Biological psychiatry · 2026
Genomic Study of Resilience to Posttraumatic Stress Disorder in the Million Veteran Program.
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Overstreet Cassie, Levey Daniel F, Adhikari Keyrun, Galimberti Marco, Pathak Gita A, Pietrzak Robert H, Zhou Hang, Løkhammer Solveig, Polimanti Renato, Harrington Kelly M, Quaden Rachel, Amstadter Ananda B, Gaziano J Michael, VA Million Veteran Program, Stein Murray B, Gelernter Joel
Аннотация
BACKGROUND: 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.
METHODS: 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 (rg) between DBPR scores and psychosocial/psychiatric variables, and performed a transcriptome-wide association study (TWAS) and fine mapping.
RESULTS: 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).
CONCLUSIONS: These findings extend the literature regarding DBPR as a resilience measure and help inform our understanding of the underlying biological mechanisms.
METHODS: 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 (rg) between DBPR scores and psychosocial/psychiatric variables, and performed a transcriptome-wide association study (TWAS) and fine mapping.
RESULTS: 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).
CONCLUSIONS: These findings extend the literature regarding DBPR as a resilience measure and help inform our understanding of the underlying biological mechanisms.