Forero Diego A, López-León Sandra, Shin Hyoung Doo, Park Byung Lae, Kim Dai-Jin
Laboratory of NeuroPsychiatric Genetics, Biomedical Sciences Research Group, School of Medicine, Universidad Antonio Nariño, Bogotá, Colombia.
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
Drug Alcohol Depend. 2015 Apr 1;149:259-63. doi: 10.1016/j.drugalcdep.2015.01.017. Epub 2015 Jan 24.
Alcohol-related problems have a large impact on human health, accounting for around 4% of deaths and 4.5% of disability-adjusted life-years around the world. Genetic factors could explain a significant fraction of the risk for alcohol dependence (AD). Recent meta-analyses have found significant pooled odds ratios (ORs) for variants in the ADH1B, ADH1C, DRD2 and HTR2A genes.
In the present study, we carried out a meta-analysis of common variants in 6 candidate genes involved in neurotransmission and neuroplasticity: BDNF, DRD1, DRD3, DRD4, GRIN2B and MAOA. We carried out a systematic search for published association studies that analyzed the genes of interest. Relevant articles were retrieved and demographic and genetic data were extracted. Pooled ORs were calculated using a random-effects model using the Meta-Analyst program. Dominant, recessive and allelic models were tested and analyses were also stratified by ethnicity.
Forty two published studies were included in the current meta-analysis: BDNF-rs6265 (nine studies), DRD1-rs4532 (four studies), DRD3-rs6280 (eleven studies), DRD4-VNTR (seven studies), GRIN2B-rs1806201 (three studies) and MAOA-uVNTR (eight studies). We did not find significant pooled ORs for any of the six genes, under different models and stratifying for ethnicity.
In terms of the number of candidate genes included, this is one of the most comprehensive meta-analyses for genetics of AD. Pooled ORs did not support consistent associations with any of the six candidate genes tested. Future studies of novel genes of functional relevance and meta-analyses of quantitative endophenotypes could identify further susceptibility molecular factors for AD.
酒精相关问题对人类健康有重大影响，在全球约占死亡人数的4%和伤残调整生命年的4.5%。遗传因素可解释很大一部分酒精依赖（AD）风险。最近的荟萃分析发现，乙醇脱氢酶1B（ADH1B）、乙醇脱氢酶1C（ADH1C）、多巴胺D2受体（DRD2）和5-羟色胺受体2A（HTR2A）基因的变异存在显著的合并比值比（OR）。
在本研究中，我们对参与神经传递和神经可塑性的6个候选基因中的常见变异进行了荟萃分析：脑源性神经营养因子（BDNF）、多巴胺D1受体（DRD1）、多巴胺D3受体（DRD3）、多巴胺D4受体（DRD4）、谷氨酸受体离子型N-甲基-D-天冬氨酸2B（GRIN2B）和单胺氧化酶A（MAOA）。我们对已发表的分析相关基因的关联研究进行了系统检索。检索相关文章并提取人口统计学和遗传数据。使用Meta-Analyst程序通过随机效应模型计算合并OR。对显性、隐性和等位基因模型进行了检验，分析也按种族进行了分层。
本荟萃分析纳入了42项已发表的研究：BDNF-rs6265（9项研究）、DRD1-rs4532（4项研究）、DRD3-rs6280（11项研究）、DRD4可变数目串联重复序列（VNTR）（7项研究）、GRIN2B-rs1806201（3项研究）和MAOA-uVNTR（8项研究）。在不同模型和种族分层下，我们未发现这六个基因中的任何一个存在显著的合并OR。
就纳入的候选基因数量而言，这是AD遗传学方面最全面的荟萃分析之一。合并OR不支持与所检测的六个候选基因中的任何一个存在一致关联。未来对具有功能相关性的新基因的研究以及对定量内表型的荟萃分析可能会确定AD的更多易感性分子因素。
