Taar1 gene variants have a causal role in methamphetamine intake and response and interact with Oprm1

Abstract

We identified a locus on mouse chromosome 10 that accounts for 60% of the genetic variance in methamphetamine intake in mice selectively bred for high versus low methamphetamine consumption. We nominated the trace amine-associated receptor 1 gene, Taar1, as the strongest candidate and identified regulation of the mu-opioid receptor 1 gene, Oprm1, as another contributor. This study exploited CRISPR-Cas9 to test the causal role of Taar1 in methamphetamine intake and a genetically-associated thermal response to methamphetamine. The methamphetamine-related traits were rescued, converting them to levels found in methamphetamine-avoiding animals. We used a family of recombinant inbred mouse strains for interval mapping and to examine independent and epistatic effects of Taar1 and Oprm1. Both methamphetamine intake and the thermal response mapped to Taar1 and the independent effect of Taar1 was dependent on genotype at Oprm1. Our findings encourage investigation of the contribution of Taar1 and Oprm1 variants to human methamphetamine addiction.

Differential genetic risk for methamphetamine intake confers differential sensitivity to the temperature‐altering effects of other addictive drugs

“…Overall, saline‐treated mice had a decrease in body temperature over time, which can be attributed to loss of body heat due to isolate housing . Taar1 impacts sensitivity to the hypothermic effect of MA and the current results are consistent with a similar role for Taar1 in sensitivity to the hypothermic effect of MDMA. The MADR lines differ in thermal response to the opioid, morphine.…”

“…We have determined that Taar1 is a quantitative trait gene for MA intake, and also impacts sensitivity to the hypothermic effect of MA . Because the Taar1 m1J mutation codes for a nonfunctional receptor, the MAHDR line is a naturally occurring functional knockout.…”

“…To identify the genes that may confer high vs low risk, we performed a quantitative trait locus (QTL) analysis and identified a region on mouse chromosome 10 accounting for 60% of the genetic variance in MA intake between the MADR lines . The trace amine‐associated receptor 1 gene ( Taar1 ), at 23.9 Mb on chromosome 10, was identified as a major contributor . We discovered a spontaneous mutation within the coding region of Taar1 in one of the founder strains of the MADR lines, the DBA/2J (D2) inbred strain, and found that this mutant allele ( Taar1 m1J ) codes for a nonfunctional form of the receptor (TAAR1) .…”

“…Taar1 knockout mice do not become hypothermic following MA treatment, whereas their wildtype littermates do . Likewise, Taar1 +/+ mice from recombinant inbred (RI) mouse strains derived from the F2 cross of the B6 and D2 progenitors (the BXD RI strains) become hypothermic, whereas Taar1 m1J/m1J BXD RI mice do not . Further, D2 mice from The Jackson Laboratory, which are homozygous for the mutant Taar1 m1J allele, are insensitive to MA‐induced hypothermia, whereas D2 mice from three other vendors, which are homozygous for the reference Taar1 + allele, become hypothermic after MA treatment .…”

5’ UTR variants in the quantitative trait geneHnrnph1support reduced 5’ UTR usage and hnRNP H protein as a molecular mechanism underlying reduced methamphetamine sensitivity

“…Specifically, we found differential exon usage of the 5' UTR of Hnrnph1 in 114 kb mice that was independently validated via qPCR ( Fig.6) and was associated with the inheritance of four SNP/indel variants near the 5' UTR as demonstrated by a reporter assay to measure Hnrnph1 promoter strength (Fig.8). (38), Grm2 (13), and Taar1 (39). With regard to Hnrnph1, a human candidate gene association study identified a functional intronic variant in OPRM1 (mRNA target of hnRNP H) affects binding to hnRNP H to regulate splicing that was associated with the severity of heroin addiction (40).…”