Mauro Kelsey L, Helton Sarah G, Rosoff Dan B, Luo Audrey, Schwandt Melanie, Jung Jeesun, Lee Jisoo, Muench Christine, Lohoff Falk W
Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 10 Center Drive (10CRC), Bethesda, MD, USA.
Office of the Clinical Director, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 10 Center Drive (10CRC), Bethesda, MD, USA.
Alcohol Alcohol. 2018 Jul 1;53(4):361-367. doi: 10.1093/alcalc/agx120.
Previous genetic association studies have shown that variation in the GATA4 gene encoding the GATA binding protein 4, a binding protein that binds to the ANA sequence GATA, increase susceptibility for alcohol use disorder (AUD). In this study, we aimed to replicate those findings in an independent sample and analyze their association with anxiety.
Overall, 1044 individuals with AUD [534 European American (EA), 510 African Americans (AA)] and 645 controls [413 EA, 232 AA] were genotyped using 34 markers. Genotype and allele frequencies were compared between cases and controls using chi-square analysis. Other phenotype data were analyzed for possible associations with GATA4 single-nucleotide polymorphisms (SNPs) in individuals with AUD.
Rs6601604 was nominally significantly associated with AUD in EA, and 3 SNPs (rs6990313, rs11250159 and rs17153694) showed trend-level significance (P < 0.10) in AA. However, none of the SNPs were significant after correcting for multiple testing. Haplotype analysis of the 34 SNPs did not find a significant association between haplotype blocks and AUD diagnosis after correcting for multiple testing. From the phenotype analysis, anxiety was associated with GATA4 SNP rs10112596 among the AA group with AUD after a correction for multiple testing.
Although previous studies have shown a relationship between variants of the GATA4 gene and a diagnosis of AUD, we did not replicate these findings in our sample. Additional studies of variation in this gene are needed to elucidate whether polymorphisms of the GATA4 gene are associated with AUD and other alcohol-related phenotypes.
GATA4 variants were not associated with AUD in either the European ancestry or African ancestry groups after correcting for multiple comparisons. Rs10112596 demonstrated a significant relationship with an anxiety measure among the African ancestry group with AUD.
先前的基因关联研究表明，编码GATA结合蛋白4（一种与ANA序列GATA结合的结合蛋白）的GATA4基因变异会增加酒精使用障碍（AUD）的易感性。在本研究中，我们旨在在一个独立样本中重复这些发现，并分析它们与焦虑的关联。
总共对1044名AUD患者[534名欧美裔（EA）、510名非裔美国人（AA）]和645名对照者[413名EA、232名AA]使用34个标记进行基因分型。使用卡方分析比较病例组和对照组之间的基因型和等位基因频率。分析了其他表型数据与AUD患者中GATA4单核苷酸多态性（SNP）的可能关联。
Rs6601604在欧美裔中与AUD存在名义上的显著关联，3个SNP（rs6990313、rs11250159和rs17153694）在非裔美国人中显示出趋势水平的显著性（P < 0.10）。然而，在进行多重检验校正后，没有一个SNP具有显著性。对34个SNP进行单倍型分析，在进行多重检验校正后，未发现单倍型块与AUD诊断之间存在显著关联。从表型分析来看，在对多重检验进行校正后，AUD的非裔美国人组中焦虑与GATA4 SNP rs10112596相关。
尽管先前的研究表明GATA4基因变异与AUD诊断之间存在关联，但我们在样本中并未重复这些发现。需要对该基因的变异进行更多研究，以阐明GATA4基因的多态性是否与AUD及其他酒精相关表型有关。
在进行多重比较校正后，GATA4变异在欧洲血统或非洲血统组中均与AUD无关。Rs10112596在患有AUD的非洲血统组中与一项焦虑指标显示出显著关系。
