TH43. A NOVEL INTEGRATIVE OMICS APPROACH FOR POST-TRAUMATIC STRESS DISORDER

Abstract

Background: Genome-wide association studies (GWAS) have established the polygenic nature of PTSD. To date, only four distinct genome-wide significant loci have been identified in the (largest) meta-analysed GWAS of Million Veteran Program and PGC-PTSD case-control of European ancestry. Given the complex genetic architecture and polygenic nature of the disease, multi-omics analysis can elucidate further on the disease aetiology and risk prediction. Here, we present a multi-omics pipeline that leverages the power of largescale GWAS and our multi-omics datasets of war veterans to robustly identify disease-associated loci, methylation biomarkers and genes. Methods: The multi-omics pipeline involves imputation-based and conventional methylome-wide association analyses to discover the genetically regulated methylation sites (CpGs) and genetic loci associated with PTSD risk. First, we use the imputation-based approach to identify the differentially methylated (DM) CpGs followed by differential methylation analysis of PTSD cases and controls to validate the predicted DM CpGs. Downstream analyses include further characterisation of identified CpGs, associated genetic loci and genes, via pathway and functional enrichment, and differential expression to provide deeper insights into disease aetiology and underpinning biological mechanisms. Results: Using our pipeline, preliminary imputation-based analysis using PGC-PTSD GWAS summary results (∼200,00 cases and controls) identified 492 CpG sites significantly associated with PTSD risk (P < 0.005), several of which were novel and have not been previously reported to be associated with PTSD. Pathway analysis of the associated 254 genes identified 24 significant pathways (FDR < 0.05). Top pathways included regulation of RAC1 activity, signalling by G protein-coupled receptor, signaling by GTPases, endochondral ossification and purine metabolism. Discussion: More than 70% of adults worldwide experience an extreme, life-threatening stress at some time in their lives. Post-traumatic stress disorder (PTSD) is a serious mental illness which can occur as a consequence of exposure to traumatic events. Additionally, with the current Covid-19 pandemic, the prevalence of PTSD is increasingly seen among first responders, healthcare workers, young adults, and general population due to quarantine. Our multi-omics pipeline by leveraging the power of largescale GWAS results, pre-built methylation prediction models and multi-omics data, has the potential to overcome current GWAS limitations to identify novel PTSD risk loci, biomarkers and genes that can guide in diagnosis and treatment. Disclosure: Nothing to disclose.