Forero Diego A, Arboleda Gonzalo H, Vasquez Rafael, Arboleda Humberto
Neurosciences Research Group, School of Medicine, Universidad Nacional de Colombia, Bogotá, Colombia.
J Psychiatry Neurosci. 2009 Sep;34(5):361-6.
Attention-deficit hyperactivity disorder (ADHD) is an important psychiatric condition in terms of its prevalence and impact on quality of life. It has one of the highest heritabilities found in psychiatric disorders. A number of association studies exploring several candidate genes in different populations around the world have been carried out. The objective of the present study was to carry out a meta-analysis for 8 common variants located in 5 top candidate genes for ADHD (BDNF, HTR1B, SLC6A2, SLC6A4 and SNAP25); these genes are known to be involved in synaptic transmission and plasticity.
We performed a search for published genetic association studies that analyzed the candidate polymorphisms in different populations, and we applied state-of-the-art meta-analytical procedures to obtain pooled odds ratios (ORs) and to evaluate potential basis of heterogeneity. We included 75 genetic association studies in these meta-analyses.
A major part of the previously postulated associations were nonconsistent in the pooled odds ratios. We observed a weak significant association with a single nucleotide polymorphism (SNP) located in the 3' UTR region of the SNAP25 gene (rs3746544, T allele, OR 1.15, 95% confidence interval 1.01-1.31, p = 0.028, I(2) = 0%). In addition to the low coverage of genetic variability given by these variants, phenotypic heterogeneity between samples (ADHD subtypes, comorbidities) and genetic background may explain these differences.
Limitations of our study include the retrospective nature of our meta-analysis with the incorporation of study-level data from published articles.
To our knowledge, the present study is the largest meta-analysis carried out for ADHD genetics; previously proposed cumulative associations with common polymorphisms in SLC6A4 and HTR1B genes were not supported. We identified a weak consistent association with a common SNP in the SNAP25 gene, a molecule that is known to be central for synaptic transmission and plasticity mechanisms.
注意缺陷多动障碍（ADHD）在患病率及其对生活质量的影响方面是一种重要的精神疾病。它是精神疾病中遗传度最高的疾病之一。世界各地已经开展了多项关联研究，探索不同人群中的多个候选基因。本研究的目的是对位于ADHD的5个顶级候选基因（BDNF、HTR1B、SLC6A2、SLC6A4和SNAP25）中的8个常见变异进行荟萃分析；已知这些基因参与突触传递和可塑性。
我们搜索了已发表的分析不同人群中候选多态性的遗传关联研究，并应用了最先进的荟萃分析程序来获得合并比值比（OR）并评估异质性的潜在基础。我们在这些荟萃分析中纳入了75项遗传关联研究。
先前假设的关联中，大部分在合并比值比中并不一致。我们观察到与位于SNAP25基因3'UTR区域的一个单核苷酸多态性（SNP）（rs3746544，T等位基因，OR 1.15，95%置信区间1.01 - 1.31，p = 0.028，I(2)=0%）存在微弱的显著关联。除了这些变异所提供的遗传变异性覆盖范围较低外，样本之间的表型异质性（ADHD亚型、共病情况）和遗传背景可能解释了这些差异。
我们研究的局限性包括荟萃分析的回顾性性质以及纳入了已发表文章中的研究水平数据。
据我们所知，本研究是针对ADHD遗传学进行的最大规模的荟萃分析；先前提出的SLC6A4和HTR1B基因常见多态性的累积关联未得到支持。我们发现与SNAP25基因中的一个常见SNP存在微弱的一致关联，SNAP25是一种已知在突触传递和可塑性机制中起核心作用的分子。
