Towards compendia of negative genetic association studies: an example for Alzheimer disease
Towards compendia of negative genetic association studies: an example for Alzheimer disease
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DOI：
10.1007/s00439-005-0078-9
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发表时间：
2006-03-01
期刊：
影响因子：
5.3
通讯作者：
Prince, JA
中科院分区：
文献类型：
--
作者：
Blomqvist, MEL;Reynolds, C;Prince, JA
大多数导致复杂人类性状变异的基因序列变异具有很小的影响，这些影响在遗传关联研究中通常使用的人群样本中不易检测到。基因发现过程中一个潜在有价值的工具是对累积的已发表数据进行荟萃分析，但为了有效，这些需要代表真实遗传效应的研究样本，因此假设应该包括一些积极的和大量的负面报告。对2004年1月至2005年4月阿尔茨海默病（AD）相关研究的文献进行了一项调查，确定了138项研究，其中86项报告了载脂蛋白E（APOE）以外的阳性结果，强烈表明了发表偏倚。我们在这里报告了62个遗传标记的分析，测试了与AD风险的相关性以及对AD严重程度定量指标（简易精神状态检查评分、发病年龄和脑脊液（CSF）β-淀粉样蛋白（A β）和CSF tau蛋白）的可能影响。在这一组中，只有适度的信号，除了APOE很容易丢失时，适用于多个假设的校正。因此，孤立地看，结果基本上是负面的。研究的基因包括两种新的候选基因以及最近声称与AD相关的几种基因（例如尿激酶纤溶酶原激活物（PLAU）和乙酰辅酶A乙酰转移酶1（ACAT 1））。通过报告这些数据，我们希望鼓励基因纲要的出版，以指导进一步的研究，并帮助未来的荟萃分析，旨在解决基因在复杂的人类特征的参与。
Most genetic sequence variants that contribute to variability in complex human traits will have small effects that are not readily detectable with population samples typically used in genetic association studies. A potentially valuable tool in the gene discovery process is meta-analysis of the accumulated published data, but in order to be valid these require a sample of studies representative of the true genetic effect and thus hypothetically should include some positive and an abundance of negative reports. A survey of the literature on association studies for Alzheimer disease (AD) from January 2004-April 2005, identified 138 studies, 86 of which reported positive findings other than for apolipoprotein E (APOE), strongly indicative of publication bias. We report here an analysis of 62 genetic markers, tested for association with AD risk as well as for possible effects upon quantitative indices of AD severity (mini-mental state examination scores, age-at-onset, and cerebrospinal fluid (CSF) beta-amyloid (A beta) and CSF tau proteins). Within this set, only modest signals were present that, with the exception of APOE are easily lost when corrections for multiple hypotheses are applied. In isolation, results are thus broadly negative. Genes studied encompass both novel candidates as well as several recently claimed to be associated with AD (e.g. urokinase plasminogen activator (PLAU) and acetyl-coenzyme A acetyltransferase 1 (ACAT1)). By reporting these data we hope to encourage the publication of gene compendia to guide further studies and aid future meta-analyses aimed at resolving the involvement of genes in complex human traits.