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

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.

Keywords: Depression; Genetic variation; Genetics; Molecular genetics.

Figure 1. Shared causal variants and genomic loci between the depressive phenotypes and posttraumatic stress disorder (PTSD).

(A–C) Venn diagrams of unique and shared causal variants, showing polygenic overlap between PTSD and the depressive phenotypes. The numbers indicate the estimated quantity of causal variants (in thousands) per component, explaining 90% of SNP-attributed heritability for each phenotype. The numbers within parentheses indicate SEM. DEP, depression; DAF, depressed affect. (D) Venn diagram of genomic loci that overlap between major depressive disorder (MDD) and PTSD. The numbers indicate amounts of genomic loci either unique for each condition or shared between MDD and PTSD.

Figure 2. The causal effect between posttraumatic stress disorder (PTSD) and major depressive disorder (MDD), depression (DEP), and depressed affect (DAF).

The trait on the x axis denotes exposure, the trait on the y axis denotes outcome, and each cross point represents an instrumental variant. The lines denote effect sizes (b) of exposure on outcome.

Figure 3. A meta-analysis of major depressive disorder (MDD) and posttraumatic stress disorder (PTSD).

(A) Manhattan plot of meta-analysis of MDD with PTSD. The x axis is the chromosomal position of SNPs and the y axis is the significance of the SNPs (–log₁₀[P]). (B–D) Three genomic loci. Each SNP is color coded based on its correlation (r²) with one of the independent significant SNPs (IndSigSNPs) if that correlation is greater than or equal to the r² threshold of 0.6. Other SNPs (below an r² of 0.6) are colored in gray. The top lead SNPs in genomic risk loci, lead SNPs, and IndSigSNPs are circled in black and colored in dark purple, purple, and red, respectively. Red lines: Genes mapped by positional mapping (mapped genes). Blue lines: Nonmapped protein-coding genes. Dark gray lines: Nonmapped, noncoding genes.

Figure 4. Shared genes between PTSD and MDD and their associations with common mental traits reported by previous GWASs.

SZ, schizophrenia; MDD, major depressive disorder; BD, bipolar disorder; ASD, autism spectrum disorder; ADHD, attention deficit/hyperactivity disorder; PTSD, posttraumatic stress disorder.