A quantitative trait variant in Gabra2 underlies increased methamphetamine stimulant sensitivity.

Autor:	Goldberg LR; Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Psychiatry, Boston, Massachusetts, USA.; NIGMS T32 Ph.D. Training Program in Biomolecular Pharmacology, Boston University School of Medicine, Boston, Massachusetts, USA., Yao EJ; Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Psychiatry, Boston, Massachusetts, USA., Kelliher JC; Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Psychiatry, Boston, Massachusetts, USA., Reed ER; Ph.D. Program in Bioinformatics, Boston University, Boston, Massachusetts, USA., Wu Cox J; Program in Biomedical Sciences, Graduate Program in Genetics and Genomics, Boston University School of Medicine, Boston, Massachusetts, USA., Parks C; Department of Agricultural, Biology, and Health Sciences, Cameron University, Lawton, Oklahoma, USA., Kirkpatrick SL; Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Psychiatry, Boston, Massachusetts, USA., Beierle JA; Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Psychiatry, Boston, Massachusetts, USA.; NIGMS T32 Ph.D. Training Program in Biomolecular Pharmacology, Boston University School of Medicine, Boston, Massachusetts, USA., Chen MM; Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Psychiatry, Boston, Massachusetts, USA., Johnson WE; Department of Medicine, Computational Medicine, Boston University School of Medicine, Boston, Massachusetts, USA., Homanics GE; Departments of Anesthesiology, Neurobiology, and Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Williams RW; Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee, USA., Bryant CD; Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Psychiatry, Boston, Massachusetts, USA., Mulligan MK; Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
Jazyk:	angličtina
Zdroj:	Genes, brain, and behavior [Genes Brain Behav] 2021 Nov; Vol. 20 (8), pp. e12774. Date of Electronic Publication: 2021 Oct 22.
DOI:	10.1111/gbb.12774
Abstrakt:	Psychostimulant (methamphetamine, cocaine) use disorders have a genetic component that remains mostly unknown. We conducted genome-wide quantitative trait locus (QTL) analysis of methamphetamine stimulant sensitivity. To facilitate gene identification, we employed a Reduced Complexity Cross between closely related C57BL/6 mouse substrains and examined maximum speed and distance traveled over 30 min following methamphetamine (2 mg/kg, i.p.). For maximum methamphetamine-induced speed following the second and third administration, we identified a single genome-wide significant QTL on chromosome 11 that peaked near the Cyfip2 locus (LOD = 3.5, 4.2; peak = 21 cM [36 Mb]). For methamphetamine-induced distance traveled following the first and second administration, we identified a genome-wide significant QTL on chromosome 5 that peaked near a functional intronic indel in Gabra2 coding for the alpha-2 subunit of the GABA-A receptor (LOD = 3.6-5.2; peak = 34-35 cM [66-67 Mb]). Striatal cis-expression QTL mapping corroborated Gabra2 as a functional candidate gene underlying methamphetamine-induced distance traveled. CRISPR/Cas9-mediated correction of the mutant intronic deletion on the C57BL/6J background to the wild-type C57BL/6NJ allele was sufficient to reduce methamphetamine-induced locomotor activity toward the wild-type C57BL/6NJ-like level, thus validating the quantitative trait variant (QTV). These studies show the power and efficiency of Reduced Complexity Crosses in identifying causal variants underlying complex traits. Functionally restoring Gabra2 expression decreased methamphetamine stimulant sensitivity and supports preclinical and human genetic studies implicating the GABA-A receptor in psychostimulant addiction-relevant traits. Importantly, our findings have major implications for studying psychostimulants in the C57BL/6J strain-the gold standard strain in biomedical research. (© 2021 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.)
Databáze:	MEDLINE
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