Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, 800 E Leigh Street, Richmond, VA 23298, USA.
Hum Mol Genet. 2010 Jun 15;19(12):2497-506. doi: 10.1093/hmg/ddq112. Epub 2010 Mar 23.
Studies of alcohol dependence (AD) have consistently found evidence of linkage on chromosome 4q21-q32. A genome-wide linkage scan in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD) sample also provided its strongest evidence of linkage on chromosome 4q22-q32 using an index of AD severity based on the count of DSM-IV AD symptoms (ADSX; LOD = 4.59). We conducted a systematic, gene-centric association study using 518 LD-tagging single nucleotide polymorphisms (SNPs) in the 65 known and predicted genes within the 1-LOD interval surrounding the linkage peak. Case-only regression analysis with the quantitative variable of ADSX was performed in the 562 genetically independent cases; nominal support for association was demonstrated by 32 tagging SNPs in 14 genes. We did not observe study-wide significance, but gene-wise correction for multiple testing with the Nyholt procedure yielded empirical evidence of association with two genes, DKK2 (dickkopf homolog 2) (P = 0.007) and EGF (epidermal growth factor) (P = 0.025) in the IASPSAD sample. Three SNPs in DKK2 (rs427983; rs419558; rs399087) demonstrated empirical significance. Assessment of possible replication in 847 cases of European descent from a large independent sample, the Collaborative Study of the Genetics of Alcoholism, yielded replication for DKK2 but not EGF. We observed genotypic and phenotypic replication for DKK2 with the three SNPs yielding significant association with ADSX in the IASPSAD sample. Haplotype-specific expression measurements in post-mortem tissue samples suggested a functional role for DKK2. This evidence notwithstanding, replication is needed before confidence can be placed in these findings.
对酒精依赖（AD）的研究一直发现染色体 4q21-q32 上存在连锁证据。在爱尔兰受影响的同胞对酒精依赖研究（IASPSAD）样本的全基因组连锁扫描中，也使用基于 DSM-IV AD 症状数目的 AD 严重程度指数（ADSX；LOD = 4.59），在染色体 4q22-q32 上提供了最强的连锁证据。我们使用围绕连锁峰的 65 个已知和预测基因内的 518 个 LD 标记单核苷酸多态性（SNP）进行了系统的、基于基因的关联研究。在 562 个遗传上独立的病例中，仅对病例进行了 ADSX 定量变量的回归分析；14 个基因中的 32 个标记 SNP 表现出了关联的显著支持。我们没有观察到全研究的显著性，但 Nyholt 程序对多测试进行基因校正后，得出了与两个基因关联的经验证据，即 IASPSAD 样本中的 DKK2（Dickkopf 同源物 2）（P = 0.007）和 EGF（表皮生长因子）（P = 0.025）。在 DKK2 中，三个 SNP（rs427983；rs419558；rs399087）表现出了经验上的显著性。在来自大型独立样本的 847 例欧洲血统的病例中评估了可能的复制，协作酒精遗传研究的复制结果表明，在 IASPSAD 样本中，DKK2 得到了复制，但 EGF 没有得到复制。我们观察到 DKK2 与三个 SNP 的基因型和表型复制，它们与 ADSX 有显著的关联。在死后组织样本中的特定单倍型表达测量表明 DKK2 具有功能作用。尽管有这些证据，但需要进行复制，才能对这些发现有信心。
