PTSD Linked to Genetic Cardiometabolic, Respiratory, Digestive Conditions

Credit: Yale School of Medicine

PTSD symptoms can put an individual at risk of developing somatic cardiometabolic, respiratory, or digestive conditions if the individual has certain genetics, according to new research.

The genetic association study, led by Gita A. Pathak, PhD, of the department of psychiatry at Yale University School of Medicine, was conducted using data collected from participants across 4 biobanks from July 14, 2021 - January 24, 2023. The biobanks included Vanderbilt University Medical Center’s biobank (BioVu); Mass General Brigham (MGB); Michigan Genomics Initiative (MGI); and UK Biobank (UKBB). The study intended to find genetic associations relating to PTSD through 2-sample mendelian randomization (MR), as well as overrepresented disease categories.

“Our findings suggest that posttraumatic symptoms, when interacting with individual genetic variation, may play a role in the risk of developing somatic conditions, such as cardiometabolic, respiratory, or digestive conditions,” wrote the investigators. “These findings further prompt the critical need to identify transcriptional and cellular effects of genetic variants associated with PTSD32-34 through which they might be mediating risk to physical and somatic conditions.”

The study included 1680 phecodes across the 4 biobanks and 490 laboratory tests across 2 biobanks. There were 496,317 individuals, with a mean age of 56.8 years old. Over half (52%) of the participants were female.

Each biobank used a phenome-wide association (PheWAS) approach to identify associations between PTSD PGS and clinical phenome. For each phenotype, the study included a minimum number of 1000 cases and controls, and therefore there were 1340 phecodes in 70,439 individuals in Vanderbilt University Medical Center’s Biobank, 1316 phecodes in 24798 individuals in the Mass General Brigham cohort, 1568 phecodes in 46775individuals in the Michigan Genomics Initiative cohort, and 1298 phecodes in 361,820 individuals of European ancestry in the UK Biobank cohort. The investigators also tested 699 phecodes in 15,102 individuals of African descent. In total, 88,917 were of European ancestry and 15,102 of African descent.

The investigators found polygenetic scores (PGS-PTSD) were significantly associated with PTSD in all biobanks.

In the Vanderbilt University Medical Center’s biobank, the team observed 275 associations after multiple testing corrections. Top associations were caused by mental health and circulatory system phenotypes, such as tobacco use disorder (1.19; 95% CI, 1.17 – 1.23; P = 5.57 × 10−34) and ischemic heart disease (1.11; 95% CI, 1.09 – 1.14; P = 1.89 × 10−15) The study found significant associations were overrepresented in mental health, circulatory system, and respiratory system category.

In the Mass General Brigham cohort, the investigators found 314 phecodes were significantly associated with PGS-PTSD, including depression (1.20; 95% CI, 1.17 – 1.24; P = 1.48 ×10−28) and diseases of the esophagus (1.12; 95% CI, 1.10 – 1.16; P = 3.29 ×10−15). Significant associations were overrepresented in mental health disorders, circulatory system, and digestive system.

In the Michigan Genomics Initiative cohort, 483 of the phecodes were significantly associated with PGS-PTSD, including tobacco use disorder (1.20; 95% CI, 1.17 – 1.23; P = 6.62 ×10−49) and obstructive chronic bronchitis (1.26; 95% CI, 1.21 – 1.30; P = 1.80 ×10−36). The overrepresented categories for significant associations were mental health disorders, respiratory and circulatory systems, and nonspecific systems.

In the UK Biobank, 394 phecodes were significantly associated with PGS-PTSD, and the top associations were essential hypertension (1.11; 95% CI, 1.10 – 1.12; P = 1.67 × 10−138) and tobacco use disorder (1.23; P = 2.12 ×10−117). Many of the significant associations were for mental health disorders, circulatory system, respiratory, digestive, and musculoskeletal system.

“Stress is known to trigger corticotropin-releasing factor and increase the production of cortisol, which may interfere with intestinal digestion and absorption, neurotransmission, and impairing migrating motor complex within the gut,” the investigators wrote. “Higher cortisol levels may lead to muscle pain and inhibit muscle mass growth in individuals affected by PTSD.”

Overall, Pathak and colleagues found overrepresentation for mental health disorders, as well as circulatory system, digestive, and respiratory conditions. When conducting the LabWAS approach of PGS-PTSD, there was no overrepresentation for a specific category of significant associations, but most of the associations were related to metabolic traits (27%), hematologic parameters (24%), and immune measures (20%).

LabWas identified the following measures: triglycerides, high-density lipoprotein, glucose, erythrocyte distribution, and C-reactive protein, leading to 40 significant associations. The significant associations were metabolic traits (40%), hematologic parameters (22.5%), immune system (22.2%), liver (10%), kidney (2.5%), and urinary system (2.5%). Among these significant associations, the metabolic category was overrepresented.

The team found 12 traits affected by genetic liability to PTSD symptoms, including alcoholism and substance addiction; circulatory system; precordial pain; cardiac dysrhythmias; respiratory traits; and other respiratory system and digestive phenotypes.

“Our results suggest genetic epidemiology evidence that parallels observational studies of PTSD that report its association with higher cholesterol, hypertension, gastrointestinal, and cardiometabolic dysfunction, thereby providing novel insights into the genetic architecture of PTSD comorbidity,” the investigators wrote.

References

^{Pathak, G, Singh, K, Choi K, et al. Genetic Liability to Posttraumatic Stress Disorder Symptoms and Its Association with Cardiometabolic and Respiratory Outcomes. Jama Psychiatry. 2023. doi:10.1001/jamapsychiatry.2023.4127}