Gelernter Joel, Panhuysen Carolien, Weiss Roger, Brady Kathleen, Hesselbrock Victor, Rounsaville Bruce, Poling James, Wilcox Marsha, Farrer Lindsay, Kranzler Henry R
Yale University School of Medicine, Department of Psychiatry, Division of Human Genetics; and VA CT Healthcare Center, West Haven, CT 06516, USA.
Am J Med Genet B Neuropsychiatr Genet. 2005 Jul 5;136B(1):45-52. doi: 10.1002/ajmg.b.30189.
Risk for cocaine dependence (CD) is genetically influenced. We recruited a sample of small nuclear families (528 full and 155 half sibpairs) with at least one subject affected with CD. The sample was classified via Bayesian clustering as 45.5% European American (EA) and 54.5% African American (AA). Assessment, via the Semi-Structured Assessment for Drug Dependence and Alcoholism, allowed for detailed evaluation of substance dependence-related traits. To define subgroups with increased genetic homogeneity, consistent with our a priori analytic plan, we used cluster analytic methods to identify six cocaine-related symptom clusters; membership was shown to be significantly heritable. We then completed a genomewide linkage scan (409 markers) for the CD diagnosis, cocaine-induced paranoia (CIP; an outcome that occurs in some cocaine users) and the clusters (three of which contained >80% of the CD subjects). We observed a "suggestive" linkage signal on chromosome 10 for the trait of CD in the full sample; and two "suggestive" linkage signals at different locations on chromosome 3, in the EA part of the sample. We observed a genomewide-significant lod score of 3.65 for the trait of CIP on chromosome 9, in the AA part of the sample only. Our strongest results were observed for the cluster membership traits, including a lod score of 4.66 for membership in the "Heavy Use, Cocaine Predominant" cluster on chromosome 12 (in EAs only) and a lod score of 3.35 for membership in the "Moderate Cocaine and Opioid Abuse" cluster on chromosome 18. These results provide a basis for the identification of specific genes contributing to risk for these traits.
可卡因成瘾（CD）风险受遗传影响。我们招募了一个包含小核家庭的样本（528个完整家庭和155个半同胞对），其中至少有一名受CD影响的受试者。该样本通过贝叶斯聚类分类为45.5%的欧裔美国人（EA）和54.5%的非裔美国人（AA）。通过药物依赖和酒精中毒半结构化评估进行评估，可对物质依赖相关特征进行详细评估。为了定义遗传同质性增加的亚组，与我们的先验分析计划一致，我们使用聚类分析方法识别了六个与可卡因相关的症状簇；结果显示成员身份具有显著遗传性。然后，我们针对CD诊断、可卡因诱发的偏执狂（CIP；一些可卡因使用者出现的一种结果）和这些簇（其中三个包含>80%的CD受试者）完成了全基因组连锁扫描（409个标记）。在完整样本中，我们在10号染色体上观察到一个关于CD特征的“提示性”连锁信号；在样本的EA部分，在3号染色体的不同位置观察到两个“提示性”连锁信号。仅在样本的AA部分，我们在9号染色体上观察到CIP特征的全基因组显著lod分数为3.65。我们在簇成员特征方面观察到最强的结果，包括在12号染色体上“大量使用，以可卡因为主”簇的成员身份lod分数为4.66（仅在EA中），以及在18号染色体上“中度可卡因和阿片类药物滥用”簇的成员身份lod分数为3.35。这些结果为识别导致这些特征风险的特定基因提供了基础。
