Harnessing the genetics of chronic pain to inform the development of non-additive analgesic medications

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

Project Summary/Abstract Chronic pain is a major health burden and constitutes the greatest cause of years lived with disability. Current treatment options for pain are largely non-specific and often have clinically significant adverse effects, poor efficacy in many patients, and addictive potential. A greater understanding of the molecular mechanisms underlying chronic pain is critical to enable identification of novel or repurposed analgesics that are safe and effective. Chronic pain has a substantial genetic component and efforts to inform drug development using genetics are more than twice as likely to yield medication approvals. However, the genetic mechanisms associated with chronic pain are not well understood and studies are limited by a near-exclusive focus on individuals of European ancestry. The principal investigator, Dr. Sylvanus Toikumo, recently conducted the largest multi-ancestry genome-wide association study (GWAS) of pain intensity (N = 598,339) to date, which identified 125 independent genetic loci. This proposal capitalizes on findings from that GWAS and enables Dr. Toikumo to acquire methods and skills to elucidate the genetic risk for chronic pain, and potentially help to identify new analgesic medications. Training opportunities linked to each of the specific aims will enhance Dr. Toikumo's development as an independent investigator. Aim 1 will characterize the genetic architecture underlying chronic pain liability and addiction, which he will achieve by using a) genomic structural equation modeling to derive a common genetic liability factor for pain from the multi-ancestry GWAS of pain intensity and other pain related GWASs b) multivariate GWAS meta-analysis of the chronic pain factor and c) analyses of the unique and shared genetic architectures of pain and addiction risk. Aim 2 will estimate the causal effect of brain and plasma proteins and curate drug targets for causal proteins in silico using drug databases. Aim 3 will use gene mapping to integrate existing GWAS data with functional genomic annotations in ATAC-seq and high-resolution genome- wide promoter-focused Capture C/Hi-C data from human iPSC-derived cortical neurons to identify effector genes. Aim 4 developing mechanistic to identify novel treatments. Specifically, the K99/R00 Pathway to Independence award will provide Dr. Toikumo with training in pain phenotyping, statistical genetics, computational genomics, and gene mapping techniques. These training objectives will be supported by Drs. Kranzler, Kember, Grant, Gandal, Diatchenko, Farrar, Cheatle, and Corder and the technical and intellectual resources of the University of Pennsylvania, the Children's Hospital of Philadelphia, and a yet-to-be determined research institution. Together, the proposed scientific aims and training objectives will form the foundation for an independent research program aimed at identifying risk mechanisms and novel medications for chronic pain. will rioritize risk genes and pathways underlying genomic regulation using i so-QTL data from human fetal brain tissues. Together, these aims will elucidate t he genetic architecture and underpinnings of chronic pain and inform translational models p