Yang Bao-Zhu, Kranzler Henry R, Zhao Hongyu, Gruen Jeffrey R, Luo Xingguang, Gelernter Joel
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
Hum Mol Genet. 2007 Dec 1;16(23):2844-53. doi: 10.1093/hmg/ddm240. Epub 2007 Aug 30.
There have been many conflicting reports concerning the association of the DRD2 locus with alcohol dependence (AD). To investigate whether these findings could be reconciled by considering the genomic region of DRD2 in greater detail, we conducted two separate association studies of AD in 1220 European-American subjects using family-based (488 subjects) and case-control (318 cases and 414 controls) designs, and 43 single nucleotide polymorphisms mapped to the gene cluster of NCAM1, TTC12, ANKK1 and DRD2. We used a generalized linear model and haplotype score tests for the case-control sample, and the family-based association test for the family sample. Haplotype associations centered on TTC12 exon 3 [rs1893699-rs723077; optimal individual haplotype simulated P-value (P(oihs)) = 0.00021] in both independent samples (family and case-control). Additional AD-associated haplotypes centered around NCAM1 exon 12 in the family sample (P(oihs) = 0.0032), and at exons 2 and 5 of ANKK1 in the case-control sample (P(oihs) = 0.00058). LD contrasts between cases and controls support selection at TTC12 exon 3 and ANKK1 exon 2. The armadillo repeat domains encoded by TTC12 and dopamine interact in the Wnt pathway and may have effects on dopamine cell development in the ventral midbrain. We conclude that risk for AD is attributable in part to variants in four regions within this cluster: exon 3 of TTC12, exon 12/intron13 of NCAM1 and exons 2 and 5 of ANKK1. The complexity of these relationships, many of which replicate between our independent samples, may explain prior inconsistent results.
关于多巴胺D2受体（DRD2）基因座与酒精依赖（AD）之间的关联，已经有许多相互矛盾的报道。为了研究通过更详细地考虑DRD2的基因组区域，这些研究结果是否能够相互协调，我们使用基于家系（488名受试者）和病例对照（318例病例和414名对照）设计，对1220名欧美受试者进行了两项关于AD的独立关联研究，并对映射到NCAM1、TTC12、ANKK1和DRD2基因簇的43个单核苷酸多态性进行了分析。我们对病例对照样本使用广义线性模型和单倍型评分检验，对家系样本使用基于家系的关联检验。在两个独立样本（家系和病例对照）中，单倍型关联均集中在TTC12外显子3[rs1893699 - rs723077；最佳个体单倍型模拟P值（P(oihs)）= 0.00021]。在家系样本中，其他与AD相关的单倍型集中在NCAM1外显子12周围（P(oihs) = 0.0032），在病例对照样本中集中在ANKK1的外显子2和5周围（P(oihs) = 0.00058）。病例与对照之间的连锁不平衡对比支持TTC12外显子3和ANKK1外显子2处存在选择。由TTC12编码的犰狳重复结构域与多巴胺在Wnt信号通路中相互作用，可能对腹侧中脑多巴胺细胞的发育产生影响。我们得出结论，AD的风险部分归因于该基因簇内四个区域的变异：TTC12的外显子3、NCAM1的外显子12/内含子13以及ANKK1的外显子2和5。这些关系的复杂性，其中许多在我们的独立样本之间具有重复性，可能解释了先前不一致的结果。
