Fine mapping versus replication in whole-genome association studies
Fine mapping versus replication in whole-genome association studies
复制标题
DOI：
10.1086/521952
复制
发表时间：
2007-11-01
影响因子：
9.8
通讯作者：
Cardon, Lon R.
中科院分区：
文献类型：
--
作者：
Clarke, Geraldine M.;Carter, Kim W.;Cardon, Lon R.
关联复制研究的跟踪记录不佳，即使成功，也常常声称与主要研究中报告的标记、等位基因和表型不同。目前尚不清楚这些结果是否反映了真正的关联或假阳性结果。更好地理解这些观察结果对于全基因组关联（GWA）研究至关重要，因为它们有可能识别出需要外部验证的多个新关联。从理论上讲，在一个独立的样本中与完全相同的变异重复关联是复制的金标准，但在复制研究中测试额外的变异是司空见惯的。在最初鉴定的相同基因或区域内发现不同的相关SNP通常被报告为确证性证据。在这里，我们比较了两种常用的标记选择策略下复制基因或区域的概率：一种“精确”的方法，只涉及原来显着的标记和“本地”的方法，涉及原来显着的标记和其他人在同一地区。当一个标记间高度连锁不平衡的区域被用来重复与疾病只有弱关联的最初发现时，局部方法是一个很好的策略。否则，最强大和最有效的复制策略只涉及测试最初确定的变体。与最初鉴定的标记物以外的标记物的关联可能频繁发生，即使在低功率复制研究中存在真实的效应，并且这种关联的实例随着包括的变体的数量增加而增加。我们的研究结果为GWA复制研究的设计和解释提供了基础，并指出了GWA后精细映射和复制之间明确区分的重要性。
Association replication studies have a poor track record and, even when successful, often claim association with different markers, alleles, and phenotypes than those reported in the primary study. It is unknown whether these outcomes reflect genuine associations or false-positive results. A greater understanding of these observations is essential for genomewide association (GWA) studies, since they have the potential to identify multiple new associations that that will require external validation. Theoretically, a repeat association with precisely the same variant in an independent sample is the gold standard for replication, but testing additional variants is commonplace in replication studies. Finding different associated SNPs within the same gene or region as that originally identified is often reported as confirmatory evidence. Here, we compare the probability of replicating a gene or region under two commonly used marker-selection strategies: an "exact" approach that involves only the originally significant markers and a "local" approach that involves both the originally significant markers and others in the same region. When a region of high intermarker linkage disequilibrium is tested to replicate an initial finding that is only weak association with disease, the local approach is a good strategy. Otherwise, the most powerful and efficient strategy for replication involves testing only the initially identified variants. Association with a marker other than that originally identified can occur frequently, even in the presence of real effects in a low-powered replication study, and instances of such association increase as the number of included variants increases. Our results provide a basis for the design and interpretation of GWA replication studies and point to the importance of a clear distinction between fine mapping and replication after GWA.