Genetic mapping in Diversity Outbred mice identifies a Trpa1 variant influencing late-phase formalin response.
Document Type
Article
Publication Date
8-2019
Keywords
JMG
JAX Location
Reprint Collection
JAX Source
Pain 2019 Aug; 160(8):1740-1753
Volume
160
Issue
8
First Page
1740
Last Page
1753
ISSN
1872-6623
PMID
31335644
DOI
https://doi.org/10.1097/j.pain.0000000000001571
Grant
DOD grant W81XWH-11-1-0762,DA37927,AA18776,CA034196
Abstract
Identification of genetic variants that influence susceptibility to pain is key to identifying molecular mechanisms and targets for effective and safe therapeutic alternatives to opioids. To identify genes and variants associated with persistent pain, we measured late-phase response to formalin injection in 275 male and female Diversity Outbred mice genotyped for over 70,000 single nucleotide polymorphisms. One quantitative trait locus reached genome-wide significance on chromosome 1 with a support interval of 3.1 Mb. This locus, Nociq4 (nociceptive sensitivity quantitative trait locus 4; MGI: 5661503), harbors the well-known pain gene Trpa1 (transient receptor potential cation channel, subfamily A, member 1). Trpa1 is a cation channel known to play an important role in acute and chronic pain in both humans and mice. Analysis of Diversity Outbred founder strain allele effects revealed a significant effect of the CAST/EiJ allele at Trpa1, with CAST/EiJ carrier mice showing an early, but not late, response to formalin relative to carriers of the 7 other inbred founder alleles (A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HlLtJ, PWK/PhJ, and WSB/EiJ). We characterized possible functional consequences of sequence variants in Trpa1 by assessing channel conductance, TRPA1-TRPV1 interactions, and isoform expression. The phenotypic differences observed in CAST/EiJ relative to C57BL/6J carriers were best explained by Trpa1 isoform expression differences, implicating a splice junction variant as the causal functional variant. This study demonstrates the utility of advanced, high-precision genetic mapping populations in resolving specific molecular mechanisms of variation in pain sensitivity.
Recommended Citation
Recla JM,
Bubier JA,
Gatti D,
Ryan J,
Long K,
Robledo RF,
Glidden N,
Hou G,
Churchill G,
Maser RS,
Zhang Z,
Young E,
Chesler E,
Bult C.
Genetic mapping in Diversity Outbred mice identifies a Trpa1 variant influencing late-phase formalin response. Pain 2019 Aug; 160(8):1740-1753
Comments
We gratefully acknowledge The Jackson Laboratory (JAX) Scientific Services supported by NIH P30 CA034196, as well as the technical efforts of Andrew Garrett and Robert Burgess (JAX) for their work on HEK cell transfections.