A quantitative trait variant in Gabra2 underlies increased methamphetamine stimulant sensitivity.
A quantitative trait variant in Gabra2 underlies increased methamphetamine stimulant sensitivity.
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DOI：
10.1111/gbb.12774
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发表时间：
2021-11
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影响因子：
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精神兴奋剂（甲基苯丙胺、可卡因）使用障碍的遗传成分大部分仍不为人知。我们对甲基苯丙胺兴奋剂敏感性进行了全基因组数量性状位点（QTL）分析。为了便于基因鉴定，我们在密切相关的C57BL/6小鼠亚系之间采用了降低复杂性的杂交方法，并检测了甲基苯丙胺（2mg /kg, i.p）后30分钟内的最大速度和行进距离。为了在第二次和第三次给药后甲基苯丙胺诱导的最大速度，我们在11号染色体上发现了一个全基因组显著的QTL，其峰值位于Cyfip2位点附近（LOD = 3.5, 4.2；峰值= 21 cM [36 Mb]）。对于甲基苯丙胺诱导的第一次和第二次注射后的距离，我们在第5号染色体上发现了一个全基因组显著的QTL，其峰值位于Gabra2编码GABA-A受体α -2亚基的功能内含子索引附近（LOD = 3.6-5.2；峰= 34-35 cM [66-67 Mb]）。纹状体顺式表达QTL定位证实了Gabra2是甲基苯丙胺诱导距离移动的功能候选基因。CRISPR/ cas9介导的将C57BL/6J背景上的突变子缺失纠正为野生型C57BL/6NJ等位基因，足以将甲基苯丙胺诱导的运动活性降低到野生型C57BL/6NJ样水平，从而验证了数量性状变异（QTV）。这些研究表明，降低复杂性杂交在识别复杂性状的因果变异方面的能力和效率。从功能上恢复Gabra2表达可降低甲基苯丙胺兴奋剂的敏感性，并支持临床前和人类遗传学研究暗示GABA-A受体与精神兴奋剂成瘾相关的特征。重要的是，我们的发现对C57BL/6J菌株（生物医学研究的金标准菌株）的精神兴奋剂研究具有重要意义。
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.
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影响因子：
3.7
作者：
Bryant, Camron D.;Kole, Loren A.;Palmer, Abraham A.
通讯作者：
Palmer, Abraham A.
影响因子：
2.5
作者：
Bryant, C. D.;Kole, L. A.;Palmer, A. A.
通讯作者：
Palmer, A. A.
影响因子：
16.6
作者：
Gonzales, Natalia M.;Seo, Jungkyun;Palmer, Abraham A.
通讯作者：
Palmer, Abraham A.
影响因子：
1.7
作者：
Ducci, Francesca;Goldman, David
通讯作者：
Goldman, David
DOI：
10.1111/j.1521-0391.2012.00253.x
发表时间：
2012-09
期刊：
The American journal on addictions
影响因子：
--
作者：
Smelson D;Yu L;Buyske S;Gonzalez G;Tischfield J;Deutsch CK;Ziedonis D
通讯作者：
Ziedonis D