The cell-type–specific genetic architecture of chronic pain in brain and dorsal root ganglia
Sylvanus Toikumo, Marc Parisien, Michael J. Leone, Chaitanya Srinivasan, Huasheng Yu, Asta Arendt-Tranholm, Úrzula Franco-Enzástiga, Christoph Hofstetter, Michele Curatolo, Wenqin Luo, Andreas R. Pfenning, Rebecca P. Seal, Rachel L. Kember, Theodore J. Price, Luda Diatchenko, Stephen G. Waxman, Henry R. Kranzler
Sylvanus Toikumo, Marc Parisien, Michael J. Leone, Chaitanya Srinivasan, Huasheng Yu, Asta Arendt-Tranholm, Úrzula Franco-Enzástiga, Christoph Hofstetter, Michele Curatolo, Wenqin Luo, Andreas R. Pfenning, Rebecca P. Seal, Rachel L. Kember, Theodore J. Price, Luda Diatchenko, Stephen G. Waxman, Henry R. Kranzler
View: Text | PDF
Research Article Cell biology Genetics Neuroscience

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

Abstract

Chronic pain is a complex clinical problem comprising multiple conditions that may share a common genetic profile. GWAS have identified many risk loci whose cell-type context remains unclear. Here, we integrated GWAS data on chronic pain with single-cell RNA-Seq (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 the 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 the 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 were related to glutamatergic signaling and neuronal projection. In cervical DRG of patients with acute versus chronic pain, 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 PNS circuits provides a foundation for targeted translational research.

Authors

Sylvanus Toikumo, Marc Parisien, Michael J. Leone, Chaitanya Srinivasan, Huasheng Yu, Asta Arendt-Tranholm, Úrzula Franco-Enzástiga, Christoph Hofstetter, Michele Curatolo, Wenqin Luo, Andreas R. Pfenning, Rebecca P. Seal, Rachel L. Kember, Theodore J. Price, Luda Diatchenko, Stephen G. Waxman, Henry R. Kranzler

×

Figure 2

Cell-type enrichments for chronic pain.

Options: View larger image (or click on image) Download as PowerPoint
Cell-type enrichments for chronic pain. Cell-type numbers are denoted on...
Cell-type numbers are denoted on the x axis, and statistical significance is shown on the y axis [–log10(P)]. (A) The significantly enriched cell types for chronic pain (n = 91, FDR P < 0.05) among 461 human brain cell clusters. Each cell type is colored according to its supercluster, and cell types are grouped into GABAergic (n = 15) or glutamatergic (n = 76) on the basis of their neurotransmitter annotation. See Supplemental Table 1 for full results. (B) Human single-soma DRG cell-type enrichment. (C) Human brain open chromatin cell-type enrichment. (D) Mouse dorsal horn open chromatin enrichment. Cell-type enrichments denoted by red in B–D are significantly enriched for chronic pain (FDR-corrected P < 0.05).