The Effects of Socioeconomic Position on Endogenous Pain Modulation: A Quasi-Experimental Approach

Journal of Pain, Год журнала: 2025, Номер unknown, С. 104778 - 104778

Опубликована: Янв. 1, 2025

Язык: Английский

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Decomposing the genetic background of chronic back pain

Human Molecular Genetics, Год журнала: 2025, Номер unknown

Опубликована: Фев. 3, 2025

Chronic back pain (CBP) is a disabling condition with lifetime prevalence of 40% and substantial socioeconomic burden. Because the high heterogeneity CBP, subphenotyping may help to improve prediction support personalized treatment CBP. To investigate CBP subphenotypes, we decomposed its genetic background into shared one common other chronic conditions (back, neck, hip, knee, stomach, head pain) unshared specific We identified replicated 18 genes impact across different two that were for Among people demonstrated polygenic risk scores accounting backgrounds underpin subphenotypes. These subphenotypes are characterized by varying predisposition diverse medical interventions such as diabetes mellitus, myocardial infarction, diagnostic endoscopic procedures, surgery involving muscles, bones, joints.

Язык: Английский

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Integrating HiTOP and RDoC Frameworks Part II: Shared and Distinct Biological Mechanisms of Externalizing and Internalizing Psychopathology

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 6, 2025

Abstract Background The Hierarchical Taxonomy of Psychopathology (HiTOP) and Research Domain Criteria (RDoC) frameworks emphasize transdiagnostic mechanistic aspects psychopathology, respectively. We used a multi-omics approach to examine how externalizing (EXT), internalizing (INT), shared EXT+INT liability map onto these models. Methods conducted analyses across five RDoC units analysis: genes, molecules, cells, circuits, physiology. Using genome-wide association studies from the companion Part I article, we identified genes tissue-specific expression patterns. drug repurposing that integrate gene annotations identify potential therapeutic targets single-cell RNA sequencing data implicate brain cell types. then magnetic resonance imaging regions circuits associated with each psychopathology spectrum. Finally, tested causal relationships between spectrum physical health conditions. Results identification methods, EXT was 1,759 INT 454 1,138 genes. Drug targets, including those affect dopamine serotonin pathways. Expression enriched in GABAergic, cortical, hippocampal neurons, while were more narrowly linked GABAergic neurons. reduced gray matter volume amygdala subcallosal cortex. Mendelian randomization, showed stronger effects on health—including chronic pain cardiovascular diseases—than EXT. Conclusions Our findings revealed distinct pathways underlying psychopathology. Integrating genomic insights HiTOP advanced our understanding mechanisms underlie

Язык: Английский

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Gene discovery and pleiotropic architecture of Chronic Pain in a Genome-wide Association Study of >1.2 million Individuals

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 5, 2025

ABSTRACT Chronic pain is highly prevalent worldwide, and genome-wide association studies (GWAS) have identified a growing number of chronic loci. To further elucidate its genetic architecture, we leveraged data from 1,235,695 European ancestry individuals across three biobanks. In meta-analytic GWAS, 343 independent loci for pain, 92 which were new. Sex-specific meta-analyses revealed 115 (12 new) males (N = 583,066) 12 (two females 241,266). Multi-omics gene prioritization analyses highlighted 490 genes associated with through their effects on brain- blood-specific regulation. Loci increased risk also multiple other traits, Mendelian randomization showing that was causally psychiatric disorders, substance use C-reactive protein levels. variants exhibited pleiotropic associations cortical area brain structures. This study expands our knowledge the genetics pathogenesis, highlighting importance pleiotropy disorders elucidating multi-omic pathophysiology.

Язык: Английский

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

Cell Reports, Год журнала: 2024, Номер 43(11), С. 114876 - 114876

Опубликована: Окт. 24, 2024

Язык: Английский

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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

Neuropsychopharmacology, Год журнала: 2024, Номер 49(13), С. 1958 - 1967

Опубликована: Июль 23, 2024

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

Язык: Английский

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Multivariate, Multi-omic Analysis in 799,429 Individuals Identifies 134 Loci Associated with Somatoform Traits

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 29, 2024

Abstract Somatoform traits, which manifest as persistent physical symptoms without a clear medical cause, are prevalent and pose challenges to clinical practice. Understanding the genetic basis of these disorders could improve diagnostic therapeutic approaches. With publicly available summary statistics, we conducted multivariate genome-wide association study (GWAS) multi-omic analysis four somatoform traits—fatigue, irritable bowel syndrome, pain intensity, health satisfaction—in 799,429 individuals genetically similar Europeans. Using genomic structural equation modeling, GWAS identified 134 loci significantly associated with common factor, including 44 not significant in input 8 novel for traits. Gene-property analyses highlighted an enrichment genes involved synaptic transmission enriched gene expression 12 brain tissues. Six genes, members CD300 family, had putatively causal effects mediated by protein abundance. There was substantial polygenic overlap (76-83%) between externalizing, internalizing, general psychopathology factors. scores were most strongly obesity, Type 2 diabetes, tobacco use disorder, mood/anxiety independent biobanks. Drug repurposing suggested potential targets, MEK inhibitors. Mendelian randomization indicated potentially protective gut microbiota, Ruminococcus bromii . These biological insights provide promising avenues treatment development.

Язык: Английский

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Role of the Dorsal Raphe Nucleus in Pain Processing

Brain Sciences, Год журнала: 2024, Номер 14(10), С. 982 - 982

Опубликована: Сен. 28, 2024

The dorsal raphe nucleus (DRN) has gained attention owing to its involvement in various physiological functions, such as sleep–awake, feeding, and emotion, with analgesic role being particularly significant. It is described the “pain inhibitory nucleus” brain. DRN diverse projections from hypothalamus, midbrain, pons. In turn, a major source of cortex, limbic forebrain thalamus, midbrain contains highly heterogeneous neuronal subtypes. activation neurons mice prevents establishment neuropathic, chronic pain symptoms. Chemogenetic or optogenetic inhibition are sufficient establish phenotypes, including long-lasting tactile allodynia, that scale extent stimulation, thereby promoting nociplastic pain. Recent progress been made identifying neural circuits cellular mechanisms responsible for sensory modulation. However, there still lack comprehensive review addressing specific neuron types involved This summarizes function cell within regulation, aims improve understanding underlying regulation DRN, ultimately offering insights further exploration.

Язык: Английский

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It all began in Issaquah 50 years ago

Pain, Год журнала: 2024, Номер 165(11S), С. S3 - S14

Опубликована: Окт. 14, 2024

Abstract “Somehow scientists still pursue the same questions, if now on higher levels of theoretical abstraction rooted in deeper layers empirical evidence… To paraphrase an old philosophy joke, science is more like it today than has ever been. In other words, remains as challenging to human inquiry. And need communicate its progress… essential then.” — Tom Siegfried, Science News 2021 fact, questions about pain have not changed since IASP's creation Issaquah: what causes and how can we treat it? Are any closer answering these or just widened gap between bench bedside? The technology used answer mechanisms certainly changed, whether focus sensory neurons, spinal cord circuitry, descending controls cortical processing. this paper, will describe transgenics, transcriptomics, optogenetics, calcium imaging, fMRI, neuroimmunology silico drug development transformed way examine complexity But does all, our founders hoped, help people with pain? voltage-gated Na channels new holy grail for analgesic development, there a biomarker, completely replace opioids, proteomic analyses identify novel targets, “pain matrix,” be targeted? Do answers lie tangible discoveries, seemingly intangible? Our could barely imagine know now, yet their remain.

Язык: Английский

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Cellular and Molecular Organization of the Rhesus Macaque Dorsal Horn with Comparison to Mouse

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2022, Номер unknown

Опубликована: Апрель 5, 2022

Summary Key mechanisms underlying chronic pain occur within the neural circuitry of dorsal horn. Recent genome-wide association studies (GWAS) have identified genetic variants associated with predisposition to pain. However, most these lie in regulatory non-coding regions that so far not been linked spinal cord function. Here, we take a multi-species approach determine whether impact elements horn neurons. We first built more comprehensive single cell atlas; filling gaps by generating high-quality Rhesus macaque atlas and integrating it human mouse. With cellular-resolution spatial transcriptomics, mapped laminar distributions resulting species-conserved neuron subtypes, uncovering an unexpected organization. Lastly, generated mouse single-nucleus open chromatin partition heritability traits. From this, strong, selective associations between specific, conserved subtypes major forms

Язык: Английский

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