Xu X, Hawi Z, Brookes K J, Anney R, Bellgrove M, Franke B, Barry E, Chen W, Kuntsi J, Banaschewski T, Buitelaar J, Ebstein R, Fitzgerald M, Miranda A, Oades R D, Roeyers H, Rothenberger A, Sergeant J, Sonuga-Barke E, Steinhausen H-C, Faraone S V, Gill M, Asherson P
MRC Social Genetic Developmental and Psychiatry Centre, Institute of Psychiatry, London, UK.
Am J Med Genet B Neuropsychiatr Genet. 2008 Dec 5;147B(8):1564-7. doi: 10.1002/ajmg.b.30872.
Replication is a key to resolving whether a reported genetic association represents a false positive finding or an actual genetic risk factor. In a previous study screening 51 candidate genes for association with ADHD in a multi-centre European sample (the IMAGE project), two single nucleotide polymorphisms (SNPs) within the norepinephrine transporter (SLC6A2) gene were found to be associated with attention deficit hyperactivity disorder (ADHD). The same SNP alleles were also reported to be associated with ADHD in a separate study from the Massachusetts General Hospital in the US. Using two independent samples of ADHD DSM-IV combined subtype trios we attempted to replicate the reported associations with SNPs rs11568324 and rs3785143 in SLC6A2. Significant association of the two markers was not observed in the two independent replication samples. However, across all four datasets the overall evidence of association with ADHD was significant (for SNP rs11568324 P = 0.0001; average odds ratio = 0.33; for SNP rs3785143 P = 0.008; average odds ratio = 1.3). The data were consistent for rs11568324, suggesting the existence of a rare allele conferring protection for ADHD within the SLC6A2 gene. Further investigations should focus on identifying the mechanisms underlying the protective effect.
重复验证是判断所报道的基因关联是代表假阳性结果还是实际基因风险因素的关键。在之前一项针对欧洲多中心样本（IMAGE项目）中与注意力缺陷多动障碍（ADHD）相关的51个候选基因进行筛查的研究中，发现去甲肾上腺素转运体（SLC6A2）基因内的两个单核苷酸多态性（SNP）与注意力缺陷多动障碍（ADHD）相关。在美国马萨诸塞州总医院的另一项研究中也报道了相同的SNP等位基因与ADHD相关。我们使用两个独立的ADHD DSM-IV合并亚型三联体样本，试图重复所报道的SLC6A2基因中SNP rs11568324和rs3785143的关联。在这两个独立的重复验证样本中未观察到这两个标记的显著关联。然而，在所有四个数据集中，与ADHD关联的总体证据是显著的（对于SNP rs11568324，P = 0.0001；平均优势比 = 0.33；对于SNP rs3785143，P = 0.008；平均优势比 = 1.3）。rs11568324的数据是一致的，表明SLC6A2基因内存在一种赋予ADHD保护作用的罕见等位基因。进一步的研究应侧重于确定这种保护作用背后的机制。
