A multi-ancestry genetic study of pain intensity in 598,339 veterans

Toikumo, Sylvanus; Vickers-Smith, Rachel; Jinwala, Zeal; Xu, Heng; Saini, Divya; Hartwell, Emily E.; Pavicic, Mirko; Sullivan, Kyle A.; Xu, Ke; Jacobson, Daniel A.; Gelernter, Joel; Rentsch, Christopher T.; ,; Pavicic, Mirko; Stahl, Eli; Cheatle, Martin; Zhou, Hang; Waxman, Stephen G.; Justice, Amy C.; Kember, Rachel L.; Kranzler, Henry R.

doi:10.1038/s41591-024-02839-5

Cited by 11 publications

(4 citation statements)

References 109 publications

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“…MAPKAP1 is a subunit of the mTOR complex 2, a component of the mTOR signalling pathway vital for growth and metabolism 29,30,41 . MAPKAP1 has been identified in GWAS of pain intensity 42 , and dysregulation of the mTOR signalling pathway has been implicated in various neurodegenerative and neuropsychiatric disorders, including epilepsy 43 . OR4C12 and OR4C13 are G-protein coupled receptors predominantly expressed in nasal epithelium olfactory sensory neurons and involved in neural response to odorant stimuli 29,30 .…”

Section: Discussionmentioning

confidence: 99%

Genomics of chronic cough unravels neurological pathways

Coley,

John,

Ghouse

et al. 2024

Preprint

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BackgroundChronic cough is a symptom of common lung conditions, occurs as a side effect of ACE inhibitors (ACEis), or may be unexplained. Despite chronic cough representing a substantial health burden, its biological mechanisms remain unclear. We hypothesised shared genetic architecture between chronic dry cough and ACEi-induced cough and aimed to identify causal genes underlying both phenotypes.MethodsWe performed multi-ancestry genome-wide association studies (GWAS) of chronic dry cough and ACEi-induced cough, and a multi-trait GWAS of both phenotypes, utilising data from five cohort studies. Chronic dry cough was defined by questionnaire responses, and ACEi-induced cough by treatment switches or clinical diagnosis in electronic health records. We mapped putative causal genes and performed phenome-wide association studies (PheWAS) of associated variants and genetic risk scores (GRS) for these phenotypes to identify pleotropic effects.FindingsWe found seven novel genetic association signals reachingp-value <5×10-8in the multi-trait or single-trait analyses of chronic dry cough and ACEi-induced cough. The novel variants mapped to 10 novel genes, and we mapped an additional three novel genes to known risk variants, many of which implicating neurological functions (CTNNA1,KCNA10,MAPKAP1,OR4C12,OR4C13,SIL1). The GRS-PheWAS highlighted associations with increased risk of several conditions reported as comorbidities of chronic cough, including fibromyalgia pain, and with spirometry measurements.InterpretationOur findings advance the understanding of neuronal dysfunction underlying cough hypersensitivity in chronic dry cough and ACEi-induced cough at the population-level, and the identification of comorbidities associated with genetic predisposition to cough could inform drug target discovery.FundingMedical Research Council, Wellcome Trust, National Institute for Health and Care Research, Orion Pharma.

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Section: Discussionmentioning

confidence: 99%

Genomics of chronic cough unravels neurological pathways

Coley,

John,

Ghouse

et al. 2024

Preprint

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“…Macaque snRNA-seq: The filtered digital gene expression matrices were then loaded into Scanpy to perform the pre-clustering needed for Scran normalization 23,25 . Each biological replicate expression count matrix was then normalized with log counts per million (CPM), and denoised using iterative pca with 50 components.…”

Section: Methodsmentioning

confidence: 99%

“…We identified the top 100 most enriched and most-depleted makers for each of the mouse cell classes (Excitatory, Inhibitory, and MidVentral). Mouse and macaque markers for comparison were selected using the Wilcoxon rank sum approach in the rank_genes_groups() function 25 . The relative levels of those markers, weighted by their cluster enrichment scores, created a score that we could use to annotate each cell in the macaque population for each of the major cell classes.…”

Section: Methodsmentioning

confidence: 99%

“…Without direct measures of cell-type-specific regulatory regions, genetic analyses are limited to annotations via marker genes, bulk epigenomic measures, or expression quantitative trait loci (eQTLs), which are loci associated with changes in gene expression, an indirect measure of gene regulation. Notably, two recent analyses based on gene expression and eQTLs of chronic pain GWAS found no significant enrichment in bulk spinal cord RNA-seq 25,26 .…”

Section: Introductionmentioning

confidence: 98%

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Spatial, transcriptomic and epigenomic analyses link dorsal horn neurons to chronic pain genetic predisposition

Arokiaraj

Kleyman

Chamessian

et al. 2022

Preprint

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SummaryThe spinal dorsal horn transforms incoming somatosensory information and transmits it supraspinally to generate modality-specific sensory percepts. The lack of an established framework for the molecular and cellular organization of the dorsal horn across species has greatly hampered delineating precisely how this region processes somatosensory information, including pain. Furthermore, the translation potential of the rodent work is unclear without data from higher order species. To fill these gaps, we performed single nucleus RNA-sequencing of Rhesus macaque dorsal horn and compared the results to a recently reported meta-analysis of mouse. Because dorsal horn laminae serve as a key organizing principle for function, we also determined the laminar location of each identified cell type. The work provides a comprehensive cross-species cellular and molecular database that will be critical for decoding the logic of dorsal horn somatosensory circuits and validating preclinical targets.

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A genome‐wide association study of European advanced cancer patients treated with opioids identifies regulatory variants on chromosome 20 associated with pain intensity

Minnai,

Shkodra,

Noci

et al. 2024

European Journal of Pain

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BackgroundOpioids in step III of the WHO analgesic ladder are the standard of care for treating cancer pain. However, a significant minority of patients do not benefit from therapy. Genetics might play a role in predisposing patients to a good or poor response to opioids. Here, we investigated this issue by conducting a genome‐wide association study (GWAS).MethodsWe genotyped 2057 European advanced cancer patients treated with morphine, buprenorphine, fentanyl and oxycodone. We carried out a whole‐genome regression model (using REGENIE software) between genotypes and the opioid response phenotype, defined as a numerical score measuring patient pain intensity.ResultsThe GWAS identified five non‐coding variants on chromosome 20 with a p‐value <5.0 × 10−8. For all of them, the minor allele was associated with lower pain intensity. These variants were intronic to the PCMTD2 gene and were 200 kbp downstream of OPRL1, the opioid related nociceptin receptor 1. Notably according to the eQTLGen database, these variants act as expression quantitative trait loci, modulating the expression mainly of PCMTD2 but also of OPRL1. Variants in the same chromosomal region were recently reported to be significantly associated with pain intensity in a GWAS conducted in subjects with different chronic pain conditions.ConclusionsOur results support the role of genetics in the opioid response in advanced cancer patients. Further functional analyses are needed to understand the biological mechanism underlying the observed association and lead to the development of individualized pain treatment plans, ultimately improving the quality of life for cancer patients.Significance StatementThis genome‐wide association study on European advanced cancer patients treated with opioids identifies novel regulatory variants on chromosome 20 (near PCMTD2 and OPRL1 genes) associated with pain intensity. These findings enhance our understanding of the genetic basis of opioid response, suggesting new potential markers for opioid efficacy. The study is a significant advancement in pharmacogenomics, providing a robust dataset and new insights into the genetic factors influencing pain intensity, which could lead to personalized cancer pain management.

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A multi-ancestry genetic study of pain intensity in 598,339 veterans

Cited by 11 publications

References 109 publications

Genomics of chronic cough unravels neurological pathways

Genomics of chronic cough unravels neurological pathways

Spatial, transcriptomic and epigenomic analyses link dorsal horn neurons to chronic pain genetic predisposition

A genome‐wide association study of European advanced cancer patients treated with opioids identifies regulatory variants on chromosome 20 associated with pain intensity

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