Molecular genetics of trauma exposure and PTSD

Background: The notion that genetic factors play a role in response to exposure to traumatic events was made over 75 years ago. Great progress has been made since this early inception in understanding the role of genetic liability on both trauma exposure, as well as posttraumatic stress disorder (PTSD). The field has recently undergone tremendous growth in the area of molecular genetic investigations utilizing agnostic genome wide association study (GWAS) designs of traumatic stress related outcomes, largely due to team science efforts such as the Psychiatric Genomics Consortia (PGC). Objective: The objective of this presentation is to provide an overview of the PGC-PTSD workgroup and samples, and present the most up-to-date analyses of GWAS analyses on trauma exposure and PTSD, using quantitative phenotypes from both the PGC-PTSD broader literature, including the Million Veterans Program (MVP). Methods: The PGC PTSD workgroup sample size in Freeze 2.0 was ~200,000, consisting of ~30,000 PTSD cases and focused on PTSD diagnostic status (Nievergelt et al., 2019). An overview of recently published analyses (e.g., recent GWAS analyses of childhood maltreatment (Dalvie et al., 2020)), as well as recent analyses examining PTSD as a quantitative variable will be presented, including analyses jointly analysing trauma exposure and PTSD symptoms from MTAG, a novel method that allows for joint analysis of summary statistics from GWAS of different traits. Recent findings from MVP (Gelernter et al., 2019) will also be reviewed, ending with a meta-analysis of PTSD as a quantitative trait in the PGC and re-experiencing symptoms from MVP. Results: Childhood maltreatment, defined as a quantitative variable, was found to have a significant molecular heritability, and to be genetically correlated with depression (Dalvie et al., 2020). Further, trauma exposure defined as a quantitative variable, was found to have molecular influence and to be genetically correlated with PTSD. Analyses of PTSD as a quantitative variable yielded significant loci, with some replicating in MVP. MTAG analyses yielded additional hits, and again, some with replication in MVP. Lastly, the meta-analysis of Freeze 2.0 with MVP, resulting in ~339,000 subjects, yielded >20 significant hits, including novel loci. Conclusions: Quantitative analyses of childhood maltreatment, trauma exposure, and PTSD prove to increase statistical power across analyses conducted in the PGC-PTSD as well as MVP. Additionally, the joint analysis using MTAG revealed novel GWAS hits. With more samples and sophisticated analytic techniques the genetic architecture of PTSD will become elucidated, bringing with it critical treatment implications.