Opiate responses are controlled by interactions of Oprm1 and Fgf12 loci in the murine BXD family: Correspondence to human GWAS findings

We analyzed time-dependent behavioral responses to morphine and naloxone obtained from a large family of young adult BXD mice (n = 63–64 strains, including C57BL/6J and DBA/2J parents, n = 4–9/strain) using new whole genome sequencing (WGS)-based genetic markers. Opiate behavioral data include locomotor and behavior responses measured over a four hour period in 15 min bins after an acute morphine injection (50 mg/kg i.p.), followed by naloxone-induced withdrawal (see Philip et al. (2010). Sexes were mapped jointly and independently for males and females using 20,000 markers and linear mixed models that account for kinship structure. We confirmed a highly significant association between locomotor response and a genomic region that overlaps Oprm1 on Chr 10 at 6.8 Mb (LOD of 11.4) 15 to 105 min after injection, with a peak at 75 min. Effects were only weakly dependent of sex. Strains that inherited B haplotypes ran 76 meters farther than those that inherited D haplotypes. We discovered a novel association between a locus on Chr 16 and a late-phase locomotor response 150 min after morphine in both sexes. This locus had a significant but transient epistatic interaction with Oprm1 at 45–90 min—well before its main additive 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). Single nuclei transcriptomic analysis further validated a functional epistatic relationship between Oprm1 and Fgf12, showing that their expression is correlated in a specific subtype of Drd1-expressing medium spiny neurons. Nucleus accumens core tissue punches from two female heterogenous stock rats were obtained from a tissue repository (Carrette et. al, 2021).