic processes consistent with a role in PTSD. Pathway analysis of the top genes identified alternative splicing as the top GO term in all three analyses (FDR q<3.5×10(-5)). No individual SNPs met genome-wide significance in the analyses. This multi-racial PTSD GWAS identified biologically plausible candidate genes and suggests that post-transcriptional regulation may be important to the pathology of PTSD; however, replication of these findings is needed. Copyright © 2015 Elsevier B.V. All rights reserved.
    Full-text · Article · Mar 2015 · Journal of Affective Disorders
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    • "A difficulty with PTSD studies in humans is the poor ability to distinguish between pre-existing risk factors and trauma-induced outcomes. Co-twin studies, in which only one twin has experienced trauma, found that certain parameters that were thought to be caused by trauma may actually be pre-existing risk factors for PTSD, including impaired cognitive function and reduced hippocampal volume (Kremen et al., 2012). It can also be difficult to separate out epigenetic outcomes from epigenetic risk factors in non-controlled studies of human patients, although cumulative effects of trauma on DNA methylation of immune system genes suggest that traumatic experiences are key drivers of epigenetic outcomes in this scenario (Uddin et al., 2010). "
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    ABSTRACT: Post-traumatic stress disorder (PTSD) is a psychiatric condition characterized by intrusive and persistent memories of a psychologically traumatic event that leads to significant functional and social impairment in affected individuals. The molecular bases underlying persistent outcomes of a transient traumatic event have remained elusive for many years, but recent studies in rodents have implicated epigenetic modifications of chromatin structure and DNA methylation as fundamental mechanisms for the induction and stabilization of fear memory. In addition to mediating adaptations to traumatic events that ultimately cause PTSD, epigenetic mechanisms are also involved in establishing individual differences in PTSD risk and resilience by mediating long-lasting effects of genes and early environment on adult function and behavior. In this review, we discuss the current evidence for epigenetic regulation of PTSD in human studies and in animal models and comment on ways in which these models can be expanded. In addition, we identify key outstanding questions in the study of epigenetic mechanisms of PTSD in the context of rapidly evolving technologies that are constantly updating and adjusting our understanding of epigenetic modifications and their functional roles. Finally, we discuss the potential application of epigenetic approaches in identifying markers of risk and resilience that can be utilized to promote early intervention and develop therapeutic strategies to combat PTSD after symptom onset.
    Full-text · Article · Jun 2013 · Frontiers in Psychiatry
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    • "The biological factors associated with the risk for (and resilience to) PTSD are also poorly understood. Although susceptibility to PTSD appears to be moderately heritable, nongenetic factors (most prominently the type and extent of the precipitating trauma, and social support) and gene–environment interactions likely also contribute to each individual's overall susceptibility to the disorder [True et al., 1993; Stein et al., 2002; Kremen et al., 2012]. Given the less-than-absolute heritability of PTSD, pursuit of genetic markers alone (e.g., single nucleotide polymorphisms and copy-number variations) will leave much of the variance in vulnerability unexplained [Yehuda et al., 2011; Mehta and Binder, 2012]. "
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    ABSTRACT: Susceptibility to PTSD is determined by both genes and envi-ronment. Similarly, gene-expression levels in peripheral blood are influenced by both genes and environment, and expression levels of many genes show good correspondence between pe-ripheral blood and brain. Therefore, our objectives were to test the following hypotheses: (1) pre-trauma expression levels of a gene subset (particularly immune-system genes) in peripheral blood would differ between trauma-exposed Marines who later developed PTSD and those who did not; (2) a predictive bio-marker panel of the eventual emergence of PTSD among high-risk individuals could be developed based on gene expression in How to Cite this Article:
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