Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol-Response Behaviors in Model Organisms.
Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol-Response Behaviors in Model Organisms.
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DOI：
10.1111/acer.13362
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发表时间：
2017-05
期刊：
影响因子：
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通讯作者：
Riley BP
中科院分区：
文献类型：
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作者：
Adkins AE;Hack LM;Bigdeli TB;Williamson VS;McMichael GO;Mamdani M;Edwards AC;Aliev F;Chan RF;Bhandari P;Raabe RC;Alaimo JT;Blackwell GG;Moscati A;Poland RS;Rood B;Patterson DG;Walsh D;Collaborative Study of the Genetics of Alcoholism Consortium;Whitfield JB;Zhu G;Montgomery GW;Henders AK;Martin NG;Heath AC;Madden PAF;Frank J;Ridinger M;Wodarz N;Soyka M;Zill P;Ising M;Nöthen MM;Kiefer F;Rietschel M;German Study of the Genetics of Addiction Consortium;Gelernter J;Sherva R;Koesterer R;Almasy L;Zhao H;Kranzler HR;Farrer LA;Maher BS;Prescott CA;Dick DM;Bacanu SA;Mathies LD;Davies AG;Vladimirov VI;Grotewiel M;Bowers MS;Bettinger JC;Webb BT;Miles MF;Kendler KS;Riley BP
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确定。我们对来自爱尔兰的706例相关AD病例和1748例未筛查人群对照进行了全基因组关联研究。我们在15,496个欧洲血统的样本中寻找复制品。我们使用模式生物，以评估乙醇反应行为的orthopathic基因的作用。我们测试了一个灵长类动物特异性基因在病例/对照死后脑组织中的表达差异。我们在COL 6A 3中检测到显著关联，并在先前涉及的两个位点KLF 12和RYR 3中检测到暗示关联。这些信号在复制中没有显著性。在病例：对照荟萃分析中，长非编码RNA LOC 339975中的提示信号是显著的，但在群体样本中不显著。在C. elegans降低乙醇敏感性。Col 6a 3表达与小鼠处理诱导的惊厥相关。在C. elegans损害急性功能性耐受的发展。Klf 12的表达与乙醇注射后小鼠的自发活动相关。RYR 3直系同源物功能的丧失降低了C.和果蝇的快速耐受性。Ryanodine受体拮抗剂丹曲林降低了大鼠自我给药乙醇的动机。LOC 339975的表达在病例组和对照组之间没有差异，但在核中相关rs 11726136等位基因的携带者中减少。我们检测AD与COL 6A 3、KLF 12、RYR 3和LOC 339975之间的关联。尽管COL 6A 3，KLF 12和RYR 3信号的非复制，但这些基因的直系同源物影响模型生物对乙醇的行为反应，表明可能参与人类乙醇反应和AD易感性。相关的LOC 339975等位基因可能影响人类丘脑核基因表达。虽然长的非编码RNA的功能知之甚少，但越来越多的证据表明这些基因与多种脑功能和疾病有关。
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 1748 unscreened population controls from Ireland. We sought replication in 15,496 samples of European descent. We used model organisms to assess the role of orthologous genes in ethanol response behaviors. We tested one primate-specific gene for expression differences in case/control post-mortem brain tissue. We detected significant association in COL6A3 and suggestive association in two 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 C. elegans reduced ethanol 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. Klf12 expression correlated with locomotor activation following ethanol injection in mice. Loss of function of the RYR3 ortholog reduced ethanol sensitivity in C. elegans and rapid tolerance in Drosophila. The ryanodine receptor antagonist dantrolene reduced motivation to self-administer ethanol 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. We detect association between AD and COL6A3, KLF12, RYR3 and LOC339975. Despite non-replication of COL6A3, KLF12 and RYR3 signals, orthologs of these genes influence behavioral response to ethanol in model organisms, suggesting potential involvement in human ethanol response and AD liability. The associated LOC339975 allele may influence gene expression in human nucleus accumbens. Although the functions of long noncoding RNAs are poorly understood, there is mounting evidence implicating these genes in multiple brain functions and disorders.