Neuroimaging Phenotypes Implicated For GWAS of PTSD Through The PGC And ENIGMA Worldwide Consortia

Here, we present the results of a large-scale neuroimaging-genetics consortium study on PTSD conducted by the Psychiatric Genomic Consortium (PGC) and Enhancing Neuroimaging Genetics Through Meta-Analysis (ENIGMA) PTSD Working Group. Hippocampus, hippocampal subfield, and amygdala volume differences are strongly implicated in PTSD, but findings have not always been consistent. Our goal was to characterize these neuroimaging phenotypes for subsequent GWAS. We analyzed neuroimaging and clinical data from 1,868 subjects (794 PTSD patients) contributed by 16 cohorts, representing the largest neuroimaging study of PTSD to date. We assessed the volumes of eight subcortical structures (nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, and lateral ventricle) in n=1,868. We assessed 11 hippocampal subfield volumes bilaterally (cornu ammonis 1 (CA1), CA3, CA4, dentate gyrus (DG), fimbria, fissure, hippocampus-amygdala transition area (HATA), molecular layer, parasubiculum, presubiculum, subiculum, and tail) in n=1,398. We used a standardized image-analysis and quality-control pipeline established by the ENIGMA consortium to assess groups with current PTSD, lifetime PTSD, and current PTSD in participants exposed to childhood trauma. We found that hippocampus and amygdala were smaller in subjects with current PTSD compared to trauma-exposed controls (hippocampus, Cohen’s D=-0.17, p=0.00054; amygdala, D=-0.11, p=0.025). Even though the female-only analysis contained approximately 1,100 fewer subjects than the full sample, the hippocampal results were more significant in females (p=0.00012), and Cohen’s D estimates indicated a stronger effect than in the full sample (D=-0.31 vs. D=-0.17). Current PTSD was associated with smaller subfield volume in the right hippocampal tail (p=0.002, D=0.26) and larger volumes in the right CA1 (p=0.002, D=0.26) in individuals exposed to at least one traumatic event in childhood. Our study is not subject to the biases of meta-analyses of published data, and represents an important milestone in an ongoing collaborative effort to examine the neurobiological underpinnings of PTSD and the brain’s response to trauma. The association of PTSD and abnormalities in the CA1 are consistent with its role in contextual fear memory, which is a widely accepted behavioral model for PTSD. The hippocampus and amygdala are crucial for fear processing, episodic and contextual learning and memory, processes related to PTSD symptomatology. This meta-analysis firmly establishes the importance of the hippocampus and amygdala in PTSD, which by itself represents a substantial step forward in identifying the most plausible neuroimaging phenotypes for a GWAS of PTSD.