Genome-wide association study of post-traumatic stress disorder reexperiencing symptoms in >165,000 US veterans

Abstract

Post-traumatic stress disorder (PTSD) is a major problem among military veterans and civilians alike, yet its pathophysiology remains poorly understood. We performed a genome-wide association study and bioinformatic analyses, which included 146,660 European Americans and 19,983 African Americans in the US Million Veteran Program, to identify genetic risk factors relevant to intrusive reexperiencing of trauma, which is the most characteristic symptom cluster of PTSD. In European Americans, eight distinct significant regions were identified. Three regions had values of P < 5 × 10^-10: CAMKV; chromosome 17 closest to KANSL1, but within a large high linkage disequilibrium region that also includes CRHR1; and TCF4. Associations were enriched with respect to the transcriptomic profiles of striatal medium spiny neurons. No significant associations were observed in the African American cohort of the sample. Results in European Americans were replicated in the UK Biobank data. These results provide new insights into the biology of PTSD in a well-powered genome-wide association study.

Figure 1:

Manhattan plots – European-Americans (top; N=146,660), and meta-analyzed European- and African-Americans (bottom; AA N=19,983). Negative logarithm of the association two-sided p value (from a linear regression model) for each variant tested is reported on the y-axis. Red and blue line indicates the Bonferroni multiple testing correction and suggestive significances, respectively.

Figure 2:

Regional Manhattan plots, associated region on chromosome 17, European-Americans, African-Americans, and European- and African-Americans, meta-analyzed – showing that associated region localizes to gene CRHR1 only on trans-population meta-analysis. Details regarding sample size and statistical test are reported in the Figure 1 legend.

Figure 3:

eQTLs observed with respect to the eight GWS variants identified in EUR meta-analysis (N=146,660) considering protein-coding genes and 13 brain tissues. The eQTL IDs (x-axis, gene*variant) are reported only for those with at least one result surviving FDR multiple testing correction. Negative logarithm of the association two-sided p value for each eQTL tested is reported on the y-axis. The number reported between parentheses in each eQTL corresponds to the significant results observed with respect to the 13 brain tissues tested. The red line corresponds to the FDR multiple testing correction (q<5%).

Figure 4:

Manhattan plot reporting gene-based association results generated from the EA cohort (N=146,660). Details are reported in Supplemental Table S7. Negative logarithm of the association p value for each gene tested is reported on the y-axis. The red dotted line represents the Bonferroni threshold for gene-based association (0.05/18120).

Figure 5:

a. Enrichment analysis between human tissue specific expression and PTSD re-experiencing genetic associations obtained from the EUR sample (N=146,660). Each bar represents the negative logarithm of the enrichment p value for each tissue tested obtained from two different statistical methods (LDSC and MAGMA, see details in the method section). The black bar represents the Bonferroni threshold (0.05/(53+24+149)). b. Enrichment analysis between mouse brain cell type specific expression (broadly defined) and PTSD re-experiencing genetic associations obtained from the EUR sample (N=146,660). Each bar represents the negative logarithm of the enrichment p value for each cell type tested obtained from two different statistical methods (LDSC and MAGMA, see details in the method section). The black bar represents the Bonferroni threshold (0.05/(53+24+149)).