罕见变异关联方法的进展。
Progress in methods for rare variant association.
作者信息
Santorico Stephanie A, Hendricks Audrey E
机构信息
Department of Mathematical and Statistical Sciences, University of Colorado Denver, Denver, CO, 80217-3364, USA.
出版信息
BMC Genet. 2016 Feb 3;17 Suppl 2(Suppl 2):6. doi: 10.1186/s12863-015-0316-7.
Empirical studies and evolutionary theory support a role for rare variants in the etiology of complex traits. Given this motivation and increasing affordability of whole-exome and whole-genome sequencing, methods for rare variant association have been an active area of research for the past decade. Here, we provide a survey of the current literature and developments from the Genetics Analysis Workshop 19 (GAW19) Collapsing Rare Variants working group. In particular, we present the generalized linear regression framework and associated score statistic for the 2 major types of methods: burden and variance components methods. We further show that by simply modifying weights within these frameworks we arrive at many of the popular existing methods, for example, the cohort allelic sums test and sequence kernel association test. Meta-analysis techniques are also described. Next, we describe the 6 contributions from the GAW19 Collapsing Rare Variants working group. These included development of new methods, such as a retrospective likelihood for family data, a method using genomic structure to compare cases and controls, a haplotype-based meta-analysis, and a permutation-based method for combining different statistical tests. In addition, one contribution compared a mega-analysis of family-based and population-based data to meta-analysis. Finally, the power of existing family-based methods for binary traits was compared. We conclude with suggestions for open research questions.
实证研究和进化理论支持罕见变异在复杂性状病因学中的作用。鉴于这一动机以及全外显子组测序和全基因组测序成本的不断降低,在过去十年中,罕见变异关联方法一直是一个活跃的研究领域。在此,我们对当前文献以及遗传分析研讨会19(GAW19)的合并罕见变异工作组的进展进行综述。特别是,我们介绍了广义线性回归框架以及两种主要方法类型(负担法和方差成分法)的相关得分统计量。我们进一步表明,通过简单地在这些框架内修改权重,我们就能得到许多现有的流行方法,例如队列等位基因总和检验和序列核关联检验。还描述了荟萃分析技术。接下来,我们描述GAW19合并罕见变异工作组的6项贡献。这些贡献包括新方法的开发,如家庭数据的回顾性似然法、一种利用基因组结构比较病例和对照的方法、基于单倍型的荟萃分析以及一种用于组合不同统计检验的基于置换的方法。此外,有一项贡献将基于家庭和基于人群的数据的大型分析与荟萃分析进行了比较。最后,比较了现有的基于家庭的二元性状方法的效能。我们以对开放性研究问题的建议作为结论。
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