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

AbstractWe mapped high-precision time-series data (15 min bins for 3 hours) generated for ~ 700 adult BXD mice across 105 morphine- and naloxone-related traits using new sequence-derived marker maps and a linear-mixed model. We confirm a previously mapped sex-independent effect of initial locomotor responses to morphine (50 mg/kg ip) that maps precisely toOprm1on chromosome (Chr) 10, with the linkage score reaching −log10P of ~12.4 (with a high B allele) at 75 min and exhausted by 160 min. We detected a new modulator of opiate locomotor activation in both sexes on Chr 16, with a peak linkage that climbs from 105 through to 180 min after injection. This locus includes one compelling candidate—fibroblast growth factor 12 (Fgf12). We also detected a strong, but transient epistatic interaction between these two loci. Single nuclei transcriptomic analyses in rats demonstrates that expression ofOprm1andFgf12mRNA covary in one specific subtype ofDrd1medium spiny neurons. Our Bayesian network analysis identified that a cascade of MAP kinases—Mapk8ip2, Map3k11, andMap3k12—are part of theOprm1–Fgf12network. This is the first demonstration of a time-dependent epistatic interaction modulating drug response in mammals with interesting mechanistic implications. Analysis ofOPRM1andFGF12gene networks in human GWAS data highlights enrichment of signals associated with substance use disorder.