Identifying Novel Brain Proteins Contributing to PTSD and Alcohol Use Disorder

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Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are among the most prevalent and debilitating psychiatric disorders in U.S. Veterans. They are highly comorbid and have shared genetic susceptibility. Treatments for PTSD or AUD are ineffective in many patients, and comorbid PTSD and AUD are often more difficult to treat and associated with more severe symptoms, higher suicide risk, and poorer outcomes. Thus, the overarching goal of this proposal is to identify brain proteins predisposing to PTSD, AUD, or both as potential promising drug targets to support the development of novel treatments for these disorders. Our proposal builds on insights into the complex genetic architecture of PTSD and AUD gained through large genome-wide association studies (GWAS). GWAS tests allele frequency difference between cases and controls for individual single nucleotide polymorphisms (SNPs) to identify SNPs associated with disease. A genetic locus may have tens to dozens of SNPs associated with the disease. Disentangling which SNPs are important in predisposing to the disease versus those coincidentally associated because they are physically close to important genetic variant sites (i.e., due to linkage) is the next great challenge of human genetics. To address this challenge, several analytical approaches have emerged to integrate information about genetic control of mRNA expression with GWAS results to identify potentially causal genes. To date, these approaches have focused on mRNA expression, but there are two major advantages gained by focusing on protein expression. First, the vast majority of drug targets and biomarkers are proteins. Second, studying brain proteins directly will provide more confidence on the nominated therapeutic targets because mRNAs may not frequently be optimal surrogates for proteins given the complex post-transcriptional, translational, and post- translational regulation. Thus, we propose to leverage human brain proteomes to test the hypothesis that some genetic variants are associated with PTSD or AUD because they modulate brain protein expression in a way that predisposes to PTSD, AUD, or both. To test this hypothesis, we will integrate PTSD and AUD GWAS summary statistics, respectively, from participants of the Million Veteran Program and Psychiatric Genomics Consortium with human brain proteomes using the state-of-the-art analytical techniques to identify genes that modulate brain protein expression to predispose to PTSD, AUD, or both. We aim to identify genes with evidence consistent with being causal in PTSD or AUD, which means that they meet the following three conditions. First, the gene has one or more alleles strongly associated with the disease. Second, the brain protein expression regulated by proximal genetic variants (referred to as cis-regulated brain protein level) is associated with the disease. Third, the cis- regulated brain protein expression mediates the effect of the gene on the disease. The causal inference of this integrative strategy has been experimentally tested and shown to be robust. The first aim of the proposal will focus on merging all available human brain proteomic and genetic data available from our own work and that of our collaborators to estimate effect of SNPs on human brain protein expression. In the second aim, we will integrate PTSD or AUD GWAS summary statistics with the brain protein expression data to identify potentially causal genes for PTSD, AUD, or both. Finally, in the third aim, we will test whether genetic regulation of protein expression for the causal genes identified in Aim 2 is similar in multiple specific brain regions relevant to PTSD or AUD (amygdala, hippocampus, anterior cingulate cortex, and nucleus accumbens). Findings from our proposed studies will identify specific genes and brain proteins as potential promising targets for further mechanistic study to support novel therapeutic development for PTSD, AUD, or both and will have important and long-lasting impact on the mental health and well-being of Veterans.