Systems genetic and pharmacological analysis identifies candidate genes underlying mechanosensation in the von Frey test

E. E. Young, C. D. Bryant, S. E. Lee, X. Peng, B. Cook, H. K. Nair, K. J. Dreher, X. Zhang, A. A. Palmer, Jin Chung, J. S. Mogil, E. J. Chesler, W. R. Lariviere

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Mechanical sensitivity is commonly affected in chronic pain and other neurological disorders. To discover mechanisms of individual differences in punctate mechanosensation, we performed quantitative trait locus (QTL) mapping of the response to von Frey monofilament stimulation in BXD recombinant inbred (BXD) mice. Significant loci were detected on mouse chromosome (Chr) 5 and 15, indicating the location of underlying polymorphisms that cause heritable variation in von Frey response. Convergent evidence from public gene expression data implicates candidate genes within the loci: von Frey thresholds were strongly correlated with baseline expression of Cacna2d1, Ift27 and Csnk1e in multiple brain regions of BXD strains. Systemic gabapentin and PF-670462, which target the protein products of Cacna2d1 and Csnk1e, respectively, significantly increased von Frey thresholds in a genotype-dependent manner in progenitors and BXD strains. Real-time polymerase chain reaction confirmed differential expression of Cacna2d1 and Csnk1e in multiple brain regions in progenitors and showed differential expression of Cacna2d1 and Csnk1e in the dorsal root ganglia of the progenitors and BXD strains grouped by QTL genotype. Thus, linkage mapping, transcript covariance and pharmacological testing suggest that genetic variation affecting Cacna2d1 and Csnk1e may contribute to individual differences in von Frey filament response. This study implicates Cacna2d1 and Ift27 in basal mechanosensation in line with their previously suspected role in mechanical hypersensitivity. Csnk1e is implicated for von Frey response for the first time. Further investigation is warranted to identify the specific polymorphisms involved and assess the relevance of these findings to clinical conditions of disturbed mechanosensation.

Original languageEnglish (US)
Pages (from-to)604-615
Number of pages12
JournalGenes, Brain and Behavior
Volume15
Issue number6
DOIs
StatePublished - Jul 1 2016

Fingerprint

Quantitative Trait Loci
Genetic Association Studies
Individuality
Genotype
Pharmacology
Chromosomes, Human, Pair 15
Chromosomes, Human, Pair 5
Chromosome Mapping
Brain
Spinal Ganglia
Nervous System Diseases
Chronic Pain
Real-Time Polymerase Chain Reaction
Hypersensitivity
Gene Expression
Genes
Proteins
PF-670462
gabapentin

Keywords

  • Casein kinase 1
  • linkage mapping
  • microarray
  • quantitative trait locus
  • transcript abundance
  • voltage-gated calcium channels
  • von Frey

ASJC Scopus subject areas

  • Genetics
  • Neurology
  • Behavioral Neuroscience

Cite this

Young, E. E., Bryant, C. D., Lee, S. E., Peng, X., Cook, B., Nair, H. K., ... Lariviere, W. R. (2016). Systems genetic and pharmacological analysis identifies candidate genes underlying mechanosensation in the von Frey test. Genes, Brain and Behavior, 15(6), 604-615. https://doi.org/10.1111/gbb.12302

Systems genetic and pharmacological analysis identifies candidate genes underlying mechanosensation in the von Frey test. / Young, E. E.; Bryant, C. D.; Lee, S. E.; Peng, X.; Cook, B.; Nair, H. K.; Dreher, K. J.; Zhang, X.; Palmer, A. A.; Chung, Jin; Mogil, J. S.; Chesler, E. J.; Lariviere, W. R.

In: Genes, Brain and Behavior, Vol. 15, No. 6, 01.07.2016, p. 604-615.

Research output: Contribution to journalArticle

Young, EE, Bryant, CD, Lee, SE, Peng, X, Cook, B, Nair, HK, Dreher, KJ, Zhang, X, Palmer, AA, Chung, J, Mogil, JS, Chesler, EJ & Lariviere, WR 2016, 'Systems genetic and pharmacological analysis identifies candidate genes underlying mechanosensation in the von Frey test', Genes, Brain and Behavior, vol. 15, no. 6, pp. 604-615. https://doi.org/10.1111/gbb.12302
Young, E. E. ; Bryant, C. D. ; Lee, S. E. ; Peng, X. ; Cook, B. ; Nair, H. K. ; Dreher, K. J. ; Zhang, X. ; Palmer, A. A. ; Chung, Jin ; Mogil, J. S. ; Chesler, E. J. ; Lariviere, W. R. / Systems genetic and pharmacological analysis identifies candidate genes underlying mechanosensation in the von Frey test. In: Genes, Brain and Behavior. 2016 ; Vol. 15, No. 6. pp. 604-615.
@article{ea4fe79bd7a64f279d16bdcd32d1b296,
title = "Systems genetic and pharmacological analysis identifies candidate genes underlying mechanosensation in the von Frey test",
abstract = "Mechanical sensitivity is commonly affected in chronic pain and other neurological disorders. To discover mechanisms of individual differences in punctate mechanosensation, we performed quantitative trait locus (QTL) mapping of the response to von Frey monofilament stimulation in BXD recombinant inbred (BXD) mice. Significant loci were detected on mouse chromosome (Chr) 5 and 15, indicating the location of underlying polymorphisms that cause heritable variation in von Frey response. Convergent evidence from public gene expression data implicates candidate genes within the loci: von Frey thresholds were strongly correlated with baseline expression of Cacna2d1, Ift27 and Csnk1e in multiple brain regions of BXD strains. Systemic gabapentin and PF-670462, which target the protein products of Cacna2d1 and Csnk1e, respectively, significantly increased von Frey thresholds in a genotype-dependent manner in progenitors and BXD strains. Real-time polymerase chain reaction confirmed differential expression of Cacna2d1 and Csnk1e in multiple brain regions in progenitors and showed differential expression of Cacna2d1 and Csnk1e in the dorsal root ganglia of the progenitors and BXD strains grouped by QTL genotype. Thus, linkage mapping, transcript covariance and pharmacological testing suggest that genetic variation affecting Cacna2d1 and Csnk1e may contribute to individual differences in von Frey filament response. This study implicates Cacna2d1 and Ift27 in basal mechanosensation in line with their previously suspected role in mechanical hypersensitivity. Csnk1e is implicated for von Frey response for the first time. Further investigation is warranted to identify the specific polymorphisms involved and assess the relevance of these findings to clinical conditions of disturbed mechanosensation.",
keywords = "Casein kinase 1, linkage mapping, microarray, quantitative trait locus, transcript abundance, voltage-gated calcium channels, von Frey",
author = "Young, {E. E.} and Bryant, {C. D.} and Lee, {S. E.} and X. Peng and B. Cook and Nair, {H. K.} and Dreher, {K. J.} and X. Zhang and Palmer, {A. A.} and Jin Chung and Mogil, {J. S.} and Chesler, {E. J.} and Lariviere, {W. R.}",
year = "2016",
month = "7",
day = "1",
doi = "10.1111/gbb.12302",
language = "English (US)",
volume = "15",
pages = "604--615",
journal = "Genes, Brain and Behavior",
issn = "1601-1848",
publisher = "Wiley-Blackwell",
number = "6",

}

TY - JOUR

T1 - Systems genetic and pharmacological analysis identifies candidate genes underlying mechanosensation in the von Frey test

AU - Young, E. E.

AU - Bryant, C. D.

AU - Lee, S. E.

AU - Peng, X.

AU - Cook, B.

AU - Nair, H. K.

AU - Dreher, K. J.

AU - Zhang, X.

AU - Palmer, A. A.

AU - Chung, Jin

AU - Mogil, J. S.

AU - Chesler, E. J.

AU - Lariviere, W. R.

PY - 2016/7/1

Y1 - 2016/7/1

N2 - Mechanical sensitivity is commonly affected in chronic pain and other neurological disorders. To discover mechanisms of individual differences in punctate mechanosensation, we performed quantitative trait locus (QTL) mapping of the response to von Frey monofilament stimulation in BXD recombinant inbred (BXD) mice. Significant loci were detected on mouse chromosome (Chr) 5 and 15, indicating the location of underlying polymorphisms that cause heritable variation in von Frey response. Convergent evidence from public gene expression data implicates candidate genes within the loci: von Frey thresholds were strongly correlated with baseline expression of Cacna2d1, Ift27 and Csnk1e in multiple brain regions of BXD strains. Systemic gabapentin and PF-670462, which target the protein products of Cacna2d1 and Csnk1e, respectively, significantly increased von Frey thresholds in a genotype-dependent manner in progenitors and BXD strains. Real-time polymerase chain reaction confirmed differential expression of Cacna2d1 and Csnk1e in multiple brain regions in progenitors and showed differential expression of Cacna2d1 and Csnk1e in the dorsal root ganglia of the progenitors and BXD strains grouped by QTL genotype. Thus, linkage mapping, transcript covariance and pharmacological testing suggest that genetic variation affecting Cacna2d1 and Csnk1e may contribute to individual differences in von Frey filament response. This study implicates Cacna2d1 and Ift27 in basal mechanosensation in line with their previously suspected role in mechanical hypersensitivity. Csnk1e is implicated for von Frey response for the first time. Further investigation is warranted to identify the specific polymorphisms involved and assess the relevance of these findings to clinical conditions of disturbed mechanosensation.

AB - Mechanical sensitivity is commonly affected in chronic pain and other neurological disorders. To discover mechanisms of individual differences in punctate mechanosensation, we performed quantitative trait locus (QTL) mapping of the response to von Frey monofilament stimulation in BXD recombinant inbred (BXD) mice. Significant loci were detected on mouse chromosome (Chr) 5 and 15, indicating the location of underlying polymorphisms that cause heritable variation in von Frey response. Convergent evidence from public gene expression data implicates candidate genes within the loci: von Frey thresholds were strongly correlated with baseline expression of Cacna2d1, Ift27 and Csnk1e in multiple brain regions of BXD strains. Systemic gabapentin and PF-670462, which target the protein products of Cacna2d1 and Csnk1e, respectively, significantly increased von Frey thresholds in a genotype-dependent manner in progenitors and BXD strains. Real-time polymerase chain reaction confirmed differential expression of Cacna2d1 and Csnk1e in multiple brain regions in progenitors and showed differential expression of Cacna2d1 and Csnk1e in the dorsal root ganglia of the progenitors and BXD strains grouped by QTL genotype. Thus, linkage mapping, transcript covariance and pharmacological testing suggest that genetic variation affecting Cacna2d1 and Csnk1e may contribute to individual differences in von Frey filament response. This study implicates Cacna2d1 and Ift27 in basal mechanosensation in line with their previously suspected role in mechanical hypersensitivity. Csnk1e is implicated for von Frey response for the first time. Further investigation is warranted to identify the specific polymorphisms involved and assess the relevance of these findings to clinical conditions of disturbed mechanosensation.

KW - Casein kinase 1

KW - linkage mapping

KW - microarray

KW - quantitative trait locus

KW - transcript abundance

KW - voltage-gated calcium channels

KW - von Frey

UR - http://www.scopus.com/inward/record.url?scp=84978929544&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84978929544&partnerID=8YFLogxK

U2 - 10.1111/gbb.12302

DO - 10.1111/gbb.12302

M3 - Article

VL - 15

SP - 604

EP - 615

JO - Genes, Brain and Behavior

JF - Genes, Brain and Behavior

SN - 1601-1848

IS - 6

ER -