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全基因组关联研究健康志愿者对 d-苯丙胺的反应,确定了可能的关联,包括钙黏蛋白 13(CDH13)。

Genome-wide association study of d-amphetamine response in healthy volunteers identifies putative associations, including cadherin 13 (CDH13).

机构信息

Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America.

出版信息

PLoS One. 2012;7(8):e42646. doi: 10.1371/journal.pone.0042646. Epub 2012 Aug 28.

Abstract

Both the subjective response to d-amphetamine and the risk for amphetamine addiction are known to be heritable traits. Because subjective responses to drugs may predict drug addiction, identifying alleles that influence acute response may also provide insight into the genetic risk factors for drug abuse. We performed a Genome Wide Association Study (GWAS) for the subjective responses to amphetamine in 381 non-drug abusing healthy volunteers. Responses to amphetamine were measured using a double-blind, placebo-controlled, within-subjects design. We used sparse factor analysis to reduce the dimensionality of the data to ten factors. We identified several putative associations; the strongest was between a positive subjective drug-response factor and a SNP (rs3784943) in the 8(th) intron of cadherin 13 (CDH13; P = 4.58×10(-8)), a gene previously associated with a number of psychiatric traits including methamphetamine dependence. Additionally, we observed a putative association between a factor representing the degree of positive affect at baseline and a SNP (rs472402) in the 1(st) intron of steroid-5-alpha-reductase-α-polypeptide-1 (SRD5A1; P = 2.53×10(-7)), a gene whose protein product catalyzes the rate-limiting step in synthesis of the neurosteroid allopregnanolone. This SNP belongs to an LD-block that has been previously associated with the expression of SRD5A1 and differences in SRD5A1 enzymatic activity. The purpose of this study was to begin to explore the genetic basis of subjective responses to stimulant drugs using a GWAS approach in a modestly sized sample. Our approach provides a case study for analysis of high-dimensional intermediate pharmacogenomic phenotypes, which may be more tractable than clinical diagnoses.

摘要

兴奋剂主观反应和安非他命成瘾风险均具有遗传性。由于药物的主观反应可能预示着药物成瘾,确定影响急性反应的等位基因也可能为药物滥用的遗传风险因素提供深入了解。我们对 381 名无吸毒史的健康志愿者进行了一项安非他命主观反应的全基因组关联研究(GWAS)。使用双盲、安慰剂对照、个体内设计来测量安非他命的反应。我们使用稀疏因子分析将数据的维度降低到十个因素。我们发现了几个可能的关联;最强的关联是在一个正的主观药物反应因子和一个 SNP(rs3784943)之间,该 SNP 位于钙粘蛋白 13(CDH13)的第 8 内含子中(CDH13;P=4.58×10(-8)),该基因先前与多种精神特征相关,包括甲基苯丙胺依赖。此外,我们还观察到一个代表基线时正性情感程度的因子与一个 SNP(rs472402)之间的可能关联,该 SNP 位于类固醇-5-α-还原酶-α-多聚蛋白-1(SRD5A1)的第 1 内含子中(P=2.53×10(-7)),该基因的蛋白产物催化神经甾体物孕烷醇酮合成的限速步骤。这个 SNP 属于一个 LD 块,该 LD 块与 SRD5A1 的表达和 SRD5A1 酶活性的差异有关。本研究的目的是使用 GWAS 方法在一个适度大小的样本中开始探索对兴奋剂药物的主观反应的遗传基础。我们的方法为分析高维中间药物基因组表型提供了一个案例研究,这可能比临床诊断更具可操作性。

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