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

Objective Resilience following combat exposure is an important factor in understanding posttraumatic stress disorder (PTSD), associated risk, and potentially 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. Methods We leveraged the Million Veteran Program (MVP) cohort to calculate discrepancy-based psychiatric resilience (DBPR) scores by regressing PTSD symptoms (PCL-17) onto combat exposure (Deployment Risk and Resilience Inventory–Combat Experiences Scale). We conducted a genome-wide association study (GWAS) of DBPR among European-ancestry (EUR) ( n =94,360) and African-ancestry (AFR) participants ( 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 and psychosocial/psychiatric variables, performed a transcriptome-wide association study (TWAS), and fine mapping. Results SNP-based heritability was 0.079 (SE=0.007) and three independent genome-wide significant loci were associated with DBPR in EUR; no significant loci were identified in AFR. Trans-ancestry meta-analysis revealed three significant SNPs mapping to RN7SKPP19* rs4650199, MAD1L1* rs12669370, and KANSL1:KANSL1-AS1* rs62060955. In EUR, eight genes were identified in TWAS. One gene ( C7orf50 ) reached a posterior probability >0.90 in TWAS fine mapping. Significant correlations were observed between DBPR and other variables including neuroticism (-0.61), participation in religious groups (0.29) and engaging in sports (0.39, SE=0.05). The r g with PTSD in an external sample was moderate/high (-0.84). Conclusions These findings extend the literature regarding DBPR as a resilience measure and help inform our understanding of the underlying biological mechanisms.