Genomic Study of Resilience to Posttraumatic Stress Disorder in the Million Veteran Program

Resilience following combat exposure is an important factor in understanding posttraumatic stress disorder (PTSD), associated risk, and resilience more generally. Identifying underlying genetic factors requires large samples; most biobanks lack extensive resilience assessments, although data regarding trauma and psychiatric symptoms are frequently present that allow computation of a resilience measure.

We leveraged the Million Veteran Program cohort to calculate discrepancy-based psychiatric resilience (DBPR) scores by regressing PTSD symptoms (PTSD Checklist for DSM-IV) onto combat exposure (Deployment Risk and Resilience Inventory-Combat Experiences Scale). We conducted a genome-wide association study of DBPR scores among participants of European ancestry (EUR) (n = 94,360) and African ancestry (AFR) (n = 10,339). We performed conditional analyses with disorders frequently comorbid with PTSD (major depressive disorder, generalized anxiety), examined genetic correlations (r_g) between DBPR scores and psychosocial/psychiatric variables, and performed a transcriptome-wide association study (TWAS) and fine mapping.

Single nucleotide polymorphism (SNP)-based heritability was 0.079 (SE = 0.007), and 3 independent genome-wide significant loci were associated with DBPR scores in EUR participants; no significant loci were identified in AFR participants. Transancestry meta-analysis revealed 3 significant SNPs mapping to RN7SKPP19∗rs4650199, MAD1L1∗rs12669370, and KANSL1:KANSL1-AS1∗rs62060955. In EUR participants, 8 genes were identified in the TWAS. One gene (C7orf50) reached a posterior probability >0.90 in TWAS fine mapping. Significant correlations were observed between DBPR scores and other variables including neuroticism (-0.61), participation in religious groups (0.29), and engaging in sports (0.39, SE = 0.05). The genetic correlation with PTSD in an external sample was moderate/high (-0.84).

These findings extend the literature regarding DBPR as a resilience measure and help inform our understanding of the underlying biological mechanisms.