Adkins Amy E, Hack Laura M, Bigdeli Tim B, Williamson Vernell S, McMichael G Omari, Mamdani Mohammed, Edwards Alexis C, Aliev Fazil, Chan Robin F, Bhandari Poonam, Raabe Richard C, Alaimo Joseph T, Blackwell GinaMari G, Moscati Arden, Poland Ryan S, Rood Benjamin, Patterson Diana G, Walsh Dermot, Whitfield John B, Zhu Gu, Montgomery Grant W, Henders Anjali K, Martin Nicholas G, Heath Andrew C, Madden Pamela A F, Frank Josef, Ridinger Monika, Wodarz Norbert, Soyka Michael, Zill Peter, Ising Marcus, Nöthen Markus M, Kiefer Falk, Rietschel Marcella, Gelernter Joel, Sherva Richard, Koesterer Ryan, Almasy Laura, Zhao Hongyu, Kranzler Henry R, Farrer Lindsay A, Maher Brion S, Prescott Carol A, Dick Danielle M, Bacanu Silviu A, Mathies Laura D, Davies Andrew G, Vladimirov Vladimir I, Grotewiel Mike, Bowers M Scott, Bettinger Jill C, Webb Bradley T, Miles Michael F, Kendler Kenneth S, Riley Brien P
Virginia Commonwealth University Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia.
Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.
Alcohol Clin Exp Res. 2017 May;41(5):911-928. doi: 10.1111/acer.13362. Epub 2017 Mar 30.
Alcohol dependence (AD) shows evidence for genetic liability, but genes influencing risk remain largely unidentified.
We conducted a genomewide association study in 706 related AD cases and 1,748 unscreened population controls from Ireland. We sought replication in 15,496 samples of European descent. We used model organisms (MOs) to assess the role of orthologous genes in ethanol (EtOH)-response behaviors. We tested 1 primate-specific gene for expression differences in case/control postmortem brain tissue.
We detected significant association in COL6A3 and suggestive association in 2 previously implicated loci, KLF12 and RYR3. None of these signals are significant in replication. A suggestive signal in the long noncoding RNA LOC339975 is significant in case:control meta-analysis, but not in a population sample. Knockdown of a COL6A3 ortholog in Caenorhabditis elegans reduced EtOH sensitivity. Col6a3 expression correlated with handling-induced convulsions in mice. Loss of function of the KLF12 ortholog in C. elegans impaired development of acute functional tolerance (AFT). Klf12 expression correlated with locomotor activation following EtOH injection in mice. Loss of function of the RYR3 ortholog reduced EtOH sensitivity in C. elegans and rapid tolerance in Drosophila. The ryanodine receptor antagonist dantrolene reduced motivation to self-administer EtOH in rats. Expression of LOC339975 does not differ between cases and controls but is reduced in carriers of the associated rs11726136 allele in nucleus accumbens (NAc).
We detect association between AD and COL6A3, KLF12, RYR3, and LOC339975. Despite nonreplication of COL6A3, KLF12, and RYR3 signals, orthologs of these genes influence behavioral response to EtOH in MOs, suggesting potential involvement in human EtOH response and AD liability. The associated LOC339975 allele may influence gene expression in human NAc. Although the functions of long noncoding RNAs are poorly understood, there is mounting evidence implicating these genes in multiple brain functions and disorders.
酒精依赖（AD）显示出遗传易感性的证据，但影响风险的基因在很大程度上仍未明确。
我们对来自爱尔兰的706例相关AD病例和1748例未经筛选的人群对照进行了全基因组关联研究。我们在15496例欧洲血统样本中寻求重复验证。我们使用模式生物（MO）来评估直系同源基因在乙醇（EtOH）反应行为中的作用。我们检测了1个灵长类特异性基因在病例/对照尸检脑组织中的表达差异。
我们在COL6A3中检测到显著关联，并在2个先前涉及的基因座KLF12和RYR3中检测到提示性关联。这些信号在重复验证中均不显著。长链非编码RNA LOC339975中的一个提示性信号在病例：对照荟萃分析中显著，但在人群样本中不显著。秀丽隐杆线虫中COL6A3直系同源基因的敲低降低了EtOH敏感性。Col6a3表达与小鼠处理诱导的惊厥相关。秀丽隐杆线虫中KLF12直系同源基因的功能丧失损害了急性功能耐受性（AFT）的发展。Klf12表达与小鼠注射EtOH后的运动激活相关。RYR3直系同源基因的功能丧失降低了秀丽隐杆线虫的EtOH敏感性和果蝇的快速耐受性。兰尼碱受体拮抗剂丹曲林降低了大鼠自我给药EtOH的动机。病例和对照之间LOC339975的表达没有差异，但在伏隔核（NAc）中相关rs11726136等位基因的携带者中表达降低。
我们检测到AD与COL6A3、KLF12、RYR3和LOC339975之间的关联。尽管COL6A3、KLF12和RYR3信号未得到重复验证，但这些基因的直系同源基因影响MO对EtOH的行为反应，提示其可能参与人类对EtOH的反应和AD易感性。相关的LOC339975等位基因可能影响人类NAc中的基因表达。尽管对长链非编码RNA的功能了解甚少，但越来越多的证据表明这些基因参与多种脑功能和疾病。
