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Principal Investigator: Aliza Pham Wingo
Organization: VA NORTHERN CALIFORNIA HEALTH CARE SYS
Fiscal Year: 2024
Funding agency: Veterans Affairs
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.
Terms: <Address><Allele Frequency><Alleles><Allelomorphs><Ammon Horn><Amygdala><Amygdaloid Body><Amygdaloid Nucleus><Amygdaloid structure><Anterior><Brain><Brain Nervous System><Brain region><Clinical Trials><Code><Coding System><Complex><Cornu Ammonis><Data><Data Set><Development><Disease><Disorder><Drug Targeting><Encephalon><Finding by Cause><Funding><GWA study><GWAS><Gene Frequency><Gene variant><Genes><Genetic><Genetic Predisposition><Genetic Predisposition to Disease><Genetic Susceptibility><Genetic propensity><Genetic study><Goals><Hippocampus><Human><Human Genetics><Individual><Inherited Predisposition><Inherited Susceptibility><Investigators><Major Depressive Disorder><Mediating><Mediation><Mendelian randomization><Mental Depression><Mental Health><Mental Hygiene><Mental disorders><Mental health disorders><Messenger RNA><Modern Man><NIH><National Institutes of Health><Nature><Negotiating><Negotiation><Neurosciences><Nucleus Accumbens><Outcome><PTSD><Participant><Patients><Personal Satisfaction><Persons><Post-Translational Regulation><Post-Traumatic Neuroses><Post-Traumatic Stress Disorders><Posttranslational Regulation><Posttraumatic Neuroses><Predisposition gene><Prefrontal Cortex><Prognosis><Proteins><Proteome><Proteomics><Psychiatric Disease><Psychiatric Disorder><Psychological Health><Publishing><QTL><Quantitative Trait Loci><RNA Seq><RNA sequencing><RNAseq><Regulation><Research Personnel><Researchers><Role><Single Base Polymorphism><Single Nucleotide Polymorphism><Site><Susceptibility Gene><Symptoms><Techniques><Testing><Time><United States National Institutes of Health><Variant><Variation><Veterans><Weight><Work><alcohol use disorder><allele variant><allelic frequency><allelic variant><amygdaloid nuclear complex><causal allele><causal gene><causal mutation><causal variant><causative mutation><causative variant><cingulate cortex><clinical depression><co-morbid><co-morbidity><comorbidity><customized therapy><customized treatment><depression><developmental><disease model><disorder model><ethanol use disorder><gene locus><genetic architecture><genetic etiology><genetic locus><genetic mechanism of disease><genetic variant><genetic vulnerability><genetically predisposed><genome scale><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genome-wide><genomewide><genomewide association scan><genomewide association studies><genomewide association study><genomic location><genomic locus><genomic variant><high risk><hippocampal><individualized medicine><individualized patient treatment><individualized therapeutic strategy><individualized therapy><individualized treatment><insight><mRNA><mRNA Expression><major depression><major depression disorder><mental illness><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><patient specific therapies><patient specific treatment><post-trauma stress disorder><posttranscriptional><posttrauma stress disorder><precision medicine><precision-based medicine><predisposing gene><programs><protein biomarkers><protein expression><protein markers><psychiatric genomics><psychiatric illness><psychological disorder><regional difference><single nucleotide variant><social role><statistics><suicidal risk><suicide risk><susceptibility allele><susceptibility locus><susceptibility variant><tailored medical treatment><tailored therapy><tailored treatment><therapeutic agent development><therapeutic development><therapeutic target><transcriptome sequencing><transcriptomic sequencing><transcriptomics><traumatic neurosis><unique treatment><weights><well-being><wellbeing><whole genome association analysis><whole genome association studies><whole genome association study>