Advertisement

ResearchIn-Press PreviewCell biologyGeneticsNeuroscience Open Access | 10.1172/JCI197583

The cell-type-specific genetic architecture of chronic pain in brain and dorsal root ganglia

Sylvanus Toikumo,1 Marc Parisien,2 Michael J. Leone,3 Chaitanya Srinivasan,3 Huasheng Yu,4 Asta Arendt-Tranholm,5 Úrzula Franco-Enzástiga,5 Christoph Hofstetter,6 Michele Curatolo,7 Wenqin Luo,4 Andreas R. Pfenning,3 Rebecca P. Seal,8 Rachel L. Kember,1 Theodore J. Price,5 Luda Diatchenko,2 Stephen G. Waxman,10 and Henry R. Kranzler1

1Center for Studies of Addiction, University of Pennsylvania, Philadelphia, United States of America

2The Alan Edwards Center for Research on Pain, McGill University, Montreal, Canada

3Department of Computational Biology, Carnegie Mellon University, Pittsburgh, United States of America

4Department of Neuroscience, University of Pennsylvania, Philadelphia, United States of America

5Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, United States of America

6Department of Neurological Surgery, University of Washington, Seattle, United States of America

7Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, United States of America

8Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

9Center for Advanced Pain Studies, University of Texas at Dallas, Dallas, United States of America

10Department of Neurology, Yale University, New Haven, United States of America

Find articles by Toikumo, S. in: PubMed | Google Scholar

1Center for Studies of Addiction, University of Pennsylvania, Philadelphia, United States of America

2The Alan Edwards Center for Research on Pain, McGill University, Montreal, Canada

3Department of Computational Biology, Carnegie Mellon University, Pittsburgh, United States of America

4Department of Neuroscience, University of Pennsylvania, Philadelphia, United States of America

5Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, United States of America

6Department of Neurological Surgery, University of Washington, Seattle, United States of America

7Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, United States of America

8Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

9Center for Advanced Pain Studies, University of Texas at Dallas, Dallas, United States of America

10Department of Neurology, Yale University, New Haven, United States of America

Find articles by Parisien, M. in: PubMed | Google Scholar |

1Center for Studies of Addiction, University of Pennsylvania, Philadelphia, United States of America

2The Alan Edwards Center for Research on Pain, McGill University, Montreal, Canada

3Department of Computational Biology, Carnegie Mellon University, Pittsburgh, United States of America

4Department of Neuroscience, University of Pennsylvania, Philadelphia, United States of America

5Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, United States of America

6Department of Neurological Surgery, University of Washington, Seattle, United States of America

7Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, United States of America

8Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

9Center for Advanced Pain Studies, University of Texas at Dallas, Dallas, United States of America

10Department of Neurology, Yale University, New Haven, United States of America

Find articles by Leone, M. in: PubMed | Google Scholar

1Center for Studies of Addiction, University of Pennsylvania, Philadelphia, United States of America

2The Alan Edwards Center for Research on Pain, McGill University, Montreal, Canada

3Department of Computational Biology, Carnegie Mellon University, Pittsburgh, United States of America

4Department of Neuroscience, University of Pennsylvania, Philadelphia, United States of America

5Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, United States of America

6Department of Neurological Surgery, University of Washington, Seattle, United States of America

7Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, United States of America

8Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

9Center for Advanced Pain Studies, University of Texas at Dallas, Dallas, United States of America

10Department of Neurology, Yale University, New Haven, United States of America

Find articles by Srinivasan, C. in: PubMed | Google Scholar

1Center for Studies of Addiction, University of Pennsylvania, Philadelphia, United States of America

2The Alan Edwards Center for Research on Pain, McGill University, Montreal, Canada

3Department of Computational Biology, Carnegie Mellon University, Pittsburgh, United States of America

4Department of Neuroscience, University of Pennsylvania, Philadelphia, United States of America

5Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, United States of America

6Department of Neurological Surgery, University of Washington, Seattle, United States of America

7Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, United States of America

8Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

9Center for Advanced Pain Studies, University of Texas at Dallas, Dallas, United States of America

10Department of Neurology, Yale University, New Haven, United States of America

Find articles by Yu, H. in: PubMed | Google Scholar

1Center for Studies of Addiction, University of Pennsylvania, Philadelphia, United States of America

2The Alan Edwards Center for Research on Pain, McGill University, Montreal, Canada

3Department of Computational Biology, Carnegie Mellon University, Pittsburgh, United States of America

4Department of Neuroscience, University of Pennsylvania, Philadelphia, United States of America

5Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, United States of America

6Department of Neurological Surgery, University of Washington, Seattle, United States of America

7Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, United States of America

8Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

9Center for Advanced Pain Studies, University of Texas at Dallas, Dallas, United States of America

10Department of Neurology, Yale University, New Haven, United States of America

Find articles by Arendt-Tranholm, A. in: PubMed | Google Scholar

1Center for Studies of Addiction, University of Pennsylvania, Philadelphia, United States of America

2The Alan Edwards Center for Research on Pain, McGill University, Montreal, Canada

3Department of Computational Biology, Carnegie Mellon University, Pittsburgh, United States of America

4Department of Neuroscience, University of Pennsylvania, Philadelphia, United States of America

5Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, United States of America

6Department of Neurological Surgery, University of Washington, Seattle, United States of America

7Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, United States of America

8Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

9Center for Advanced Pain Studies, University of Texas at Dallas, Dallas, United States of America

10Department of Neurology, Yale University, New Haven, United States of America

Find articles by Franco-Enzástiga, Ú. in: PubMed | Google Scholar

1Center for Studies of Addiction, University of Pennsylvania, Philadelphia, United States of America

2The Alan Edwards Center for Research on Pain, McGill University, Montreal, Canada

3Department of Computational Biology, Carnegie Mellon University, Pittsburgh, United States of America

4Department of Neuroscience, University of Pennsylvania, Philadelphia, United States of America

5Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, United States of America

6Department of Neurological Surgery, University of Washington, Seattle, United States of America

7Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, United States of America

8Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

9Center for Advanced Pain Studies, University of Texas at Dallas, Dallas, United States of America

10Department of Neurology, Yale University, New Haven, United States of America

Find articles by Hofstetter, C. in: PubMed | Google Scholar

1Center for Studies of Addiction, University of Pennsylvania, Philadelphia, United States of America

2The Alan Edwards Center for Research on Pain, McGill University, Montreal, Canada

3Department of Computational Biology, Carnegie Mellon University, Pittsburgh, United States of America

4Department of Neuroscience, University of Pennsylvania, Philadelphia, United States of America

5Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, United States of America

6Department of Neurological Surgery, University of Washington, Seattle, United States of America

7Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, United States of America

8Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

9Center for Advanced Pain Studies, University of Texas at Dallas, Dallas, United States of America

10Department of Neurology, Yale University, New Haven, United States of America

Find articles by Curatolo, M. in: PubMed | Google Scholar

1Center for Studies of Addiction, University of Pennsylvania, Philadelphia, United States of America

2The Alan Edwards Center for Research on Pain, McGill University, Montreal, Canada

3Department of Computational Biology, Carnegie Mellon University, Pittsburgh, United States of America

4Department of Neuroscience, University of Pennsylvania, Philadelphia, United States of America

5Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, United States of America

6Department of Neurological Surgery, University of Washington, Seattle, United States of America

7Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, United States of America

8Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

9Center for Advanced Pain Studies, University of Texas at Dallas, Dallas, United States of America

10Department of Neurology, Yale University, New Haven, United States of America

Find articles by Luo, W. in: PubMed | Google Scholar

1Center for Studies of Addiction, University of Pennsylvania, Philadelphia, United States of America

2The Alan Edwards Center for Research on Pain, McGill University, Montreal, Canada

3Department of Computational Biology, Carnegie Mellon University, Pittsburgh, United States of America

4Department of Neuroscience, University of Pennsylvania, Philadelphia, United States of America

5Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, United States of America

6Department of Neurological Surgery, University of Washington, Seattle, United States of America

7Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, United States of America

8Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

9Center for Advanced Pain Studies, University of Texas at Dallas, Dallas, United States of America

10Department of Neurology, Yale University, New Haven, United States of America

Find articles by Pfenning, A. in: PubMed | Google Scholar

1Center for Studies of Addiction, University of Pennsylvania, Philadelphia, United States of America

2The Alan Edwards Center for Research on Pain, McGill University, Montreal, Canada

3Department of Computational Biology, Carnegie Mellon University, Pittsburgh, United States of America

4Department of Neuroscience, University of Pennsylvania, Philadelphia, United States of America

5Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, United States of America

6Department of Neurological Surgery, University of Washington, Seattle, United States of America

7Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, United States of America

8Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

9Center for Advanced Pain Studies, University of Texas at Dallas, Dallas, United States of America

10Department of Neurology, Yale University, New Haven, United States of America

Find articles by Seal, R. in: PubMed | Google Scholar

1Center for Studies of Addiction, University of Pennsylvania, Philadelphia, United States of America

2The Alan Edwards Center for Research on Pain, McGill University, Montreal, Canada

3Department of Computational Biology, Carnegie Mellon University, Pittsburgh, United States of America

4Department of Neuroscience, University of Pennsylvania, Philadelphia, United States of America

5Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, United States of America

6Department of Neurological Surgery, University of Washington, Seattle, United States of America

7Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, United States of America

8Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

9Center for Advanced Pain Studies, University of Texas at Dallas, Dallas, United States of America

10Department of Neurology, Yale University, New Haven, United States of America

Find articles by Kember, R. in: PubMed | Google Scholar |

1Center for Studies of Addiction, University of Pennsylvania, Philadelphia, United States of America

2The Alan Edwards Center for Research on Pain, McGill University, Montreal, Canada

3Department of Computational Biology, Carnegie Mellon University, Pittsburgh, United States of America

4Department of Neuroscience, University of Pennsylvania, Philadelphia, United States of America

5Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, United States of America

6Department of Neurological Surgery, University of Washington, Seattle, United States of America

7Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, United States of America

8Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

9Center for Advanced Pain Studies, University of Texas at Dallas, Dallas, United States of America

10Department of Neurology, Yale University, New Haven, United States of America

Find articles by Price, T. in: PubMed | Google Scholar |

1Center for Studies of Addiction, University of Pennsylvania, Philadelphia, United States of America

2The Alan Edwards Center for Research on Pain, McGill University, Montreal, Canada

3Department of Computational Biology, Carnegie Mellon University, Pittsburgh, United States of America

4Department of Neuroscience, University of Pennsylvania, Philadelphia, United States of America

5Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, United States of America

6Department of Neurological Surgery, University of Washington, Seattle, United States of America

7Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, United States of America

8Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

9Center for Advanced Pain Studies, University of Texas at Dallas, Dallas, United States of America

10Department of Neurology, Yale University, New Haven, United States of America

Find articles by Diatchenko, L. in: PubMed | Google Scholar |

1Center for Studies of Addiction, University of Pennsylvania, Philadelphia, United States of America

2The Alan Edwards Center for Research on Pain, McGill University, Montreal, Canada

3Department of Computational Biology, Carnegie Mellon University, Pittsburgh, United States of America

4Department of Neuroscience, University of Pennsylvania, Philadelphia, United States of America

5Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, United States of America

6Department of Neurological Surgery, University of Washington, Seattle, United States of America

7Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, United States of America

8Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

9Center for Advanced Pain Studies, University of Texas at Dallas, Dallas, United States of America

10Department of Neurology, Yale University, New Haven, United States of America

Find articles by Waxman, S. in: PubMed | Google Scholar |

1Center for Studies of Addiction, University of Pennsylvania, Philadelphia, United States of America

2The Alan Edwards Center for Research on Pain, McGill University, Montreal, Canada

3Department of Computational Biology, Carnegie Mellon University, Pittsburgh, United States of America

4Department of Neuroscience, University of Pennsylvania, Philadelphia, United States of America

5Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, United States of America

6Department of Neurological Surgery, University of Washington, Seattle, United States of America

7Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, United States of America

8Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America

9Center for Advanced Pain Studies, University of Texas at Dallas, Dallas, United States of America

10Department of Neurology, Yale University, New Haven, United States of America

Find articles by Kranzler, H. in: PubMed | Google Scholar

Published October 7, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI197583.
Copyright © 2025, Toikumo et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published October 7, 2025 - Version history
View PDF
Abstract

Chronic pain is a complex clinical problem comprising multiple conditions that may share a common genetic profile. Genome-wide association studies (GWAS) have identified many risk loci whose cell-type context remains unclear. Here, we integrated GWAS data on chronic pain (N = 1,235,695) with single-cell RNA sequencing (scRNA-seq) data from human brain and dorsal root ganglia (hDRG), and single-cell chromatin accessibility data from human brain and mouse dorsal horn. Pain-associated variants were enriched in glutamatergic neurons; mainly in prefrontal cortex, hippocampal CA1-3, and amygdala. In hDRG, the hPEP.TRPV1/A1.2 neuronal subtype showed robust enrichment. Chromatin accessibility analyses revealed variant enrichment in excitatory and inhibitory neocortical neurons in brain and in midventral neurons and oligodendrocyte precursor cells in the mouse dorsal horn. Gene-level heritability in the brain highlighted roles for kinase activity, GABAergic synapses, axon guidance, and neuron projection development. In hDRG, implicated genes related to glutamatergic signaling and neuronal projection. In cervical DRG of patients with acute or chronic pain (N = 12), scRNA-seq data from neuronal or non-neuronal cells were enriched for chronic pain-associated genes (e.g., EFNB2, GABBR1, NCAM1, SCN11A). This cell-type-specific genetic architecture of chronic pain across central and peripheral nervous system circuits provides a foundation for targeted translational research.

Graphical Abstract
graphical abstract
Supplemental material

View

View Supplemental Tables 1-19

Version history
  • Version 1 (October 7, 2025): In-Press Preview
Advertisement
Advertisement