The search for genenotype/phenotype associations and the phenome scan
The search for genenotype/phenotype associations and the phenome scan
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DOI：
10.1111/j.1365-3016.2005.00664.x
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发表时间：
2005-07-01
影响因子：
2.8
通讯作者：
Herrick, D
中科院分区：
文献类型：
--
作者：
Jones, R;Pembrey, M;Herrick, D
所有寻找基因型/表型关联的方法都有其共同的问题。比较基因组扫描和候选基因方法，前者在遗传水平或机制方面做出的假设较少，但统计难度较大，而后者部分解决了统计问题，但在遗传和机制水平上做出了更多的假设。当前的困难之一是缺乏有关基因变异/表型关联性质的信息：涉及不同类别基因或序列的频率；最常涉及的遗传变异类型；应用于分析的适当遗传模型。最重要的问题是多重测试，解决方案之一是整合遗传信息以创建较少数量的复合变量。另一方面，关于表型识别的复杂程度的决定也会影响多重测试问题：是在疾病结果的水平上进行定位，还是在中间表型或性状的多个水平上进行定位。第三个问题是如何最好地处理基因与基因或基因与环境的相互作用，或者是否忽略它们。只有当更多的基因型/表型关联出现时，无论通过何种方式，结果的数量才能回答这些问题。我们在这里描述了一种基因型/表型关联研究的新方法，即表型扫描，其中扫描人类群体中的密集表型信息以查找与个体遗传变异的关联。我们相信，这种方法可以生成有助于回答有关基因型/表型关联的一般问题以及发现新的关联的数据。
All the approaches to the search for genotype/phenotype associations have their share of problems. Comparing the genome scan and candidate gene approaches, the former makes fewer assumptions at the genetic level or about mechanism but has greater statistical difficulties while the latter partially solves the statistical problem but makes more assumptions at both genetic and mechanistic levels. Among current difficulties is a lack of information about the nature of gene variant/phenotype associations: the frequency with which different classes of gene or sequence are involved; the type of genetic variation most commonly involved; the appropriate genetic models to apply to analysis. The overarching problem is that of multiple testing, one solution to which is to integrate genetic information to create a smaller number of compound variables. At the other end of the scale, decisions about the level of complexity at which to pitch the identification of phenotypes also affect the multiple testing problem: whether to pitch them at the level of disease outcomes, or at any of the multiple levels of intermediate phenotypes or traits. The third issue is how best to deal with gene/gene or gene/environment interactions, or whether to ignore them. Only as more genotype/phenotype associations emerge, by whatever means, will the numbers of results allow these questions to be answered. We describe here a new approach to genotype/phenotype association studies, the phenome scan, in which dense phenotypic information in human cohorts is scanned for associations with individual genetic variants. We believe that this approach can generate data that will be useful in answering generic questions about genotype/phenotype associations as well as in discovering novel ones.