Key points

Introduction

Posttraumatic stress disorder (PTSD) is a common psychiatric diagnosis that occurs in the aftermath of life events that precipitate symptoms spanning intrusive thoughts, hyperarousal, avoidance, and negative alterations in cognition and mood. For full PTSD diagnosis, these symptoms must persist for at least 30 days and produce significant distress and impairment across domains of daily life. The index trauma that spurs PTSD symptom expression is often a harrowing or stressful life event that between 65% and 90% of individuals will experience in their lifetime. However, following trauma, only a smaller subset (5%–30%) of traumatized individuals will experience a subsequent PTSD diagnosis with some groups being at higher risk for trauma exposure (eg, first responders, law enforcement, military service members and Veterans, living in the presence of significant social determinants of risk). This degree of susceptibility has long begged the question as to why some individuals develop long-term, clinically relevant symptoms while others do not.

Through decades of translational neuroscience research, the pathophysiology of PTSD has been linked to altered fear processing, dysregulation of prefrontal cortical inhibition of limbic amygdala output, immune dysfunction, and alterations in the neuroendocrine functions of the hypothalamic-pituitary-adrenal (HPA) axis. From a genomic perspective, most of the work related to PTSD has traditionally been limited to smaller scale twin and candidate gene studies and has revealed likely gene x environment interactions that underlie PTSD symptomatology. However, more recent advances are being made due to the development and refinement of methodologies in the age of genome-wide association studies (GWASs). ^,

Origins of genomic studies of posttraumatic stress disorder

Early work in the area of PTSD genetic risks occurred through the study of twin pairs, often one of whom was affected by trauma and PTSD while a co-twin was not ^, ; studies such as these revealed approximately 30% to 40% heritability estimates for PTSD. The reader is directed to earlier review literature for a detailed discussion of PTSD twin studies.

Gene-by-environment interactions and posttraumatic stress disorder

A primary focus of studies (at least prior to the last decade) aimed at the genomic underpinnings of PTSD have centered on interactions between a traumatized individual’s genetics and their environment (ie, gene-by-environment [GxE]). From an experiential and environmental standpoint, factors that have been shown to moderate PTSD risk include biological sex, parameters of a traumatic event (timing, chronicity, severity, interpersonal nature, degree of violence), race and ethnicity, previous psychiatric diagnoses, occupation or academic status, and personality type. ^, From a genomics standpoint, much of the literature in this area has been derived from smaller scale, candidate gene studies ^{, ,} ; these studies are characterized by significant limitations including insufficient statistical power, reduced sample sizes, and lacking reproducibility, replication, and validation. Interested readers are directed to a recent comprehensive review by Marchese and Huckins (2023) which provides a concise overview of candidate GxE studies that contributed to the literature over the past 2 decades.

Single nucleotide polymorphism (SNP) candidate gene studies such as those summarized by Marchese and Huckins have identified SNPs within neurotransmitter systems (namely, dopamine and serotonin ) as well as within the hypothalamic-pituitary-adrenal (HPA) axis. Two prominent SNPs received heavy examination in the candidate gene literature: FKBP5 and 5HTTLPR gene polymorphisms. A series of studies of 4 variants of the FKBP5 gene (eg, rs9296158, rs3800373, rs1360780, rs9470080) revealed a GxE interaction between childhood trauma and PTSD risk. Variants of SLC6A4 , the gene that encodes the serotonin transporter ( 5HTTLPR) , were shown to interact with trauma exposure spanning childhood and adulthood as well as index events including hurricane natural disasters and genocide. At the time of this writing, larger scale, independent follow-up studies to these early GxE investigations are still lacking, most notably, because of the increased use and availability of “big-data,” genome-wide methodologies. In addition, these early candidate gene studies were largely driven by hypotheses regarding known contributors to PTSD symptomatology and, as such, were limited in scope.

Genome-wide association studies of posttraumatic stress disorder

The first genome wide study of PTSD was conducted by Logue and colleagues (2013) who showed that a single SNP (rs8042149) in the retinoid-related orphan receptor alpha ( RORA ) gene reached genome-wide significance. The gene product protein of RORA regulates processes related to neuroprotection, inflammation, oxidative stress, and steroid hormone alterations. At about the same time, Xie and colleagues (2013) reported that an SNP (rs6812849) in the first intron of the Tolloid-Like 1 gene ( TLL-1 ) was significantly associated with PTSD in their GWAS. Rodent studies have found the Tolloid proteins for which this gene codes to be localized to cerebellum and hippocampus with potential roles in stress hormone and neurotrophic factor release.

A gene-based association test of GWAS data was conducted in 2016 in the Grady Trauma Project, arguably the largest civilian urban trauma study worldwide. This new, complementary approach to traditional GWAS identified a significant association between NLGN1 and PTSD after correcting for multiple tests ; the latter finding being replicated in one collaborative cohort (Cape Town, South Africa). NLGN1 codes for a protein, neuroligin 1, that is implicated in synapse formation, learning, and memory and has been linked to autism symptomatology. Additionally, the Grady group found that an SNP of NLGN1 (rs6779753) was significantly associated with previously identified PTSD biomarkers including elevated acoustic startle and increased activation in the amygdala, orbitofrontal cortex, thalamus, and fusiform gyrus upon fearful face provocation. These data, like many of the early PTSD GWAS studies, identified a potentially novel pathway for PTSD pathogenesis and maintenance.

The early GWAS studies of PTSD that were produced in the 2010s were plagued by common limitations. These shortcomings included accounting for the presence of comorbidities, insufficient sample sizes in primary and replication populations, and inconsistent results. For example, the Xie (2013) group was not able to replicate the first GWAS finding with RORA reported by the Logue (2013) study team. As demonstrated throughout this article, this is a recurring and stubborn problem for genetic researchers within the PTSD realm.

Recently, a relatively large study ( N = 297) by Wuchty and colleagues (2020) used a multi-omics approach to identify 13 potential driver genes for PTSD and 11 driver causal genes for major depressive disorder. The latter team also identified 22 driver causal genes related to PTSD and/or MDD, with the 2 often comorbid disorders sharing 4 driver genes: ESR1 , RUNX1 , PPARA , and WWOX . The identification of the ESR1 pathway in this study is of particular interest due to the wealth of literature supporting sex differences with respect to traumatization and PTSD but also because of widely reported estrogen effects on fear processes such as fear extinction ^, RUNX1 pathways have been linked to cellular function and development as well as long-term fear memory consolidation through interactions with the Wnt/Beta-catenin and Notch pathways. Preclinical and animal modeling data suggest that PPARA pathways may be critical for neuronal plasticity, cognitive function, and neuroprotection. An important feature of the Wuchty and colleagues (2020) study is that several of the causal driver gene pathways they revealed have been previously identified in prior translational work focused on PTSD and depression neurobiology as well as amygdala function and fear processing; a welcome sign of concordance to those in the field.

Historically, a significant inflection point in the study of PTSD genomics was fostered by large-scale endeavors such as the Psychiatric Genomic Consortium for PTSD (PGC-PTSD) ^, and the US Department of Veterans Affairs’ Million Veterans Project (MVP) which helped to reveal the complex polygenic nature of PTSD risk versus resilience. Importantly, the PGC-PTSD and MVP identified shortcomings to contemporary genome-wide approaches, namely : the need for sample sizes in the hundreds of thousands of cases, the dearth of sex-linked analyses, the common presence of psychiatric and general medical comorbidities with PTSD, and the low translatability of findings from largely European ancestry datasets with groups of differing, non-European ancestries. Of note, a 2019 meta-analysis by Nievergelt and colleagues spanning over 30,000 PTSD cases and more than 170,000 controls revealed a heritability estimate of between 5% and 20% for PTSD, with variability by biological sex, and identified new genes implicated at the genome-wide level, namely PARK2 , PODXL , SH3RF3 , ZDHHC14 , KAZN , and HLA-B .

The results of the Nievergelt meta-analysis strongly imply that there are shared genetic underpinnings between PTSD and other mental disorders. For example, PARK2 is a gene linked to Parkinson’s disease pathology and plays a role in dopamine regulation. PODXL codes for a protein involved in neurite outgrowth and synapse formation. SH3RF3 has been linked to neurocognitive disorder and Alzheimer’s dementia. ^, Preclinical and human studies showed ZDHHC14 to be associated with beta-2 adrenergic receptor activity. ^, HLA-B is implicated in the relationship between immune dysfunction and stressor-related disorders. ^, In fact, an important feature of the Nievergelt and colleagues (2019) study is the authors’ revelation that there appear to be key genetic origins in the reported associations between PTSD and immune disorders.

An exciting recent meta-analysis by Nievergelt and colleagues (2024) aimed to address many of the limitations previously described as part of the largest GWAS study of PTSD (>1,000,000 people) to date. For example, the Nievergelt team identified 95 genome-wide risk loci with the confirmation of 14 previously identified while uncovering 80 new PTSD loci. Forty-three of the 95 loci were classified as “likely causal” spanning genes coding for neurotransmitter and ion channel regulators (eg, GRIA1 , GRM8 , CACNA1E ), neurodevelopment, axon guidance, and transcription factors (eg, FOXP2 , EFNA5 , DCC ), synaptic structure and function (eg, PCLO , NCAM1 , PDE4B ), and endocrine or immune regulators (eg, ESR1 , TRAF3 , TANK ). Within less “causal” loci, the authors identified 3 that have been linked to stress responding, and fear-related and threat-related processing (eg, CRHR1 , WNT3 , FOXP2 ). One important takeaway from the Nievergelt study is the power the team had to detect both shared and PTSD-specific genetic signaling which creates the possibility of therapeutic interventions based on genetic counseling in the not-so-distant future.

Genome-wide by environment interactions and posttraumatic stress disorder

At the time of this writing, PTSD studies utilizing genome-wide by environment interaction (GWEIS) analyses remain in their infancy. This is due, in part, to shared limitations with GWAS investigations themselves, namely, the appropriate accounting of factors such as operational and functional definitions for variables across studies, confounding factors both known and unknown, sample size, and power. ^, Yet, GWEIS analyses obviate the reliance on a priori hypotheses that are consistent with reduced sample candidate gene examinations. To date, GWEIS studies within the domain of mental health and disease have been limited to major depression, alcohol use, and trauma/suicidality. With regard to trauma, PTSD, and suicidality, Wendt and colleagues (2021) investigated the association between suicidality and 26 “environments” linked to traumatic experiences (eg, witnessed sudden violent death), trauma response (eg, trouble concentrating), posttraumatic stress (eg, PTSD Check List 6 scores), socioeconomic status, and social support (eg, avoids activities due to stress). Through the use of a linear mixed-model analysis (see Moore and colleagues, 2019 for in-depth methodological description ), Wendt and colleagues revealed 5 suicidality risk variants (ie, G), largely driven by PTSD (ie, E), that survived genome-wide indices of significance. Interestingly, the identified variants showed specificity to only male (rs2367967, rs6854286, rs72619337) or female (rs118118557) biological sex status with one variant appearing in both sexes (rs12589041). These early findings are encouraging and a likely avenue of increased exploration given the prominence of genomic by environmental interactions in experiential-based disorders such as PTSD.

Epigenetics, epigenomics, and posttraumatic stress disorder

A discussion of the genomic contributions to the risk, maintenance, and treatment of PTSD symptoms requires the inclusion of mechanisms in which RNA and DNA are modified by environmental changes to alter gene transcription while sparing genetic sequences themselves; these mechanisms are collectively referred to as epigenetics for gene target-specific studies and epigenomics when considering these RNA and DNA modifications at the level of the whole genome. Generally speaking, epigenetic effects are initiated by external factors, or insults, including : those experienced during development, toxins, drugs, and chemicals present in the environment, and bodily contributions such as dietary conditions. With regard to PTSD, epigenetic mechanisms can mediate the relationship between environmental factors (eg, early childhood trauma), gene expression, and behavioral changes (eg, maladaptive or symptomatic). Of great interest to clinicians and scientists focused on PTSD is the transgenerational transmission of trauma through epigenetic processes.

A primary mechanism by which short-term and long-term epigenetic changes occur is through DNA methylation, or the addition of methyl groups via the enzyme DNA methyltransferase most often to cytosine residues to convert them to 5-methylcytosine ; this methylation frequently occurs at “islands” characterized by a DNA sequence progressing from cytosine 5-prime to guanine with the residues connected by a phosphate group (CpG sites). In general, DNA methylation “turns off” a gene as transcription is either attenuated or blocked and, as such, serves as a dynamic mechanism for transcriptional changes in response to environmental exposures. While many studies have investigated DNA methylation in candidate gene systems, epigenome-wide methylation work has, as yet, not revealed robustly significant and reliable differences between individuals with and without PTSD.

Nevertheless, epigenome-wide association studies, or EWAS, through hypothesis-independent examinations of methylation patterns across the genome, have identified fruitful areas to pursue in relation to PTSD. For example, Rutten and colleagues (2018) reported 17 loci and 12 genomic regions with longitudinal methylation changes evident postdeployment in a sample of Dutch members of the military. The data obtained in the Dutch cohort were compared with a replication cohort of US Marines and the gene region HIST1H2APS2 showed decreased methylation and elevated PTSD symptoms in both groups. Additionally, 3 global genome-wide methylation studies in distinct PTSD populations identified alterations at a single, common CpG island within the DOCK2 gene. One of those 3 studies, by Logue and colleagues (2020), identified a site (cg19534438) within the G0S2 gene that was significantly associated with PTSD at the genome-wide level. A second EWAS study within that group of 3, conducted by Snijders and colleagues (2020), combined data from one Dutch (PRISMO) and 2 American military cohorts (Army STARRS; Marine Resiliency Study) to identify 3 differentially methylated positions and 12 differentially methylated regions potentially related to PTSD. Lastly, an EWAS study by Mehta and colleagues (2019) identified 4 CpG sites within the FKBP5 gene that were associated with PTSD and present in sperm; this finding speaks to the potential to study transgenerational transmission as briefly discussed in the preceding text.

The study of histone acetylation, noncoding RNAs, and microRNAs (miRNAs) has revealed additional epigenetic mechanisms related to the neurobiology of mental illness, including PTSD. The modification of histones, as it relates to epigenetic effects and PTSD, is largely understudied with most of the available research occurring in animal models of fear extinction ^, and a small number of human peripheral studies. Additionally, histone modification can have differential effects on transcription. For example, transcription is fostered by histone acetylation as this “opens up” chromatin formations. Mono-methylation, di-methylation, or tri-methylation of histones may facilitate or hinder transcription depending on specific histones and residues.

miRNAs are transcribed from DNA, regulate up to 60% of all protein coding genes, and most frequently bind to the 3′ untranslated region of target mRNA in a manner that silences gene expression. While implicated in a number of disease processes spanning general medical conditions from cancers to mental health disorders such as major depressive disorder, the role of miRNAs in PTSD-related symptomatology is still largely in its infancy. Similar to other epigenetic analyses of PTSD, the most compelling results are restricted to animal models.

A very recent, highly collaborative study by Daskalakis and coauthors (2024), represents one of the first endeavors to apply a systems biology approach to the underpinnings of PTSD and major depression. More specifically, this team synthesized data derived from banked postmortem brain tissue (namely central nucleus of the amygdala, medial prefrontal cortex, and dentate gyrus of the hippocampus), plasma, and available GWAS to examine PTSD and depression from the transcriptomic, methylomic, and proteomic levels. As described by the authors, most disease signals were carried by differentially expressed genes and exons with methylation alterations observed in the dentate gyrus of PTSD patients and the central amygdala of depressed individuals; these results were bolstered by replication analyses from 2 additional cohorts. In both PTSD and depression, significant contributors to molecular variation included childhood trauma and suicidality. Disease-associated pathway signatures were identified within immune function, metabolism, mitochondrial activity, stress hormone activity, and neuronal or synaptic regulation. Single nucleus RNA sequencing (snRNA-seq) analysis of dorsal prefrontal cortical tissue showed transcriptomic alterations in neuronal and nonneuronal cells, an area highlighted by the authors to be new territory for omic investigations. The combination of multiomics and gene network analyses revealed key transcription factors and regulators to be interleukin-1 beta (IL1B), glucocorticoid receptor (GR), signal tranducer and activator of transcription 3 (STAT3), and tumor necrosis factor (TNF). One of the most striking findings from the Daskalakis and colleagues (2024) study was that fine mapping of PTSD and depression GWAS studies uncovered little overlap between risk and disease processes per gene and pathway level analyses. The importance of the Daskalakis work cannot be understated as it represents the attainment, albeit limited and early, of the type of integrated multiregion, multiomic investigation that psychiatric genomics has strived to achieve for at least 2 decades.

Where do we stand?

The accumulated body of evidence generated in the literature, spanning twin studies through genome-wide epigenetic studies, provides strong support for heritability and genetic underpinnings of PTSD; in fact, the available data position PTSD on similar footing with other mental disorders (eg, major depression) regarding genomic contributions to pathophysiology. ^,

Due to the nature of PTSD as a psychiatric consequence of significantly traumatic life events, etiologic analyses of this disorder must also consider the genomic factors that underlie trauma exposure itself. Similar to the parent disorder PTSD, an inclusive model for trauma risk contains environmental and genomic factors that likely interact across many levels. On the experiential and environmental side, risk for trauma exposure has been associated with biological sex, race and ethnicity, previous psychiatric diagnoses, occupation or academic status, and personality type.

It is clear from the emerging GWAS that PTSD shares polygenicity with other psychiatric disorders (eg, major depressive disorder, attention deficit-hyperactivity disorder ); however, the degree of risk variation is largely unexplored; this limitation is primarily due to the infancy of this type of large-scale analysis. It can be reasonably expected that technological advances coupled with the standardization of genome-wide protocols will afford an increased ability to separate disorder-specific genomic contributions.

Epigenetic/genomic advances will very likely provide greater insight into the underlying genomics of PTSD as the field will be better able to probe genome-wide epigenetic processes including, but not limited to, DNA hydroxymethylation, ^, cytosine methylation, and histone modification. As these epigenetic pathways are further elucidated, novel biomarkers and putative targets for pharmacologic interventions may also be revealed.

To summate, emerging studies utilizing genome-wide analysis methodologies are bringing the field closer to the generation of polygenic risk scores for the development of PTSD in the aftermath of psychological trauma yet significant obstacles remain including, but not limited to, statistical power, the heterogeneous nature of PTSD symptom presentation, and the operational definition of healthy controls. On a positive note, the body of literature derived to date, spanning genotypic-based, epigenetic-based, transcriptomic-based, endocrine-based, and serum-based signals consistently identify neurobiological mechanisms within stress response (eg, HPA axis), inflammatory, and learning and memory systems. As such, there is translational hope for increased understanding of PTSD etiology, symptom expression, and treatment using these systems as “North Stars.” Finally, in addition to the longstanding corpus of candidate genes linked to PTSD, a small number of recent SNP studies have revealed new directions to explore, namely in the areas of neuroinflammation and endogenous cannabinoid systems. For example, an SNP (rs1800872) in the gene coding for anti-inflammatory cytokine interleukin-10 was linked to higher PTSD scores up to a year after exposure to an earthquake in China.

Clinics care points

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  Advanced genomic technologies and analytical models are bringing us closer to the development of polygenic risk scores for psychiatric illness.

  
  
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  Translational neuroscience has demonstrated that the most promise for identifying genomic “signals“ lies within stress response, inflammatory, and learning and memory systems.

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