Attachment Style Moderates Polygenic Risk for Incident Posttraumatic Stress in U.S. Military Veterans: A 7-Year, Nationally Representative, Prospective Cohort Study

Abstract

Background: Posttraumatic stress disorder (PTSD) develops consequent to complex gene-by-environment interactions beyond the precipitating trauma. To date, however, no known study has used a prospective design to examine how polygenic risk scores (PRSs) interact with social-environmental factors such as attachment style to predict PTSD development. Methods: PRSs were derived from a genome-wide association study of PTSD symptoms (N = 186,689; Million Veteran Program cohort). We evaluated combined effects of PRS and attachment style in predicting incident PTSD in a 7-year, nationally representative cohort of trauma-exposed, European-American U.S. military veterans without PTSD (N = 1083). We also conducted multivariate gene-by-environment interaction and drug repositioning analyses to identify loci that interact with multiple environmental factors and potential pharmacotherapies that may be repurposed for this disorder. Results: Veterans with higher PTSD PRS were more likely to have an incident-positive screen for PTSD over 7 years. A gene-by-environment interaction was also observed, such that higher PRS only predicted incident PTSD in veterans with an insecure attachment style and not those with a secure attachment style. At an individual locus level, the strongest gene-by-environment interaction was observed for the rs4702 variant of the FURIN gene with cumulative lifetime trauma burden. Drug repositioning revealed that genes implicated in PRS are perturbated by the drug doxylamine. Conclusions: Attachment style moderates polygenic risk for the development of PTSD in European-American veterans. These findings may inform PTSD prevention and treatment for veterans with high polygenic risk for PTSD and suggest a potential pharmacotherapeutic target for risk genes moderated by social-environmental factors.