心的外傷後ストレス障害（PTSD）に対するレジリエンスのゲノム研究：ミリオン退役軍人プログラム

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.

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.

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).

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