Genetic evidence suggests posttraumatic stress disorder as a subtype of major depressive disorder.

Fuquan Zhang,Ancha Baranova,Xijia Xu,Yong Xu,Ning Zhang,Mingqing Xu,Jiu Chen,Shuquan Rao,Jing Sun,Chun Wang,Lei Cai,Hongbao Cao,Guoqiang Wang,Lin Tian,Jianmin Yuan,Xiangrong Zhang,Qiang Wang

doi:10.1172/jci145942

Abstract

BACKGROUNDMajor 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 3 kinds of depressive phenotypes, namely, MDD, depressed affect (DAF), and depression (DEP, including both MDD and the broad definition of depression).METHODSGenetic 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.RESULTSGenetic 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 indicated 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 identified 47 genomic loci, including 29 loci shared between PTSD and MDD.CONCLUSIONEvidence 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.FUNDINGThe National Key Research and Development Program of China and the National Natural Science Foundation of China.

Highlights

Mental disorders confer a heavy burden on society [1]
Causal variants contributing to posttraumatic stress disorder (PTSD) were completely or nearly covered by causal variants defining each of the depressive phenotypes analyzed (Figure 1A-C)
MR analysis Mendelian randomization analysis indicates that the genetically determined depressive phenotypes confer a causal effect on PTSD (b = 0.21~0.31, Table 1)

Summary

Introduction

Mental disorders confer a heavy burden on society [1]. Major depressive disorder (MDD), which manifests as a persistently low mood, is the most prevalent mental disorder worldwide and is accompanied by considerable morbidity, mortality, and high risk of suicide [2]. A majority of PTSD patients meet the criteria for one or more additional psychiatric disorders, with MDD being prevalent comorbidity [4, 5]. Identifying the genetic underpinnings of this comorbidity is necessary for uncovering phenotypic relationships between MDD and PTSD. Major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) are highly comorbid and exhibit strong correlations with one another. 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. Mendelian randomization analysis indicates that the genetically determined depressive phenotypes confer a causal effect on PTSD (b = 0.21~0.31). Genetically determined PTSD confers a causal effect on DEP (b = 0.14) and DAF (b = 0.15), but not MDD.

Objectives

Methods

Results

Conclusion