A classical twin study of PTSD symptoms and resilience: Evidence for a single spectrum of vulnerability to traumatic stress

Wolf, Erika J.; Miller, Mark W.; Sullivan, Danielle R.; Amstadter, Ananda B.; Mitchell, Karen S.; Goldberg, Jack; Magruder, Kathryn M.

doi:10.1002/da.22712

Cited by 73 publications

(61 citation statements)

References 41 publications

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“…4,5 Exposure to traumatic stress is, by definition, requisite for the development of PTSD, but individual susceptibility to PTSD (conditioned on trauma exposure) varies widely. Twin studies over the past two decades provide persuasive evidence for at least some genetic influence on PTSD risk, 6,7 and the last decade has witnessed the beginnings of a concerted effort to detect specific genetic susceptibility variants for PTSD. [8][9][10][11][12] The Psychiatric Genomics Consortium -PTSD Group (PGC-PTSD) recently published results from the largest GWAS on PTSD to date, involving a transethnic sample of over 20,000 individuals, approximately 25% of whom were cases.…”

Section: Introductionmentioning

confidence: 99%

Largest genome-wide association study for PTSD identifies genetic risk loci in European and African ancestries and implicates novel biological pathways

Nievergelt

Klengel

et al. 2018

Preprint

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Post-traumatic stress disorder (PTSD) is a common and debilitating disorder. The risk of PTSD following trauma is heritable, but robust common variants have yet to be identified by genome-wide association studies (GWAS). We have collected a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls. We first demonstrate significant genetic correlations across 60 PTSD cohorts to evaluate the comparability of these phenotypically heterogeneous studies. In this largest GWAS meta-analysis of PTSD to date we identify a total of 6 genome-wide significant loci, 4 in European and 2 in African-ancestry analyses. Follow-up analyses incorporated local ancestry and sex-specific effects, and functional studies. Along with other novel genes, a non-coding RNA (ncRNA) and a Parkinson's Disease gene, PARK2, were associated with PTSD. Consistent with previous reports, SNP-based heritability estimates for PTSD range between 10-20%. Despite a significant shared liability between PTSD and major depressive disorder, we show evidence that some of our loci may be specific to PTSD. These results demonstrate the role of genetic variation contributing to the biology of differential risk for PTSD and the necessity of expanding GWAS beyond European ancestry.Comparability of PGC2 studies PGC2 compiled the largest collection of global PTSD GWAS to date, with subjects recruited from both clinically deeply characterized, small patient groups and large cohorts with self-reported PTSD symptoms. We did not restrict the type of trauma subjects were exposed to, and trauma included both civilian and/or military events, often with pre-existing exposure to childhood trauma. To evaluate the comparability of these phenotypically heterogeneous studies we first estimated genetic correlations with LDSC, 15 a method that leverages GWAS summary results, the only data type available to PGC-PTSD for several of the larger military and non-US cohorts. We found significant genetic correlations (r g ) between studies using a cross-validation approach including all PGC2 EUA subjects (10 runs with studies randomly placed into 2 groups; mean r g = 0.56, mean SE = 0.23, mean p = 0.029, Supplementary Table 8).Next, additional analyses on the UK Biobank cohort (UKBB) were performed. This cohort comprises a very large proportion of the data, with almost as many EUA cases as the rest of the EUA PGC2 combined (referred to as PGC1.5). PTSD screening in UKBB was based on self-reported symptoms from a mental health survey. 16 We found a considerable genetic correlation between the UKBB and PGC1.5 EUA subjects (r g = 0.73, SE = 0.21, p = 0.0005; Supplementary Table 9). Further, sensitivity analyses in the UKBB using 3 alternative inclusion criteria for PTSD cases and controls showed stable correlations with PGC1.5 (P1 -P3; r g = 0.72 -0.79; Supplementary Table 10). Subsequent analyses were based on the UKBB phenotype including the largest number of subjects (P1; N = 126,188). Sex-stratified genetic correlations support the findings of a significant genetic signal...

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Section: Introductionmentioning

confidence: 99%

Largest genome-wide association study for PTSD identifies genetic risk loci in European and African ancestries and implicates novel biological pathways

Nievergelt

Klengel

et al. 2018

Preprint

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“…Though a growing body of preclinical and translational research is illuminating biological mechanisms of stress resilience (McEwen et al, ), relatively little is known about the genetic basis of psychological resilience in humans (Feder, Horn, Haglund, Southwick, & Charney, ). Twin studies have suggested that self‐ (or parent‐) assessed resilience—defined as a perceived capacity to cope adaptively with stressors—is moderately heritable (~30–50%) (Amstadter, Myers, & Kendler, ; Waaktaar & Torgersen, ; Wolf et al, ). Studies in twin samples and unrelated individuals have also suggested that other traits reflecting positive psychological adjustment, such as subjective well‐being and positive affect are partially heritable (Haworth et al, ; Rietveld et al, ; Wingo et al, ).…”

Section: Introductionmentioning

confidence: 99%

Genome‐wide analyses of psychological resilience in U.S. Army soldiers

Stein

Choi

Jain

et al. 2019

American J of Med Genetics Pt B

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Though a growing body of preclinical and translational research is illuminating a biological basis for resilience to stress, little is known about the genetic basis of psychological resilience in humans. We conducted genome-wide association studies (GWASs) of self-assessed (by questionnaire) and outcome-based (incident mental disorders from predeployment to postdeployment) resilience among European (EUR) ancestry soldiers in the Army study to assess risk and resilience in servicemembers. Self-assessed resilience (N = 11,492) was found to have significant common-variant heritability (h 2 = 0.162, se = 0.050, p = 5.37 × 10 −4 ), and to be significantly negatively genetically correlated with neuroticism (r g = −0.388, p = .0092). GWAS results from the EUR soldiers revealed a genome-wide significant locus on an intergenic region on Chr 4 upstream from doublecortin-like kinase 2 (DCLK2) (four single nucleotide polymorphisms (SNPs) in LD; top SNP: rs4260523 [p = 5.65 × 10 −9 ] is an eQTL in frontal cortex), a member of the doublecortin family of kinases that promote survival and regeneration of injured neurons. A second gene, kelch-like family member 36 (KLHL36) was detected at gene-wise genomewide significance [p = 1.89 × 10 −6 ]. A polygenic risk score derived from the self-assessed resilience GWAS was not significantly associated with outcome-based resilience. In very

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“…Although most Americans (50-85%) experience traumatic events over a lifetime, most do not develop PTSD -lifetime PTSD prevalence is approximately 7% (Kessler and Wang, 2008), suggesting differential resilience to stress and vulnerability to the disorder (Atwoli et al, 2015). There is a substantial heritable basis for PTSD risk (Stein et al, 2002;Wolf et al, 2018), and evidence from genome-wide association studies (GWAS) shows that PTSD, like other mental disorders , is highly polygenic (Benjet et al, 2016;Daskalakis et al, 2018;Duncan et al, 2018;Nievergelt et al, 2018;Xie et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Genomic Characterization of Posttraumatic Stress Disorder in a Large US Military Veteran Sample

Stein

Levey

Cheng

et al. 2019

Preprint

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Individuals vary in their liability to develop Posttraumatic Stress Disorder (PTSD), the symptoms of which are highly heterogeneous, following exposure to life-threatening trauma. Understanding genetic factors that contribute to the biology of PTSD is critical for refining diagnosis and developing new treatments. Using genetic data from more than 250,000 participants in the Million Veteran Program, genomewide association analyses were conducted using a validated electronic health record-based algorithmically-defined PTSD diagnosis phenotype (48,221 cases and 217,223 controls), and PTSD quantitative symptom phenotypes (212,007 individuals). We identified several genome-wide significant loci in the case-control analyses, and numerous such loci in the quantitative trait analyses, including some (e.g., MAD1L1; TCF4; CRHR1) that were associated with multiple symptom sub-domains and total symptom score, and others that were more specific to certain symptom sub-domains (e.g., CAMKV to reexperiencing; SOX6 to hyperarousal). Genetic correlations between all pairs of symptom sub-domains and their total were very high (rg 0.93 -0.98) supporting validity of the PTSD diagnostic construct. We also demonstrate strong shared heritability with a range of traits, show that heritability persists when conditioned on other major psychiatric disorders, present independent replication results, provide support for one of the implicated genes in postmortem brain of individuals with PTSD, and use this information to identify potential drug repositioning candidates. These results point to the utility of genetics to inform and validate the biological coherence of the PTSD syndrome despite considerable heterogeneity at the symptom level, and to provide new directions for treatment development.

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A classical twin study of PTSD symptoms and resilience: Evidence for a single spectrum of vulnerability to traumatic stress

Cited by 73 publications

References 41 publications

Largest genome-wide association study for PTSD identifies genetic risk loci in European and African ancestries and implicates novel biological pathways

Largest genome-wide association study for PTSD identifies genetic risk loci in European and African ancestries and implicates novel biological pathways

Genome‐wide analyses of psychological resilience in U.S. Army soldiers

Genomic Characterization of Posttraumatic Stress Disorder in a Large US Military Veteran Sample

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