Genomic Characterization of Posttraumatic Stress Disorder in a Large US Military Veteran Sample

Abstract

Individuals vary in their liability to develop Posttraumatic Stress Disorder (PTSD), the symptoms of which are highly heterogeneous, following exposure to life-threatening trauma. Understanding genetic factors that contribute to the biology of PTSD is critical for refining diagnosis and developing new treatments. Using genetic data from more than 250,000 participants in the Million Veteran Program, genomewide association analyses were conducted using a validated electronic health record-based algorithmically-defined PTSD diagnosis phenotype (48,221 cases and 217,223 controls), and PTSD quantitative symptom phenotypes (212,007 individuals). We identified several genome-wide significant loci in the case-control analyses, and numerous such loci in the quantitative trait analyses, including some (e.g., MAD1L1; TCF4; CRHR1) that were associated with multiple symptom sub-domains and total symptom score, and others that were more specific to certain symptom sub-domains (e.g., CAMKV to reexperiencing; SOX6 to hyperarousal). Genetic correlations between all pairs of symptom sub-domains and their total were very high (rg 0.93 -0.98) supporting validity of the PTSD diagnostic construct. We also demonstrate strong shared heritability with a range of traits, show that heritability persists when conditioned on other major psychiatric disorders, present independent replication results, provide support for one of the implicated genes in postmortem brain of individuals with PTSD, and use this information to identify potential drug repositioning candidates. These results point to the utility of genetics to inform and validate the biological coherence of the PTSD syndrome despite considerable heterogeneity at the symptom level, and to provide new directions for treatment development.

Genome-wide translational profiling of amygdala Crh-expressing neurons reveals role for CREB in fear extinction learning

“…Analysis of regulation of EXT genes revealed substantial overlap with genes known to be regulated in neuropsychiatric disease. Notably, the CRH receptor (CRHR1) has now been associated with PTSD symptoms, anxiety disorders, and alcohol habitual use in large-scale GWAS studies [11][12][13][14] . In addition, prior work in GWAS association of pathways across psychiatric disorders has demonstrated that the protein encoded by CREB1 directly interacted with several risk genes of psychiatric disorders identified by GWAS 66 .…”

“…As an example, PTSD has been repeatedly associated with a failure to recover from traumatic events, conceptualized as a failure to extinguish learned fear [8][9][10] . Notably, the largest-to-date genomewide association study (GWAS) for PTSD recently found genome-wide level associations between variants of CRHR1, the gene encoding corticotropin-releasing hormone (CRH) receptortype 1, genetically regulated brain-specific CRHR1 expression, and PTSD diagnosis and symptom clusters 11,12 , along with its identification in large GWAS of anxiety and habitual alcohol use 13,14 .…”

Psychological trauma and the genetic overlap between posttraumatic stress disorder and major depressive disorder

“…These factors may alter the way the disorder overlaps genetically with MDD. As shown in Table 1, at least a quarter of the sample had been exposed to combat (Stein et al, 2020). Another factor to consider is the demographics of the sample, which overly represents males (94.4%), unlike the UK Biobank, PGC 1.5 and is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted November 27, 2020. ; https://doi.org/10.1101/2020.11.25.20229757 doi: medRxiv preprint PGC samples, which have an almost even sex division.…”

Heterogeneity and Polygenicity in Psychiatric Disorders: A Genome-Wide Perspective

“…[10][11][12][13][14][15] In psychiatry, GWAS have uncovered a high degree of polygenicity underlying mental illnesses and related complex phenotypes. 8,[16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] Polygenicity describes the contribution of many single nucleotide polymorphisms (SNPs) with relatively small effect sizes to phenotype development. This phenomenon is ubiquitously observed in psychiatric disorders and comorbid phenotypes, as evidenced by the detection of tens to hundreds of genome-wide significant (GWS) linkage disequilibrium (LD) independent loci.…”