Sex-stratified genomic structural equation models of posttraumatic stress inform PTSD etiology

Posttraumatic stress disorder (PTSD) affects 3.9%-5.6% of the worldwide population, with well-documented sex-related differences. While psychosocial and hormonal factors affecting sex differences in PTSD and posttraumatic stress (PTS) symptom etiology have been explored, there has been limited focus on genetic bases of these differences. Many symptom combinations may confer a PTSD diagnosis. We hypothesized that these symptom combinations have sex-specific patterns, the examination of which could inform etiological differences in PTSD genetics between males and females. To investigate this, we performed a sex-stratified multivariate genome-wide association study (GWAS) in unrelated UK Biobank (UKB) individuals of European ancestry. Using GWAS summary association data, genomic structural equation modeling was performed to generate sex-specific factor models using six indicator variables: trouble concentrating, feeling distant from others, irritability, disturbing thoughts, upset feelings, and avoidance of places/activities which remind the individual of a traumatic event. Models of male and female PTSD symptoms differed substantially (local standardized root mean square difference=3.12) and significantly ({chi}2(5)=28.03, p=3.6x10-5). Independent two-factor models best fit the data in both males and females; these factors were subjected to GWAS in each sex, revealing three genome-wide significant loci in females, mapping to SCAND3, WDPCP, and FAM120A. No genome-wide significant loci were identified in males. All four PTS factors (2 in males and 2 in females) were heritable (p<0.05): male PTS-f1 h2-SNP=1.85%, male PTS-f2 h2-SNP=1.47%, female PTS-f1 h2-SNP=3.87%, female PTS-f2 h2-SNP=3.53%. Male PTS-f1 was enriched for medication-related putative causal relationships (3.73-fold, p=0.032) while male PTS-f2 was enriched for body structure (2.84-fold, p=5.512x10-7) and cognitive (3.22-fold, p=0.009) putative causal relationships. In females, PTS-f1 was enriched for metabolic putative causal relationships (28.08-fold, p=0.035). By assessing the relationship between sex and PTSD symptoms, this study informs correlative and putatively causal etiological differences between males and females which support further investigation of sex differences in PTSD genetics.