On the replication of genetic associations:: Timing can be everything!
On the replication of genetic associations:: Timing can be everything!
复制标题
DOI：
10.1016/j.ajhg.2008.01.018
复制
发表时间：
2008-04-01
影响因子：
9.8
通讯作者：
Lange, Christoph
中科院分区：
文献类型：
--
作者：
Lasky-Su, Jessica;Lyon, Helen N.;Lange, Christoph
研究人员未能复制遗传关联的发现，最常见的原因是统计能力不足，人口分层，或各种形式的研究之间的异质性或环境影响。“在这里，我们说明了另一个潜在的原因，到目前为止还没有得到太多的关注，在文献中。我们举例说明，遗传效应的强度可以随年龄而变化，从而导致“年龄变化的关联”。“如果在研究的设计和分析过程中没有考虑到，年龄变化的遗传关联可能会导致非复制。通过使用心脏研究的100 K SNP扫描，我们确定了ROBO 1中的SNP与肥胖之间的年龄变化相关性，并假设了年龄-基因相互作用。这一发现在8个独立样本中进行了跟踪，包括13，584人。在8项研究中的5项研究中重复了这种关联，显示出年龄依赖性关系（单侧合并p = 3.92 x 10（-9），儿科队列的合并p值= 2.21 X 10（-8），成人队列的合并p值= 0.00422）。此外，这项研究表明，这是很难的横断面研究设计，以检测年龄变化的关联。如果在选择随访样本和统计分析时没有考虑年龄或时间变化的遗传效应，可能会错过重要的遗传关联。
The failure of researchers to replicate genetic-association findings is most commonly attributed to insufficient statistical power, population stratification, or various forms of between-study heterogeneity or environmental influences.' Here, we illustrate another potential cause for nonreplications that has so far not received much attention in the literature. We illustrate that the strength of a genetic effect can vary by age, causing "age-varying associations." If not taken into account during the design and the analysis of a study, age-varying genetic associations can cause nonreplication. By using the 100K SNP scan of the Framingham Heart Study, we identified an age-varying association between a SNP in ROBO1 and obesity and hypothesized an age-gene interaction. This finding was followed up in eight independent samples comprising 13,584 individuals. The association was replicated in five of the eight studies, showing an age-dependent relationship (one-sided combined p = 3.92 x 10(-9), combined p value from pediatric cohorts = 2.21 X 10(-8), combined p value from adult cohorts = 0.00422). Furthermore, this study illustrates that it is difficult for cross-sectional study designs to detect age-varying associations. If the specifics of age- or time-varying genetic effects are not considered in the selection of both the follow-up samples and in the statistical analysis, important genetic associations may be missed.