Opiate responses are controlled by interactions ofOprm1andFgf12loci in rodents: Correspondence to human GWAS findings

Abstract

We analyzed time dependent behavioral responses to morphine and naloxone obtained from a large family of young adult BXD mice (n = 70 strains, including C57BL/6J and DBA/2J parents, 4 to 9 cases per strain) using the latest whole genome sequencing (WGS)-based genetic markers. These data include quantitative locomotor and behavior responses measured three hours after an acute morphine injection (50 mg/kg i.p.), followed by naloxone-induced withdrawal, obtained by Philip et al (2010). Locomotor data were analyzed in 15 min bins and mapped jointly for both sexes or independently for males and females. We confirmed a highly significant association between locomotor response and a genomic region that overlaps with Oprm1 on Chr 10 at 6.8 Mb (LOD maximum of 11.4) between 15-105 min, with a peak at 75 min. Effects were modestly dependent of sex. Strains that were B homozygotes run 76 meters farther than those that are D homozygotes after a morphine injection. We discovered a novel association between a locus on Chr 16 and a late phase locomotor response (after 150 min) in both sexes. This locus had a significant but transient epistatic interaction with the Oprm1 locus between 45-90 min, well before the main effect was detectable. The Chr 16 locus includes one compelling candidate fibroblast growth factor 12 (Fgf12). Null mutation of Fgf12 has been shown to cause locomotor deficits (e.g., ataxia) in mice. Analysis of genes correlated with both OPRM1 and FGF12 in six human brain regions (GTEx, v8) demonstrated an enrichment of genetic signals associated with SUD phenotypes, and a modest corroboration of variants in the FGF12 loci on Chr 3q28. To the best of our knowledge this is the first demonstration of a transient time dependent epistatic interaction modulating drug response in mammals; a finding with interesting mechanistic implications. Finally, this work demonstrates how high-quality FAIR+ data can be used with newly acquired data sets to yield striking results, and how joint mouse and human neurogenomic and mapping data can be merged at gene and network levels for bidirectional validation of potential SUD variants and molecular networks.

A revamped rat reference genome improves the discovery of genetic diversity in laboratory rats

“… 16 While all these data were analyzed using previous versions of the reference genome, reanalyzing them using updated genomic data could lead to novel discoveries. 58 …”

A revamped rat reference genome improves the discovery of genetic diversity in laboratory rats

“…16 While all these data were analyzed using previous versions of the reference genome, reanalysing them using updated genomic data could lead to novel discoveries. 63 By generating F 1 hybrids from these inbred lines with sequenced genomes, novel phenotypes can be mapped onto completely defined genomes: the 82 sequenced HRDP strains can produce any of 6,642 isogenic but entirely replicable F 1 hybrids with completely defined genomes. Studies of these "sequenced" F 1 hybrids avoid the homozygosity of the parental HRDP strains and enable a new phase of genome-phenome mapping and prediction.…”

“…16 While all these data were analyzed using previous versions of the reference genome, reanalysing them using updated genomic data could lead to novel discoveries. 63…”