Genome-wide association mapping of loci for antipsychotic-induced extrapyramidal symptoms in mice
Genome-wide association mapping of loci for antipsychotic-induced extrapyramidal symptoms in mice
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DOI：
10.1007/s00335-011-9385-8
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发表时间：
2012-06-01
期刊：
影响因子：
2.5
通讯作者：
Sullivan, Patrick F.
中科院分区：
文献类型：
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作者：
Crowley, James J.;Kim, Yunjung;Sullivan, Patrick F.
迟发性运动障碍 (TD) 是一种使人衰弱、不可预测且通常不可逆转的副作用，是由氟哌啶醇等典型抗精神病药物长期治疗引起的。 TD 的特点是主要发生在口面部区域的重复、不自主、无目的的运动。为了研究 TD 的遗传易感性，我们使用经过验证的小鼠模型进行系统遗传学分析，旨在检测人类患者 TD 的遗传预测因素。对长期接受氟哌啶醇处理并进行空咀嚼运动表型分析的 27 个近交系的表型数据进行了全面的基因组分析，涉及 426,493 个 SNP、4,047 个 CNV、脑基因表达以及基因网络和生物信息学分析。我们的结果鉴定了类似于 50 个基因，我们预计这些基因与氟哌啶醇诱导的 TD 具有较高的先验概率，其中大多数从未测试过与人类 TD 的关联。我们的首要候选基因包括调节大脑运动控制区发育的基因（Zic4 和 Nkx6-1）、谷氨酸受体（Grin1 和 Grin2a）以及氟哌啶醇的间接靶标（Drd1a）（尚未像直接靶标 Drd2 一样进行研究）。
Tardive dyskinesia (TD) is a debilitating, unpredictable, and often irreversible side effect resulting from chronic treatment with typical antipsychotic agents such as haloperidol. TD is characterized by repetitive, involuntary, purposeless movements primarily of the orofacial region. In order to investigate genetic susceptibility to TD, we used a validated mouse model for a systems genetics analysis geared toward detecting genetic predictors of TD in human patients. Phenotypic data from 27 inbred strains chronically treated with haloperidol and phenotyped for vacuous chewing movements were subject to a comprehensive genomic analysis involving 426,493 SNPs, 4,047 CNVs, brain gene expression, along with gene network and bioinformatic analysis. Our results identified similar to 50 genes that we expect to have high prior probabilities for association with haloperidol-induced TD, most of which have never been tested for association with human TD. Among our top candidates were genes regulating the development of brain motor control regions (Zic4 and Nkx6-1), glutamate receptors (Grin1 and Grin2a), and an indirect target of haloperidol (Drd1a) that has not been studied as well as the direct target, Drd2.