Global PTSD Genetics Consortium

Global PTSD Genetics Consortium

The Challenge

Understanding Genetics and Post-Traumatic Stress Disorder

Genetics is the study of genes, which are the blueprint for how we pass on traits from generation to generation. Most psychiatric disorders are highly heritable. For example, the estimated heritability for bipolar disorder, schizophrenia, and autism is 80% or higher – much higher than that of diseases like breast cancer (12%) or hypertension (30%). When studying genetics, we look at all of our genes (the whole genome), and look for differences across people – genetic variants. However, robust genetic variants for Post-Traumatic Stress Disorder (PTSD) had yet to be identified, and the specific genes involved in PTSD remain largely unknown.

Genetics: A key to understanding brain health including brain trauma and psychiatric disorders

PTSD is a mental health condition that some people develop after experiencing or witnessing a life-threatening event, such as combat, a natural disaster, terrorist attack or sexual assault. Over eight million people in the United States suffer from PTSD, which can cause symptoms as varied as irritability, physical pain, flashbacks, anxiety, depression, insomnia and, in some cases, suicide. Our veteran population is of particular concern; PTSD is 13.5 times more prevalent among our veterans (RAND 2015).

No definitive diagnostic tests have been developed for PTSD, and no FDA-approved therapeutic for PTSD has been developed in nearly 20 years. Current PTSD treatments include behavioral therapy and selective serotonin reuptake inhibitors, which are typically used as antidepressants. Unfortunately, these interventions have differential benefit across disease severity and populations (e.g., veterans vs civilians), and no tools exist to identify which patients will respond to treatment (Steenkamp et al, 2015; Friedman and Bernardy, 2015). Additionally, the mechanisms through which traumatic stress affects the human brain are not fully known (Abdallah et al. 2017).

Individuals vary widely in their responses to traumatic and life-threatening events. (Kilpatrick, et al. 2013; Kessler, et al. 1995). Many factors, including the intensity of the event and the strength of a social support network, affect a person’s risk of developing PTSD. But initial research indicates that genetics are critical in determining whether a person develops PTSD: inheritance accounts for nearly 70 percent of the risk of the disease (Stein, et al. 2002). Previous studies confirmed the genetic basis of PTSD, but had been unable to identify any genetic variants associated with the disorder.

Our Goal

A better understanding of the genetic risk factors of PTSD to help guide the development of treatments and diagnostics for people suffering from its effects and to help inform strategies for prevention of PTSD following exposure to trauma.

Our Solution

Partnership with Psychiatric Genomics Consortium and Stanley Center for Psychiatric Research at the Broad Institute at MIT and Harvard

Stanley Center for Psychiatric Research at Broad InstitutePrevious research has demonstrated that very large numbers of patients are needed for GWAS studies to identify genetic variants associated with psychiatric diseases and drive significant findings. To this end, CVB has engaged in collaborative efforts with a global network of researchers and clinicians called the Psychiatric Genomics Consortium (PGC).

The PGC unites investigators around the world to conduct meta- and mega-analyses of genome-wide genomic data for psychiatric disorders and currently includes over 800 investigators from 38 countries, focusing on autism spectrum disorder, attention-deficit hyperactivity disorder, bipolar disorder, major depressive disorder, schizophrenia, eating disorders, substance use disorder, obsessive-compulsive disorder, Tourette’s Syndrome, and PTSD.

By investing significant resources to amplify the genomic efforts in PTSD, CVB – in partnership with the Stanley Center for Psychiatric Research at the Broad Institute and in collaboration with the Psychiatric Genetics Consortium PTSD (PGC-PTSD) Working Group – were able to scale and accelerate scientific discovery. These landmark efforts enabled the identification of the first genetic variants associated with PTSD risk. View the press release for more information.

Genome Wide Association Study

A genome-wide association study (GWAS) is an approach that involves rapidly scanning markers across the complete sets of DNA, or genomes, of many people to find genetic variations associated with a particular disease. Once new genetic associations are identified, researchers can use the information to develop better strategies to detect, treat and prevent the disease. Such studies are particularly useful in finding genetic variations that contribute to common, complex diseases, such as asthma, cancer, diabetes, heart disease and mental illnesses. [View Source]

 

Single Nucleotide Polymorphisms

Single nucleotide polymorphisms, frequently called SNPs (pronounced “snips”), are the most common type of genetic variation. Each SNP represents a difference in a single DNA building block, called a nucleotide. For example, a SNP may replace the nucleotide cytosine (C) with the nucleotide thymine (T) in a certain stretch of DNA. SNPs occur normally throughout a person’s DNA and are most commonly found in the DNA between genes. When SNPs occur within a gene or in a regulatory region near a gene, they may play a more direct role in disease by affecting the gene’s function. [View Source]

 

“These findings underscore the role and importance of better understanding the biological mechanisms and genetic risks associated with PTSD to help drive breakthroughs in prevention and treatment,” says Magali Haas, MD, PhD, CEO & President of CVB. “This landmark study also is a testament to the power of team science to dramatically accelerate progress by expanding access to PTSD cases, and to provide genetically diverse samples for robust genetic results.”

 

Global PTSD Genetics Study


Global PTSD Genetics StudyIn this largest GWAS meta-analysis of PTSD to date, analyses were conducted on data and samples collected from multi-ethnic cohorts that included over 30,000 PTSD cases and 170,000 controls. The study, International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci1, demonstrated significant genetic correlations across 60 PTSD cohorts, including participants in the UK Biobank. A total of three genome-wide significant risk loci were identified, two in European and one in African-ancestry analyses. When analyzing the data based on sex, an additional three risk loci were identified in men – two in European and one in African ancestry. Along with other novel genes and non-coding RNAs, a Parkinson’s disease gene involved in dopamine regulation, PARK2, was associated with PTSD. Consistent with previous reports, single nucleotide polymorphisms (SNP)-based heritability estimates for PTSD range between 5-20%. These heritability estimates are similar to rates observed for major depression.

These results represent an important step in a global initiative to accelerate the discovery of genetic markers that could help guide the development of treatments and diagnostics for people living with PTSD.

Based on their findings, researchers also generated a polygenic risk score (PRS) for PTSD. Larger sample sizes are needed to explore the observed variance and improve sensitivity of the PRS. However, researchers confirmed the PRS is highly predictive of “re-experiencing symptoms” – a core feature of PTSD – in an external dataset from the Million Veterans Program (which is studying how genes, lifestyle, and military exposures affect health and illness), although specific risk loci did not replicate in this population.

Looking Ahead

Global PTSD Genetics Consortium

Understanding the genetic risk factors for PTSD has the potential for profound implications on improving patient care. Genes identified in this landmark study could also provide insight into the biological mechanisms that trigger PTSD, which would enable more targeted drug discovery. Genetic tests based on these genes could be used to triage trauma patients, tailoring care to those most at risk for developing PTSD. Finally, baseline genetic tests could target PTSD-susceptible individuals for pre-emptive resiliency training.

These results demonstrate that genetic variation contributes to the biology of differential risk for PTSD and provide a foundation to advance our broader goal of understanding disease pathways for preventing and treating the devastating impacts of PTSD, including suicide.

This endeavor also included the creation of a PTSD genetics database devoted exclusively to the analysis of tens of thousands of DNA samples collected from more than 130 global research centers, which will allow for ongoing translational research.

A critical feature for the program’s success was the centralization and access to high-performance bioassays and analytic pipelines supported by the Broad Institute. In the spirit of open science, the full meta-analyses summary statistics are available for download from the Psychiatric Genomics Consortium.

 

Karestan Koenen, PhD

“We need a drug discovery revolution in PTSD. Today, the only FDA-approved drugs for treating PTSD are SSRIs, and they are only fully effective for less than a third of patients. Unbiased genetics approaches will provide the basis for new, rational therapeutics – and may eventually help us better match treatments to patients.”
– Karestan Koenen, PhD, Principal Investigator for the Stanley Center and Professor at the Harvard T. H. Chan School of Public Health

 

 

References:

  1. Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry. 1995;52:1048-1060.
  2. Kilpatrick DG, Resnick HS, Milanak ME, Miller MW, Keyes KM, Friedman MJ. National estimates of exposure to traumatic events and PTSD prevalence using DSM-IV and DSM-5 criteria. J Trauma Stress. 2013;26:537-547.
  3. Stein MB, Jang KL, Taylor S, Vernon PA, Livesley WJ. Genetic and environmental influences on trauma exposure and posttraumatic stress disorder symptoms: a twin study. Am J Psychiatry. 2002; 159: 1675–1681.
  4. Steenkamp MM, Litz BT, Hoge CW, et al: Psychotherapy for military-related PTSD: a review of randomized clinical trials. JAMA 2015; 314:489–500.
  5. M.J. Friedman, N.C. Bernardy, Considering future pharmacotherapy for PTSD. Neurosci. Lett. (2016).
  6. Abdallah, Chadi G., Steven M. Southwick, and John H. Krystal. “Neurobiology of posttraumatic stress disorder (PTSD): A path from novel pathophysiology to innovative therapeutics.” (2017): 130-132.
  7. Burmeister M, McInnis MG, Zöllner S. Psychiatric genetics: progress amid controversy. Nat Rev Genet. 2008;7: 527–40. doi:10.1038/nrg2381. PMID 18560438.
  8. Biological insights from 108 schizophrenia-associated genetic loci. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Nature. 2014;511:421–427
  9. Duncan LE, et al. Largest GWAS of PTSD (N=20 070) yields genetic overlap with schizophrenia and sex differences in heritability. Mol Psychiatry. 2017 Apr 25. doi: 10.1038/mp.2017.77.

¹ Nievergelt C. et al. International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci Nature Communications (2019). 10.1038/s41467-019-12576-w

² Gelernter J, Sun N, Polimanti R, Pietrzak R, Levey DF, Bryois J, Lu Q, Hu Y, Li B, Radhakrishnan K, Aslan M. Genome-wide association study of post-traumatic stress disorder reexperiencing symptoms in> 165,000 US veterans. Nature Neuroscience. 2019 Sep;22(9):1394-401.