Multivariate genome-wide association analysis of opioid-related traits in half a million diverse individuals

PROJECT SUMMARY/ABSTRACT We are in the middle of a global opioid epidemic. In 2020, 9.3 million Americans misused prescription opioid pain medications, with 8-12% going on to develop an opioid use disorder (OUD). OUD is highly heritable, but few of the relevant genes are known . A better understanding of how genetic differences make people susceptible or resistant to OUD will be invaluable for improving prevention, treatment, and the development of new pharmacotherapies. Genome-wide association studies (GWAS) are powerful, unbiased tools for elucidating the genetic basis of psychiatric and somatic disorders. In the past decade, hundreds of associations between specific loci and various substance use and misuse traits have been discovered. However, the greatest progress has been made for commonly used drugs, particularly tobacco and alcohol. In contrast, OUD GWAS have not yet reached the sample sizes needed to produce more than a handful of associations. In addition, current GWAS mostly focus on case:control diagnosis of OUD, missing critical pre- addiction stages, such as initial opioid use, subjective response to opioids, escalation of use, and the transition from problematic opioid use to OUD. Increasing our understanding of these pre-addiction stages will deepen our understanding of the genetic risk for OUD, and is an area that NIDA has identified as priority (e.g., NOT- DA-20-030 and NOT-DA-20-004). In this project, we focus on the genetic basis of pre-addiction. Ascertainment of clinically diagnosed OUD cases and opioid-exposed controls concentrates on extreme ends of the spectrum of risk. Focusing on pre-addiction is complementary and can be inexpensively collected at scale in already genotyped population- based cohorts. Pre-addiction traits confer risk for OUD; however, few large genetic datasets have been collected. We will use pre-addiction phenotypes that are genetically correlated with OUD in a multivariate framework for discovery, to boost power of existing opioid GWAS, and dissect the subcomponents of OUD. To accomplish these goals, we are extending our long-standing relationship with the genetics company 23andme, Inc., to deploy a survey taken from well-validated questionnaires to measure pre-addiction and related traits. Responses will be completed by 500,000 subjects from diverse ancestral populations. The results will be used to perform GWAS for pre-addiction and comorbid traits and combined with existing independent OUD GWAS using multivariate analyses available to us by our independent projects and network of collaborators. We expect that this work will demonstrate the utility of studying pre-addiction in population- based cohorts as a tool to accelerate opioid genetics research, and will provide an invaluable resource for the scientific community.