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 4 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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Application of polygenic scores to a deeply phenotyped sample enriched for substance use disorders reveals extensive pleiotropy with psychiatric and somatic traits

Hartwell,

Jinwala,

Milone

et al. 2024

Neuropsychopharmacol.

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Co-occurring psychiatric, medical, and substance use disorders (SUDs) are common, but the complex pathways leading to such comorbidities are poorly understood. A greater understanding of genetic influences on this phenomenon could inform precision medicine efforts. We used the Yale-Penn dataset, a cross-sectional sample enriched for individuals with SUDs, to examine pleiotropic effects of genetic liability for psychiatric and somatic traits. Participants completed an in-depth interview that provides information on demographics, environment, medical illnesses, and psychiatric and SUDs. Polygenic scores (PGS) for psychiatric disorders and somatic traits were calculated in European-ancestry (EUR; n = 5691) participants and, when discovery datasets were available, for African-ancestry (AFR; n = 4918) participants. Phenome-wide association studies (PheWAS) were then conducted. In AFR participants, the only PGS with significant associations was bipolar disorder (BD), all of which were with substance use phenotypes. In EUR participants, PGS for major depressive disorder (MDD), generalized anxiety disorder (GAD), post-traumatic stress disorder (PTSD), schizophrenia (SCZ), body mass index (BMI), coronary artery disease (CAD), and type 2 diabetes (T2D) all showed significant associations, the majority of which were with phenotypes in the substance use categories. For instance, PGSMDD was associated with over 200 phenotypes, 15 of which were depression-related (e.g., depression criterion count), 55 of which were other psychiatric phenotypes, and 126 of which were substance use phenotypes; and PGSBMI was associated with 138 phenotypes, 105 of which were substance related. Genetic liability for psychiatric and somatic traits is associated with numerous phenotypes across multiple categories, indicative of the broad genetic liability of these traits.

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

Cited by 4 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

Application of polygenic scores to a deeply phenotyped sample enriched for substance use disorders reveals extensive pleiotropy with psychiatric and somatic traits

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