Lydall Gregory John, Bass Nicholas J, McQuillin Andrew, Lawrence Jacob, Anjorin Adebayo, Kandaswamy Radhika, Pereira Ana, Guerrini Irene, Curtis David, Vine Anna E, Sklar Pamela, Purcell Shaun M, Gurling Hugh Malcolm Douglas
Department of Mental Health Sciences, University College London, Molecular Psychiatry Laboratory, Harvard Medical School, Boston, Massachusetts, USA.
Psychiatr Genet. 2011 Dec;21(6):294-306. doi: 10.1097/YPG.0b013e32834915c2.
Alcoholism and affective disorders are both strongly comorbid and heritable. We have investigated the genetic comorbidity between bipolar affective disorder and alcoholism.
A genome-wide allelic association study of 506 patients from the University College London bipolar disorder case-control sample and 510 ancestrally matched supernormal controls. One hundred forty-three of the bipolar patients fulfilled the Research Diagnostic Criteria diagnosis of alcoholism. A total of 372 193 single nucleotide polymorphisms (SNPs) were genotyped. Genes previously shown to be associated with alcoholism and addiction phenotypes were then tested for association in the bipolar alcoholic sample using gene-wise permutation tests of all SNPs genotyped within a 50-kb region flanking each gene.
Several central nervous system genes showed significant (P<0.05) gene-wise evidence of association with bipolar alcoholism. The genes implicated, which replicated genes previously shown to be associated with alcoholism were: cadherin 11, collagen type 11 α2, neuromedin U receptor 2, exportin7, and semaphorin-associated protein 5A. The SNPs most strongly implicated in bipolar alcoholism, but, which did not meet conventional genome-wide significance criteria were the insulin-like growth factor-binding protein 7, carboxypeptidase O, cerebellin 2, and the cadherin 12 genes.
We have confirmed the role of some genes previously shown to be associated with alcoholism in the comorbid bipolar alcoholism subgroup. In this subgroup, bipolar disorder may lower the threshold for the phenotypic expression of these alcoholism susceptibility genes. We also show that some genes may independently increase susceptibility to affective disorder and alcoholism.
酒精中毒与情感障碍都具有很强的共病性且可遗传。我们研究了双相情感障碍与酒精中毒之间的遗传共病情况。
对来自伦敦大学学院双相情感障碍病例对照样本的506名患者和510名 ancestrally matched 超常对照进行全基因组等位基因关联研究。其中143名双相情感障碍患者符合酒精中毒的研究诊断标准。共对372193个单核苷酸多态性（SNP）进行了基因分型。然后，使用每个基因侧翼50kb区域内所有基因分型SNP的基因特异性置换检验，对先前显示与酒精中毒和成瘾表型相关的基因在双相情感障碍酒精中毒样本中进行关联测试。
几个中枢神经系统基因显示出与双相情感障碍酒精中毒存在显著（P<0.05）的基因特异性关联证据。涉及的基因，其中与先前显示与酒精中毒相关的基因重复的有：钙黏蛋白11、11型胶原蛋白α2、神经降压素U受体2、输出蛋白7和信号素相关蛋白5A。在双相情感障碍酒精中毒中最强烈涉及但未达到传统全基因组显著性标准的SNP是胰岛素样生长因子结合蛋白7、羧肽酶O、小脑素2和钙黏蛋白12基因。
我们已经证实了一些先前显示与酒精中毒相关的基因在共病双相情感障碍酒精中毒亚组中的作用。在这个亚组中，双相情感障碍可能会降低这些酒精中毒易感基因表型表达的阈值。我们还表明，一些基因可能独立增加情感障碍和酒精中毒的易感性。
