Disentangling sex differences in the shared genetic architecture of posttraumatic stress disorder, traumatic experiences, and social support with body size and composition

Abstract There is a well-known association of posttraumatic stress disorder (PTSD) and traumatic experiences with body size and composition, including consistent differences between sexes. However, the biology underlying these associations is unclear. To understand this complex relationship, we investigated large-scale datasets from the Psychiatric Genomic Consortium (12 823 cases and 35 648 controls), the UK Biobank (up to 360 000 individuals), and the GIANT (Genetic Investigation of Anthropometric Traits) Consortium (up to 339 224 individuals). We used genome-wide association statistics to estimate sex-specific genetic correlations ( r g ) among PTSD, traumatic experiences, social support, and multiple anthropometric traits. After multiple testing corrections (false discovery rate, FDR q<0.05), we observed 58 significant r g relationships in females (e.g., childhood physical abuse and body mass index, BMI r g =0.245, p=3.88×10 −10 ) and 21 significant r g relationships in males (e.g., been involved in combat or exposed to warzone and leg fat percentage; r g =0.405, p=4.42×10 −10 ). We performed causal inference analyses of these genetic overlaps using Mendelian randomization and latent causal variable approaches. Multiple female-specific putative causal relationships were observed linking body composition/size with PTSD (e.g., leg fat percentage➔PTSD; beta=0.319, p=3.13×10 −9 ), traumatic experiences (e.g., childhood physical abuse➔waist circumference; beta=0.055, p=5.07×10 −4 ), and childhood neglect (e.g., “someone to take you to doctor when needed as a child”➔BMI; beta=-0.594, p=1.09×10 −5 ). In males, we observed putative causal effects linking anthropometric-trait genetic liabilities to traumatic experiences (e.g., BMI➔childhood physical abuse; beta=0.028, p=8.19×10 −3 ). In conclusion, our findings provide insights regarding sex-specific causal networks linking anthropometric traits to PTSD, traumatic experiences, and social support.