Genomics: Insight

I: Research question: 

Why do only a minority of individuals exposed to traumatic events develop Post-Traumatic Stress Disorder (PTSD) despite seventy percent of the population experiencing traumatic events in their lifetime?

II: Background and Societal Implications: 

Post-Traumatic Stress Disorder (PTSD) is a debilitating mental health condition that has a significant impact on both individuals and society, affecting millions of individuals worldwide across diverse demographics and carrying a heavy emotional and economic burden. PTSD can develop after experiencing an extremely traumatic event that goes beyond the normal stressors and may arise from acute stressors such as car accidents, isolated violence, and natural disasters, as well as chronic stressors like prolonged military combat exposure. It is important to remember that not everyone who experiences trauma will develop PTSD. In 2020, approximately thirteen million Americans were newly diagnosed with PTSD, representing five percent of the adult population in the United States in any given year (1). Rates of PTSD are much higher in post-conflict regions such as Algeria (37%), Cambodia (28%), Ethiopia (16%), and Gaza (18%)(2). Globally, the World Health Organization reports that 3.6% of the population, or over 250 million people, experience PTSD in a given year (1). Approximately 33% of those exposed to severe trauma develop PTSD, and of these cases, 22.3 % are categorized as severe (1). Additionally, about 8% of adolescents ages 13-18 have chronic PTSD in their lifetime (3). Women are twice as likely to develop PTSD compared to men, and women are two to three times more at risk of developing PTSD when compared to men (1). 

It is important to remember that not everyone who experiences trauma will develop PTSD.

A higher prevalence of PTSD is seen among Latinos, African Americans, and Native Americans/Alaska Natives than in non-Latino whites. People who served in the military are more likely to develop PTSD compared to the general population. PTSD symptoms such as persistent troubling recollections of trauma, sleep disturbances, emotional detachment, increased alertness, and intense emotional episodes can disrupt work, interpersonal relationships, and social life (4). Although PTSD symptoms may improve over time, professional treatment is key for recovery. In 2018, the financial cost of treating PTSD in the United States, affecting civilians, veterans, and active military service members, was estimated at $232.2 billion (5). This cost underscores the profound impact of PTSD, extending beyond personal suffering to societal challenges as a whole. Thus, the staggering prevalence and socioeconomic repercussions of PTSD underscore the critical need for understanding why only a minority of individuals develop this condition, exposing the complex interplay of factors that influence PTSD susceptibility.

III: Genetic Risk - Factors for PTSD:

Before the development of techniques for molecular genetic analysis in conditions like PTSD, research using twin studies revealed that genetics contribute to the development of PTSD. By examining the human genome for markers linked to people with PTSD, scientists can use this information to predict the likelihood of the condition. Landmark Twin studies, notably True et al.’s 1993 research, have highlighted the role of genetics on the risk of developing PTSD. These studies utilize the twin design to estimate the heritability of a trait. Heritability of a trait refers to the degree to which genetic factors rather than the environment control variations in a trait. To determine heritability, the study compared the similarities between identical twins, who share all genes and a common environment, and fraternal twins, who share half their genes and all common environments. The study analyzed male twins from the Vietnam Era Twin Registry that included both identical and fraternal twins, totaling 4,042 male-male veteran twin pairs, about 2,224 monozygotic and 1,818 dizygotic twins (6). The initial Twin Study concluded that the heritability of PTSD is about 30% (7). Twin studies have a major limitation in that they cannot identify which specific genes are responsible for the development of PTSD.

The initial Twin Study concluded that the heritability of PTSD is about 30%

A) Genomic Markers that Predict Risk of PTSD

The discovery of DNA sequencing marked the beginning of a new era in molecular genetics, paving the way for investigations that would delve into the complex molecular aspects of PTSD. A polymorphism is a region of the DNA for which there exist multiple different forms of a sequence. Variations in sequence can be associated with the presentation of conditions such as PTSD, thereby allowing for quantitative predictions; some variants include a large portion of DNA "polymorphism" and others, significantly smaller portions like a single nucleotide polymorphism (SNP).

Marker 1: Dopamine transporter gene SLC6A3 

A polymorphism exists in the gene encoding the dopamine transporter protein, a protein that is responsible for the reuptake of dopamine, a chemical released by nerve cells to send signals to other nerve cells. Genetic variants in the dopamine transporter SLC6A3 (also known as DAT or DAT1) have been associated with PTSD. For example, a study in 2002 involving Israel/Ashkenazi and Non-Ashkenazi Jews with 104 controls (47% of which were male) and 102 cases of patients with chronic PTSD (56% of which were male) found a strong association between the 9-repeat (9R) allele of SLC6A3 and PTSD. A meta-analysis of this study and two other studies that also examined the dopamine transporter gene found further statistical significance among the three studies, which included a total of 213 PTSD patients and 387 controls. All studies seemed to indicate that the 9R allele increased PTSD risk as the meta-analysis found the odds of possessing the 9R allele was 62% more likely in patients with PTSD than those without(8).

Marker 2: Effect of Bcl-1 SNP:

Bcl-1 SNP, another genomic marker, is a position with alleles that vary at a single base. The Bcl-1 single nucleotide polymorphism (SNP) has an impact on individuals, as homozygous carriers of the Bcl-1 SNP (G allele) exhibited a higher incidence of traumatic memories compared to heterozygous or non-carriers. Carriers are people who possess a copy of a mutated disease-causing gene but have no symptoms (7).

Marker 3: GR Promoter Methylation:

In addition to genomic markers, chemical modifications of the DNA epigenetics can also have a predictive value for PTSD. Lower modifications of the GR promoter locus region of DNA upstream of a gene, where specific proteins bind to initiate the transcription of that gene, have been shown to positively correlate with veterans with PTSD, compared to counterparts without the disorder. Methylation in a promoter region is an epigenetic mechanism relating to changes in the characteristics of a cell or organism that result from altered gene expression- which is important for suppressing the expression of genes. Individuals with lifetime PTSD exhibit distinct physiological markers, including higher GR expression and reduced overall methylation levels in examined GR promoter regions. Notably, the GR promoter methylation levels are found to be lower in veterans with PTSD compared to their counterparts without the disorder. These findings suggest a potential link between PTSD, altered cortisol dynamics, and specific epigenetic modifications in the GR promoter regions. In a study involving 118 Vietnam war veterans with PTSD, researchers investigated GR polymorphisms and two measures of glucocorticoid (GC) sensitivity. Although basal cortisol levels and low-dose dexamethasone suppression test results were similar between PTSD and control groups, there was a significant association between the Bcll GG genotype and low basal cortisol levels in PTSD patients (7).

The GR promoter methylation levels are found to be lower in veterans with PTSD.

B) Gene-environment Interactions in the Context of PTSD

Marker 4: Serotonin transporter gene SLC6A4 and Environmental Influences

A high risk of developing PTSD is associated with a specific polymorphism in a region that affects the expression of the serotonin transporter gene. Studies have shown that environmental influences such as high trauma exposure alongside possession of this polymorphism are highly linked to the development of PTSD.  This gene contains two predominant alleles or genetic variants, long (L) and short (S), with the S-allele associated with reduced serotonin transporter gene expression, leading to diminished serotonin reuptake. A study done in 2005 analyzed the presence of excess S alleles in Korean PTSD patients. This study examined 100 cases of patients with chronic PTSD (43% male) and had 197 controls (39% male). The results from this study showed statistical significance between excess S alleles and PTSD (P-value of 0.04) (9). Homozygosity, the inheritance of two of the same alleles for the S allele, is further associated with PTSD in individuals with classified high trauma exposure. In this study done in 2007, following Florida hurricanes in 2004, where some experienced traumatic events, 589 adult patients were categorized based on their risk for PTSD. High-risk patients were those with both short alleles, low social support, and high hurricane exposure. Medium-risk patients were those with the one long and one short allele, low social support, and high hurricane exposure. Low risk were all other patients. There was a strong association between the risk group and the prevalence of PTSD as the study estimated 19.94 patients would have PTSD based on the calculations done using participants' risk group and sample size, and this estimation was accurate as 19 participants presented with PTSD. High-risk individuals also had 4.5 times the risk of developing PTSD as compared to low-risk individuals (9).

Marker 5: CNR1 Gene Variants

Environmental factors such as childhood abuse have been shown to influence the genetic risk associated with PTSD. Several studies have explored the connection between post-traumatic stress disorder and genetic variations, particularly those associated with the cannabinoid receptor (CNR1) gene. CNR1 is a G protein-coupled receptor primarily found in the central nervous system, such as the brain, and is involved in regulating processes like mood, pain perception, appetite, and memory. Building on this understanding, researchers have identified a specific polymorphism within the CNR1 gene known as rs1049353. This genetic variation has been shown to interact with childhood physical abuse, thereby predicting the emergence of post-traumatic threat symptoms in individuals with PTSD. This polymorphism, when coupled with a history of childhood physical abuse, has been linked to an intensified severity of threat or fear symptoms among those with PTSD. Consequently, it is suggested that rs1049353 may contribute to the increased vulnerability of certain individuals, especially those who have experienced childhood physical abuse, to develop more severe post-traumatic symptoms.

The CNR1 gene has been shown to interact with childhood physical abuse 

IV. Genome-Wide Association Study (GWAS) 

A GWAS involves scanning markers across the genomes of a population to find genetic variations associated with a disease or risk. The investigation involved a sizable cohort of individuals of European descent, with a focus on those with PTSD compared to those without the condition. By scrutinizing the DNA of participants, the study identified common loci among individuals with PTSD, distinguishing them from those without the disorder. The study further extended its analysis to focus on lifetime trauma exposure, revealing a considerable overlap in significant DNA segments between individuals with PTSD and those exposed to trauma.  A significant 72% genetic correlation was observed between PTSD and LTE (lifetime trauma event), with both exhibiting similar genetic patterns in relation to other traits. Accounting for LTE reduced PTSD heritability by 31%, which a multivariate analysis enhanced the PTSD GWAS sample size by 20% and uncovered four additional loci (10). However, the study's exclusive reliance on individuals of European ancestry raises significant limitations in extrapolating the broader impact of PTSD.

 72% genetic correlation was observed between PTSD and LTE (lifetime trauma event),

The PTSD GWAS meta-analysis encompassed 182,199 participants from 51 cohorts, predominantly from the UK BioBank. The analysis primarily utilized PTSD symptom scores in 91% of participants, with the remaining 9% analyzed based on PTSD case-control status. In a subset of the UK Biobank data, which included 132,988 participants, the distribution of Lifetime Trauma Exposures (LTEs) was observed, with varying reported exposures (10). The data revealed various genetic variations located on different chromosomes, pinpointing their genetic positions, which are possible markers for PTSD.

V: Challenges and Future Directions 

PTSD impacts a significant portion of the global population, affecting 250 million individuals annually. Identifying genetic markers that predispose some to PTSD development after trauma exposure, understanding the role of the environment, and exploring gene-environment interactions enhance our comprehension of PTSD manifestations. Recognizing these factors, including genetic markers, facilitates easier identification of PTSD risk and holds potential for future mitigation strategies based on such markers. Further research, particularly on gene-environment interactions, is crucial to validate these findings globally and establish comprehensive systems for assessing PTSD risk based on the many different genetic markers and environmental factors.

It is important to educate ourselves about PTSD because it enables individuals to develop a deeper understanding of what people with PTSD experience. This knowledge allows us to empathize and show compassion towards those suffering from PTSD and provide them with effective support. Furthermore, learning about PTSD plays a vital role in reducing the stigma associated with mental health disorders, encouraging individuals to seek help and support whenever necessary.

While it is important to understand PTSD and its broader societal impacts, it is critical to acknowledge the limitations of current research efforts. In many instances, the sample size is not a diverse representation of the global population, thereby bringing the question of the validity of the studies’ results for the people who are excluded from them. In this paper, we attempted to cite examples of multiple studies done on multiple different types of populations, but evidently, more research needs to be done in this field. Oftentimes, the sample sizes of these studies with different populations were small, and the studies themselves were few and far between. The number of larger studies that have been done, such as the European Genome-Wide Association Study, also do not represent the global population since these studies have only been done using European participants. Analyzing the available data is currently limited by small sample sizes and a non-diverse range of studies, raising questions about the applicability of these findings on PTSD markers and interactions with the environment to the global population.

References

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