Disentangling the roles of trauma and genetics in psychiatric disorders using an Electronic Health Records-based approach

Abstract

Posttraumatic stress disorder (PTSD) requires an exposure to trauma for diagnosis by the DSM-V. Despite this, there is no documented linear relationship between degree of trauma and severity/chronicity of PTSD.To determine whether traumatic and stressful life events (TSLEs) collected from Electronic Health Records (EHR) interact with PTSD genetics to better define individual risk of developing PTSD. We collected trauma information from patient records in the Mount Sinai BioMe™ biobank population-based cohort and tested for associations with PTSD. We generated a TSLE risk score (TRS), tested its association with PTSD, and for interactions with a polygenic risk score (PRS) of PTSD and a GWAS of PTSD using our biobank population.We used the Mount Sinai BioMe™ biobank patient population of 31,704 individuals with matched genotype and EHR data, which has been enrolling patients since 2006. Patient enrollment in BioMe™ is unrestricted, resulting in high diversity. Our study includes 1,990 individuals with PTSD and 28,478 individuals without PTSD from the Mount Sinai BioMe™ biobank.A total of 1,990 individuals with PTSD and 28,478 controls were analyzed (average age 42-78 years, 58.7% women). We identified a total of 22 EHR-derived TSLEs that were associated with PTSD (β> 0.029, p<1.61×10−3). TSLEs interacted with each other to increase the risk of developing PTSD, with the most significant interaction between being female (as a proxy for experiencing sexism) and being HIV+ (β=0.013, p=8.9×10−11). PRS of PTSD and lead SNPS from GWAS interacted with TSLEs and our TRS to increase PTSD risk. In addition to TRS interactions, we found significant interactions between PTSD PRS and domestic violence, and sexual assault in European Americans (β>207.74, p<1.80×10−3). rs113282988 and rs189796944 variants reached genome-wide significance in interactions with TRS (β>0.056, p<9.04×10−9), and rs189796944 in an interaction with Physical Survival TSLEs (β>0.127, p<4×10−8).In conclusion, quantification of trauma type, severity, and magnitude—alone and in concert with genetics—provides better prediction of PTSD risk than PRS alone. Understanding who is at risk of developing PTSD allows for timely clinical intervention and possible prevention.

Common genetic variation impacts stress response in the brain

“…As traumas are known to be unequally distributed across the population by race, expression was imputed separately by race and meta-analyzed together. Traumatic experiences in this cohort were defined through the EHR as described previously 67 .…”

Trauma Matters: Integrating Genetic and Environmental Components of PTSD

“…The majority of psychiatric GWEIS so far have been performed in MDD, [ 116–119 ] with one additional study performed on alcohol misuse, [ 120 ] another in suicidality and posttraumatic stress, [ 121 ] and one study in PTSD. [ 87 ]…”

“…The majority of psychiatric GWEIS so far have been performed in MDD, [116][117][118][119] with one additional study performed on alcohol misuse, [120] another in suicidality and posttraumatic stress, [121] and one study in PTSD. [87] Results from the GWEIS of depression indicated that SNP rs10510057 interacted with stressful life events (SLEs) and work-related stress at nominal significance; [119] rs4652467 interacted with SLEs in African Americans (AA); [118] rs12789145 and rs17070072 interacted with SLEs in individuals of European ancestry; [117] and rs10485715 (BMP2) interacted with SLEs in hospital staff. [116] In alcohol misuse, PRKG1 (variant rs1729578) significantly interacted with traumatic life experiences (TLE) in an African American cohort, and independently replicated in a secondary cohort of both African and European Americans.…”

“…Incorporating data about cohort-specific traumas into PTSD association models has demonstrated significant improvements in the amount of variance explained. [87,123,124] Additionally, studies including more homogeneous cohorts have identified genomewide significant loci associated with PTSD, albeit without independent replication. For example, in a GWAS study with only 324 full PTSD cases of 3494 combat-exposed male U.S. Marines and Sailors from the Marine Resiliency Study (MRS), authors were able to identify a genome-wide significant SNP: rs6482463, mapping to PRTFDC1 (p = 2.04 × 10 −9 ) [123] (Table 1).…”

“…Perhaps unsurprisingly, exposure to trauma has been linked to nearly every risk factor for PTSD. Through trauma studies, the field has discovered that the risk of traumatic exposure is also influenced by sex, [35,36,[82][83][84] race/ethnicity, [58,59,[85][86][87] personality factors, [64,88] prior psychiatric disorders, [89] occupation [73] and the genetics of these risk factors. Furthermore, exposure to trauma increases an individual's risk of developing numerous psychiatric disorders, many of which are co-morbid with PTSD (e.g., mood and anxiety disorders).…”