PROJECT SUMMARY/ABSTRACT The overarching goal of the Integrative Omics Center for Accelerating Neurobiological Understanding of Opioid Addiction (ICAN) is to identify biologically actionable drivers of opioid addiction (OA). We will (1) conduct large-scale integrated multi-omics studies of OA in humans, (2) integrate rodent–human studies to identify genes and gene networks implicated in OA, and (3) build a publicly available national omics resource for studying OA. Our cohering principle is that by integrating multiple omics across human and animal model data we will discover robust drivers of individual variation that predispose opioid users to addiction. The omics revolution has delivered many discoveries of such individual variation for complex diseases, including for nicotine and alcohol phenotypes, but not for OA. We see five fundamental challenges to rapid progress: (1) limited sample sizes and unaccounted-for phenotypic heterogeneity in genome-wide association studies (GWAS) of OA; (2) very limited human brain studies of gene dysregulation by OA; (3) poor translation between human and animal model studies; (4) lack of concurrent integration of multiple omics; and (5) limited practical access to, and poor harmonization of, OA omics data. To overcome these challenges, ICAN harnesses four Projects and two Cores: Project 1: Electronic Health Record Phenotyping and Genomics of Opioid Addiction Project 2: Gene Regulation in the Opioid Dependent Human Brain Project 3: Multi-species Approach to Opioid Addiction Project 4: Multi-omics Gene Network Identification Cores: Administrative Core and Synergy Core Across these Projects and Cores, we will (1) conduct the largest GWAS to date (N>100,000 cases) leveraging Genomic Structural Equation Modeling; (2) examine differential gene regulation across key brain regions (prefrontal cortex, nucleus accumbens, amygdala) in the largest collection of OA informative postmortem brains to date (N=641); (3) integrate rodent and human studies using GeneWeaver.org, polygenic transcriptome risk scores, and variant functionalizing experiments; and (4) apply explainable artificial intelligence, gene network mapping, and multiple lines-of-evidence integration for gene network discovery. Each Project is rigorously designed to make novel contributions. However, by integrating the diversity of ICAN’s science through the cross-fertilization and coordinating efforts of the Cores, we will leverage the agnostic discovery power of omics and place it within the context of functional neurobiology to make field-changing breakthroughs and identify actionable targets for development of OA treatments.