Integrating human brain proteomes with genome-wide association data implicates novel proteins in post-traumatic stress disorder

Genome-wide association studies (GWAS) have identified several risk loci for post-traumatic stress disorder (PTSD); however, how they confer PTSD risk remains unclear. We aimed to identify genes that confer PTSD risk through their effects on brain protein abundance to provide new insights into PTSD pathogenesis. To that end, we integrated human brain proteomes with PTSD GWAS results to perform a proteome-wide association study (PWAS) of PTSD, followed by Mendelian randomization, using a discovery and confirmatory study design. Brain proteomes (N=525) were profiled from the dorsolateral prefrontal cortex using mass spectrometry. The Million Veteran Program (MVP) PTSD GWAS (n=186,689) was used for the discovery PWAS, and the Psychiatric Genomics Consortium PTSD GWAS (n=174,659) was used for the confirmatory PWAS. To understand whether genes identified at the protein-level were also evident at the transcript-level, we performed a transcriptome-wide association study (TWAS) using human brain transcriptomes (N=888) and the MVP PTSD GWAS results. We identified 11 genes that contribute to PTSD pathogenesis via their respective cis-regulated brain protein abundance. Seven of 11 genes (64%) replicated in the confirmatory PWAS and 4 of 11 also had their cis-regulated brain mRNA levels associated with PTSD. High confidence level was assigned to 9 of 11 genes after considering evidence from the confirmatory PWAS and TWAS. Most of the identified genes are expressed in other PTSD-relevant brain regions and several are preferentially expressed in excitatory neurons, astrocytes, and oligodendrocyte precursor cells. These genes are novel, promising targets for mechanistic and therapeutic studies to find new treatments for PTSD.