The genetic architecture of pain intensity in a sample of 598,339 U.S. veterans

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 quality of life and imposes substantial personal and economic costs. Efforts to treat chronic pain using opioids played 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 125 independent genetic loci, 82 of which are novel. 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 GWAS 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, beta-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.

Genetically Regulated Gene Expression in the Brain Associated With Chronic Pain: Relationships With Clinical Traits and Potential for Drug Repurposing

“…A recent genetic study of pain intensity was carried out in 598,339 Million Veterans Program participants ( 39 ) and included FUSION transcriptome-wide association analysis and prediction models for 6 brain tissues (anterior cingulate cortex, cerebellar hemisphere cortex, frontal cortex, cerebellum, and dorsolateral prefrontal cortex). Pain intensity was significantly genetically correlated with MCP ( r g = 0.79) ( 39 ).…”

Repurposing Antihypertensive and Statin Medications for Spinal Pain

“…In contrast, an unpublished agnostic drug repurposing MR study of pain intensity irrespective of pain location suggested potential analgesic effects of calcium channel blockers. 53 This lack of clear triangulation with evidence from observational studies and trials mirrors the complexity of calcium channel modulators affecting the pain neuraxis and reminds us that various calcium channel blockers showed early promise in preclinical studies yet disappointed in later RCTs. 19 Calcium channel blockers may be a more challenging repurposing target for spinal pain, but further study may still be useful in separating out the beneficial versus detrimental aspects of calcium channel blockade.…”

“…However, a multicenter cohort study of people with knee osteoarthritis found associations between calcium channel blocker use and worse pain outcomes, 52 consistent with the current study. In contrast, an unpublished agnostic drug repurposing MR study of pain intensity irrespective of pain location suggested potential analgesic effects of calcium channel blockers 53 . This lack of clear triangulation with evidence from observational studies and trials mirrors the complexity of calcium channel modulators affecting the pain neuraxis and reminds us that various calcium channel blockers showed early promise in preclinical studies yet disappointed in later RCTs 19 .…”

Genetic Insights into Externalizing and Internalizing Traits through Integration of the Research Domain Criteria and Hierarchical Taxonomy of Psychopathology

“…Traits were chosen across four domains-(1) pain, (2) general health, (3) cardiovascular disease, and (4) chronic illness-each of which has demonstrated associations with psychopathology. [73][74][75] We used summary statistics from GWAS of pain intensity, 76 multisite chronic pain, 77 and back pain. 78 General health indices included GWAS summary statistics from the UK Biobank for longstanding illness, disability, or infirmity; hospitalization; and age at death.…”