Brain Proteome-Wide Association Study Identifies Candidate Genes that Regulate Protein Abundance Associated with Post-Traumatic Stress Disorder

Abstract

Although previous genome-wide association studies (GWASs) on post-traumatic stress disorder (PTSD) have identified multiple risk loci, how these loci confer risk of PTSD remains unclear. Through the FUSION pipeline, we integrated two human brain proteome reference datasets (ROS/MAP and Banner) with the PTSD GWAS dataset, respectively, to conduct a proteome-wide association study (PWAS) analysis. Then two transcriptome reference weights (Rnaseq and Splicing) were applied to a transcriptome-wide association study (TWAS) analysis. Finally, the PWAS and TWAS results were investigated through brain imaging analysis. In the PWAS analysis, 8 and 13 candidate genes were identified in the ROS/MAP and Banner reference weight groups, respectively. Examples included ADK (pPWAS-ROS/MAP = 3.00 × 10−5) and C3orf18 (pPWAS-Banner = 7.07 × 10−31). Moreover, the TWAS also detected multiple candidate genes associated with PTSD in two different reference weight groups, including RIMS2 (pTWAS-Splicing = 3.84 × 10−2), CHMP1A (pTWAS-Rnaseq = 5.09 × 10−4), and SIRT5 (pTWAS-Splicing = 4.81 × 10−3). Further comparison of the PWAS and TWAS results in different populations detected the overlapping genes: MADD (pPWAS-Banner = 4.90 × 10−2, pTWAS-Splicing = 1.23 × 10−2) in the total population and GLO1(pPWAS-Banner = 4.89 × 10−3, pTWAS-Rnaseq = 1.41 × 10−3) in females. Brain imaging analysis revealed several different brain imaging phenotypes associated with MADD and GLO1 genes. Our study identified multiple candidate genes associated with PTSD in the proteome and transcriptome levels, which may provide new clues to the pathogenesis of PTSD.