Poor replication of candidate genes for major depressive disorder using genome-wide association data
Poor replication of candidate genes for major depressive disorder using genome-wide association data
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DOI：
10.1038/mp.2010.38
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发表时间：
2011-05-01
影响因子：
11
通讯作者：
Nolen, W. A.
中科院分区：
文献类型：
--
作者：
Bosker, F. J.;Hartman, C. A.;Nolen, W. A.
利用来自重性抑郁症（MDD）的遗传关联信息网络（GAIN）全基因组关联研究（GWAS）的数据，来探究先前报道的MDD中候选基因和单核苷酸多态性（SNP）的关联。在GAIN的MDD研究结果公布之前，对病例对照研究中与MDD相关的候选基因进行了系统的文献检索。在包含1738例患者和1802例对照的GAIN MDD研究中，对测量的和估算的候选SNP及基因进行了检测。估算用于增加GWAS中SNP的数量，并提高所选候选基因中SNP的覆盖度。使用不同的统计方法对单个SNP和整个基因进行检测，以置换分析作为最终的判定方法。总共确定了78篇报道57个基因的论文，从中可定位92个SNP。在GAIN MDD研究中，有两个SNP与MDD相关：C5orf20（rs12520799；P = 0.038；优势比（OR）AT = 1.10，95%置信区间（CI）0.95 - 1.29；OR TT = 1.21，95%置信区间1.01 - 1.47）和NPY（rs16139；P = 0.034；OR C等位基因 = 0.73，95% CI 0.55 - 0.97），这构成了对先前确定的SNP的直接重复验证。在基因水平上，TNF（rs76917；OR T = 1.35，95% CI 1.13 - 1.63；P = 0.0034）被确定为在多重检验校正后与MDD的关联仍显著的唯一基因。对于SLC6A2（去甲肾上腺素转运体（NET）），在考虑连锁不平衡（LD）结构的情况下，与预期相比，有显著更多的SNP（100个中有19个；P = 0.039）相关。因此，我们发现仅有4个基因支持参与MDD。然而，考虑到所检测的候选SNP和基因的数量，即使这些显著的结果也很可能是假阳性。重复验证不佳可能指向先前候选基因研究中的发表偏倚和假阳性发现，也可能与MDD表型的异质性以及环境或遗传背景因素有关。《分子精神病学》（2011年）16卷，516 - 532页；doi:10.1038/mp.2010.38；2010年3月30日在线发表
Data from the Genetic Association Information Network ( GAIN) genome-wide association study (GWAS) in major depressive disorder (MDD) were used to explore previously reported candidate gene and single-nucleotide polymorphism (SNP) associations in MDD. A systematic literature search of candidate genes associated with MDD in case-control studies was performed before the results of the GAIN MDD study became available. Measured and imputed candidate SNPs and genes were tested in the GAIN MDD study encompassing 1738 cases and 1802 controls. Imputation was used to increase the number of SNPs from the GWAS and to improve coverage of SNPs in the candidate genes selected. Tests were carried out for individual SNPs and the entire gene using different statistical approaches, with permutation analysis as the final arbiter. In all, 78 papers reporting on 57 genes were identified, from which 92 SNPs could be mapped. In the GAIN MDD study, two SNPs were associated with MDD: C5orf20 (rs12520799; P = 0.038; odds ratio (OR) AT = 1.10, 95% CI 0.95-1.29; OR TT = 1.21, 95% confidence interval (CI) 1.01-1.47) and NPY (rs16139; P = 0.034; OR C allele = 0.73, 95% CI 0.55-0.97), constituting a direct replication of previously identified SNPs. At the gene level, TNF (rs76917; OR T = 1.35, 95% CI 1.13-1.63; P = 0.0034) was identified as the only gene for which the association with MDD remained significant after correction for multiple testing. For SLC6A2 (norepinephrine transporter (NET)) significantly more SNPs (19 out of 100; P = 0.039) than expected were associated while accounting for the linkage disequilibrium (LD) structure. Thus, we found support for involvement in MDD for only four genes. However, given the number of candidate SNPs and genes that were tested, even these significant may well be false positives. The poor replication may point to publication bias and false-positive findings in previous candidate gene studies, and may also be related to heterogeneity of the MDD phenotype as well as contextual genetic or environmental factors. Molecular Psychiatry (2011) 16, 516-532; doi: 10.1038/mp.2010.38; published online 30 March 2010