Farrer Lindsay A, Kranzler Henry R, Yu Yi, Weiss Roger D, Brady Kathleen T, Anton Raymond, Cubells Joseph F, Gelernter Joel
Genetics Program, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA.
Arch Gen Psychiatry. 2009 Mar;66(3):267-74. doi: 10.1001/archgenpsychiatry.2008.538.
Cocaine dependence (CD) and related behaviors are highly heritable, but no genetic association has been consistently demonstrated. A recent genome-wide study of drug dependence identified an association between cocaine-induced paranoia (CIP) and a single-nucleotide polymorphism (SNP) in the alpha-endomannosidase (MANEA) locus in a family-based sample of European Americans and African Americans.
To conduct a comprehensive genetic association study of the MANEA locus with CD and CIP.
Genome-wide association study.
Four university hospitals.
A total of 3992 individuals from 2 family-based and 2 case-control samples.
Participants were classified as having CD or CIP or as a control using the Semi-Structured Assessment for Drug Dependence and Alcoholism. They were genotyped for 11 SNPs spanning MANEA and its surrounding region.
Association of CD and CIP with individual SNPs and haplotypes.
Cocaine-induced paranoia was associated with 6 SNPs in the European American families and 9 SNPs in the African American families. The strongest evidence in the total sample of families was observed in 3 markers located in the promoter and 3' untranslated regions (P < .001). The association of MANEA SNPs with CD in both family samples was much weaker. In the African American case-control sample, multiple markers were significantly associated with CIP and CD; CIP and CD were also significantly associated with a 2-SNP haplotype in the European American case-control sample. The A allele of the 3' untranslated region SNP rs9387522 was associated with increased risk of CIP in all 4 data sets.
Our findings suggest that CD and associated behaviors may involve biological pathways not typically thought to be associated with brain metabolism.
可卡因依赖（CD）及相关行为具有高度遗传性，但尚未有基因关联得到一致证实。最近一项关于药物依赖的全基因组研究在一个以欧美裔和非裔美国家庭为样本的研究中，发现可卡因诱发的偏执狂（CIP）与α-甘露糖苷酶（MANEA）基因座中的单核苷酸多态性（SNP）之间存在关联。
对MANEA基因座与CD和CIP进行全面的基因关联研究。
全基因组关联研究。
四家大学医院。
来自2个基于家庭的样本和2个病例对照样本的3992名个体。
使用药物依赖和酒精中毒半结构化评估将参与者分类为患有CD或CIP或作为对照。对跨越MANEA及其周边区域的11个SNP进行基因分型。
CD和CIP与个体SNP和单倍型的关联。
在欧美裔家庭中，可卡因诱发的偏执狂与6个SNP相关，在非裔美国家庭中与9个SNP相关。在整个家庭样本中，最强的证据出现在位于启动子和3'非翻译区的3个标记中（P <.001）。MANEA SNP与两个家庭样本中的CD的关联要弱得多。在非裔美国人病例对照样本中，多个标记与CIP和CD显著相关；在欧美裔病例对照样本中，CIP和CD也与一个双SNP单倍型显著相关。3'非翻译区SNP rs9387522的A等位基因在所有4个数据集中都与CIP风险增加相关。
我们的研究结果表明，CD及相关行为可能涉及通常认为与脑代谢无关的生物学途径。
