Risk loci for post-traumatic stress disorder (PTSD)

August 01, 2019 – Post-Traumatic Stress Disorder (PTSD) is a mental disorder that can develop after a person is exposed to a traumatic event, such as sexual assault, warfare, traffic collisions, or other threats on a person’s life. Symptoms may include disturbing thoughts, feelings, or dreams related to the events, mental or physical distress to trauma-related cues, attempts to avoid trauma-related cues, alterations in how a person thinks and feels, and an increase in the fight-or-flight response. A person with PTSD is at a higher risk for suicide and intentional self-harm.

While PTSD can be attributable to a range of traumatic events, the nature and intensity of traumatic events experienced by some military personnel in warfare result in particularly high prevalence rates of PTSD among US military veterans.small Some studies published previously have hinted at some of the loci and genes that might be involved in the condition, and which may pose a particular concern of genetic predisposition for PTSD for some individuals who have served in the military.

This has led a team  of researchers and investigators from the VA Connecticut Healthcare System, from the Yale University, the VA San Diego Healthcare System; and the University of California, San Diego to perform a genome-wide association study (GWAS) on 146,660 European American and 19,983 African American participants, all with the US Million VeteranProgramm (MVP) associated, searching for variants associated with the quantitative phenotype of interest: scores for the core PTSD symptom of re-experiencing traumatic events through nightmares or flashbacks. Their research was just published in an article in Nature Neurosciences.

The team identified eight distinct significant regions within the genome associated with the phenotype. Among them were three regions with very high P-values of P < 5 × 10−10, namely CAMKV, coding for CaM kinase-like vesicle-associated protein, chromosome 17 closest to KANSL1 (coding for a protein member of a histone acetyltransferase (HAT) complex), but within a large high linkage disequilibrium region that also includes CRHR1 (coding for the corticotropin-releasing hormone receptor 1, and TCF4 (coding for the transcription factor 4). Furthermore, associations were enriched with respect to the transcriptomic profiles of striatal medium spiny neurons.

Strikingly, no significant associations were observed for any of the above loci in the African American cohort of the sample.  This is a very interesting finding in that it implies that genetic risk factors for PTSD may vary in different ethnies.

Results in European Americans were replicated and validated in the UK Biobank data project by performing follow-up analyses based on genes, expression quantitative trait loci, tissue enrichment, or cell-type enrichment, demonstrating that the risk variants found in the European American cohort fell in and around CRHR1 and other genes related to corticosteroid and steroid hormone pathways. The researchers also noted enrichment for genes previously implicated in schizophrenia or other psychiatric conditions. These results indirectly confirm prior biological knowledge regarding relationships with steroid response, and suggest new biological relationships that may have implications for treatment response and precision medicine. They also highlight additional overlap between genes related to PTSD reexperiencing and genes identified in previous human or mouse studies that are expressed in striatal medium spiny neurons and in the brain cortex, hypothalamus, and other regions.

Overall, the study illustrates that using the severity of the core PTSD phenotype, namely reexperiencing symptoms, for GWAS-type of study designs obviates the reliance on a categorical phenotype such as PTSD as defined according to the DSM or the International Classification of Diseases (WHO). Because PTSD diagnostic guidelines have changed over time, those criteria have been proven to identify individuals with varying levels of symptom severity. While PTSD can be attributable to a range of traumatic events, the nature and intensity of traumatic events experienced by some military personnel may result in particularly high prevalence rates and severity among military personel, such as US military veterans.

A very interesting question would be to see how such risk factors may influence PTSD and the severity of symptoms in civilians that have survived military attacks, fighting, and bombing in war zones. It would be very interesting to learn about cultural and ethnic differences in coping with PTSD.

See here a short sequence on PTSD:

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About the Author
Joseph Gut - thasso Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.

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