Abstract
Chronic pain is a common problem, with more than one-fifth of adult Americans reporting pain daily or on most days. It adversely affects the quality of life and imposes substantial personal and economic costs. Efforts to treat chronic pain using opioids had a central role in precipitating the opioid crisis. Despite an estimated heritability of 25–50%, the genetic architecture of chronic pain is not well-characterized, in part because studies have largely been limited to samples of European ancestry. To help address this knowledge gap, we conducted a cross-ancestry meta-analysis of pain intensity in 598,339 participants in the Million Veteran Program, which identified 126 independent genetic loci, 69 of which are new. Pain intensity was genetically correlated with other pain phenotypes, level of substance use and substance use disorders, other psychiatric traits, education level and cognitive traits. Integration of the genome-wide association studies findings with functional genomics data shows enrichment for putatively causal genes (n = 142) and proteins (n = 14) expressed in brain tissues, specifically in GABAergic neurons. Drug repurposing analysis identified anticonvulsants, β-blockers and calcium-channel blockers, among other drug groups, as having potential analgesic effects. Our results provide insights into key molecular contributors to the experience of pain and highlight attractive drug targets.
| Original language | English |
|---|---|
| Pages (from-to) | 1075-1084 |
| Number of pages | 10 |
| Journal | Nature Medicine |
| Volume | 30 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 2024 |
Bibliographical note
Publisher Copyright:© The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.
Funding
This work was supported by the US Department of Veterans Affairs (grants I01 BX003341 to H.R.K. and A.C.J., IK2 CX002336 to E.E.H. and the VISN 4 Mental Illness Research, Education and Clinical Center) and NIH (grants K01 AA028292 to R.L.K. and P30 DA046345 to H.R.K.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The views expressed in this article are those of the authors and do not necessarily represent the position or policy of the Department of Veterans Affairs or the US Government. We acknowledge the PMBB for providing data to generate PRSs and conduct PheWAS analyses and thank the patients of Penn Medicine who consented to participate in this research program. We thank the PMBB team and Regeneron Genetics Center for providing genetic variant data for analysis. The PMBB is approved under IRB protocol 813913 and supported by the Perelman School of Medicine at the University of Pennsylvania, a gift from the Smilow family, and the National Center for Advancing Translational Sciences of the National Institutes of Health under CTSA award UL1TR001878. This manuscript has been co-authored by UT-Battelle, LLC under contract DE-AC05-00OR22725 with the US Department of Energy. The US Government retains and the publisher, by accepting the article for publication, acknowledges that the US Government retains a nonexclusive, paid-up, irrevocable, worldwide license to publish or reproduce the published form of this manuscript or allow others to do so, for US Government purposes. The Department of Energy will provide public access to these results of federally sponsored research in accordance with the DOE Public Access Plan (http://energy.gov/downloads/doe-public-access-plan). H.R.K. is a member of advisory boards for Dicerna Pharmaceuticals, Sophrosyne Pharmaceuticals, Enthion Pharmaceuticals and Clearmind Medicine; a consultant to Sobrera Pharmaceuticals; the recipient of research funding and medication supplies from Alkermes for an investigator-initiated study; and a member of the American Society of Clinical Psychopharmacology\u2019s Alcohol Clinical Trials Initiative, which was supported in the last 3\u2009years by Alkermes, Dicerna, Ethypharm, Lundbeck, Mitsubishi and Otsuka. H.R.K. and J.G. are named as inventors on PCT patent application 15/878,640 entitled \u2018genotype-guided dosing of opioid agonists\u2019, filed on 24 January 2018. E.S. is a full-time employee of Regeneron Pharmaceuticals. The other authors declare no competing interests.
| Funders | Funder number |
|---|---|
| University of Pennsylvania Health System | |
| Enzon Pharmaceuticals | |
| Clearmind Medicine | |
| DOE Public Access Plan | |
| US Government Accountability Office | |
| U.S. Department of Energy EPSCoR | |
| US Department of Veterans Affairs or the US government | |
| PMBB | |
| National Center for Advancing Translational Sciences (NCATS) | |
| Perelman School of Medicine, University of Pennsylvania | |
| American Society of Clinical Psychopharmacology | |
| National Institutes of Health (NIH) | K01 AA028292, P30 DA046345, 813913, UL1TR001878 |
| UT Battelle LLC | DE-AC05-00OR22725 |
| U.S. Department of Veterans Affairs | I01 BX003341, IK2 CX002336 |
ASJC Scopus subject areas
- General Medicine
- General Biochemistry, Genetics and Molecular Biology