Attachment style moderates polygenic risk for posttraumatic stress in United States military veterans: Results from the National Health and Resilience in Veterans Study

ABSTRACT Background Polygenic risk scores (PRS) derived from genome-wide association studies (GWAS) of posttraumatic stress disorder (PTSD) may inform risk for this disorder. To date, however, no known study has examined whether social environmental factors such as attachment style may moderate the relation between PRS and PTSD. Methods We evaluated main and interactive effects of PRS and attachment style on PTSD symptoms in a nationally representative sample of trauma-exposed, European-American U.S. military veterans (N=2,030). PRS were derived from a GWAS of PTSD re-experiencing symptoms (N=146,660) in the Million Veteran Program cohort. Using one-sample Mendelian randomization (MR) with data from the UK Biobank (N=115,099), we evaluated the effects of re-experiencing PRS and attachment style on PTSD symptoms. Results Higher re-experiencing PRS and secure attachment style were independently associated with PTSD symptoms. A significant PRS-by-attachment-style interaction was also observed (β=-0.11, p=0.006) with a positive association between re-experiencing PRS and PTSD symptoms observed only among veterans with an insecure attachment style. One-sample MR analyses suggested that the association between PTSD symptoms and attachment style is bidirectional. PRS enrichment analyses revealed a significant interaction between attachment style and a variant mapping to the IGSF11 gene (rs151177743; p=2.1×10-7), which is implicated in regulating excitatory synaptic transmission and plasticity. Conclusions Attachment style may moderate polygenic risk for PTSD symptoms, and a novel locus implicated in synaptic transmission and plasticity may serve as a possible biological mediator of this association. These findings may help inform interpersonally-oriented treatments for PTSD for individuals with high polygenic risk for this disorder.