Arw^C57BL/6J
QTL Variant Detail

Summary

• QTL variant: Arw^C57BL/6J
• Name: analgesic response to WIN55,212-2; C57BL/6J
• MGI ID: MGI:3777143
• QTL: Arw Location: unknown Genetic Position: Chr7, Syntenic

Variant origin

• Strain of Specimen: C57BL/6J

Variant description

• Allele Type: QTL

Notes

Mapping and Phenotype information for this QTL, its variants and associated markers

J:132291

Linkage analysis was performed on 872 animals from a (C57BL/6J x 129P3/J)F2 intercross to identify QTLs associated with analgesic sensitivity. Groups of approximately 280 to 298 mice were tested for sensitivity to clonidine, morphine, or WIN55,212-2. Thermal nociception was assessed by lowering the tail into a hot water bath and measuring the time of reflexive withdrawal. Parental strain 129P3/J displays sensitivity the effects of analgesic substances on thermal nociception whereas parental strain C57BL/6J is relatively resistant. Genome scan was performed using 100 microsatellite markers at a 15.6 cM resolution.

Significant linkage to analgesic drug response mapped to mouse Chromosome 1. Linkage to clonidine analgesia peaked at 100 cM with LOD=4.7. Formorphine analgesia, linkage peaked at 91 cM with LOD=3.2, and linkage to WIN55,212-2 analgesia peaked at 100 cM with LOD=4.4. This locus is named Manr1 (multiple analgesic response 1) and spans 75 cM to 110 cM. C57BL/6J-derived alleles at Manr1 confer sensitivity to drug-induced analgesia whereas the 129P3/J-derived allele confers resistance. This effect is opposite to what is observed in the parental phenotype. Haplotype analysis of the Manr1 region identified Kcnj9 (94.2 cM) and Kcnj10 (93.5 cM) as potential candidate genes. The 1.2 Mb haplotype block of C57BL/6J containing Kcnj9 and Kcnj10 is distinct from that of 129P3/J. Both genes are differentially expressed in the midbrain periaqueductal gray region (PAG) of C57BL/6J and 129P3J. Kcnj9 displays 3-fold higher expression in 129P3/J midbrain PAG compared to C57BL/6J, and Kcnj10 also displays higher expression in 129P3/J although to a lesser extent. In addition, Kcnj9 knockout animals displayed decreased analgesic response to clonidine and WIN55,212-2 compared to wild type C57BL/6J animals.

Significant linkage to WIN55,212-2 analgesic response mapped to mouse Chromosome 7 with LOD=4.8 at 40 cM. This locus is named Arw (analgesic response to WIN55,212) The QTL interval spans 34 cM to 62 cM.

Significant linkage to thermal nociception in male animals was detected on mouse Chromosomes 4, 7, and 11. However, these QTL will be described in a future publication.

References

• Original: J:132291 Smith SB, et al., Quantitative trait locus and computational mapping identifies Kcnj9 (GIRK3) as a candidate gene affecting analgesia from multiple drug classes. Pharmacogenet Genomics. 2008 Mar;18(3):231-41
• All: 1 reference(s)