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We conducted genome\u2010wide 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\u2009min following methamphetamine (2\u00a0mg\/kg, i.p.). For maximum methamphetamine\u2010induced speed following the second and third administration, we identified a single genome\u2010wide significant QTL on chromosome 11 that peaked near the\n                    <jats:italic>Cyfip2<\/jats:italic>\n                    locus (LOD\u00a0=\u00a03.5, 4.2; peak\u00a0=\u00a021\u2009cM [36\u2009Mb]). For methamphetamine\u2010induced distance traveled following the first and second administration, we identified a genome\u2010wide significant QTL on chromosome 5 that peaked near a functional intronic indel in\n                    <jats:italic>Gabra2<\/jats:italic>\n                    coding for the alpha\u20102 subunit of the GABA\u2010A receptor (LOD\u00a0=\u00a03.6\u20135.2; peak\u00a0=\u00a034\u201335\u2009cM [66\u201367\u2009Mb]). Striatal\n                    <jats:italic>cis<\/jats:italic>\n                    \u2010expression QTL mapping corroborated\n                    <jats:italic>Gabra2<\/jats:italic>\n                    as a functional candidate gene underlying methamphetamine\u2010induced distance traveled. CRISPR\/Cas9\u2010mediated correction of the mutant intronic deletion on the C57BL\/6J background to the wild\u2010type C57BL\/6NJ allele was sufficient to reduce methamphetamine\u2010induced locomotor activity toward the wild\u2010type C57BL\/6NJ\u2010like 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\n                    <jats:italic>Gabra2<\/jats:italic>\n                    expression decreased methamphetamine stimulant sensitivity and supports preclinical and human genetic studies implicating the GABA\u2010A receptor in psychostimulant addiction\u2010relevant traits. Importantly, our findings have major implications for studying psychostimulants in the C57BL\/6J strain\u2014the gold standard strain in biomedical research.\n                  <\/jats:p>","DOI":"10.1111\/gbb.12774","type":"journal-article","created":{"date-parts":[[2021,10,22]],"date-time":"2021-10-22T06:46:02Z","timestamp":1634885162000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A quantitative trait variant in\n                    <i>Gabra2<\/i>\n                    underlies increased methamphetamine stimulant sensitivity"],"prefix":"10.1111","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7244-7018","authenticated-orcid":false,"given":"Lisa R.","family":"Goldberg","sequence":"first","affiliation":[{"name":"Laboratory of Addiction Genetics Department of Pharmacology and Experimental Therapeutics and Psychiatry Boston Massachusetts USA"},{"name":"NIGMS T32 Ph.D. Training Program in 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