Background. Major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) are highly comorbid and exhibit strong correlations with one another. We aimed to investigate mechanisms of underlying relationships between PTSD and three kinds of depressive phenotypes, namely, MDD, depressed affect (DAF), and depression (DEP, including both MDD and the broad definition of depression). METHODS. Genetic correlations between PTSD and the depressive phenotypes were tested using linkage disequilibrium score regression. Polygenic overlap analysis was used to estimate shared and trait-specific causal variants across a pair of traits. Causal relationships between PTSD and the depressive phenotypes were investigated using Mendelian randomization. Shared genomic loci between PTSD and MDD were identified using cross-trait meta-analysis. RESULTS. Genetic correlations of PTSD with the depressive phenotypes were in the range of 0.71~0.80. The estimated numbers of causal variants were 14,565, 12,965, 10,565, and 4,986 for MDD, DEP, DAF, and PTSD, respectively. In each case, causal variants contributing to PTSD were completely or largely covered by causal variants defining each of the depressive phenotypes. Mendelian randomization analysis indicates that the genetically determined depressive phenotypes confer a causal effect on PTSD (b = 0.21~0.31). Notably, genetically determined PTSD confers a causal effect on DEP (b = 0.14) and DAF (b = 0.15), but not MDD. Cross-trait meta-analysis of MDD and PTSD identifies 47 genomic loci, including 29 loci shared between PTSD and MDD. CONCLUSION. Evidence from shared genetics suggests that PTSD is a subtype of MDD. This study provides support to the efforts in reducing diagnostic heterogeneity in psychiatric nosology. FUNDING. The National Key Research and Development Program of China (2018YFC1314300) and the National Natural Science Foundation of China (81471364 and 81971255).
Fuquan Zhang, Shuquan Rao, Hongbao Cao, Xiangrong Zhang, Qiang Wang, Yong Xu, Jing Sun, Chun Wang, Jiu Chen, Xijia Xu, Ning Zhang, Lin Tian, Jianmin Yuan, Guoqiang Wang, Lei Cai, Mingqing Xu, Ancha Baranova