Detecting Shared Genetic Architecture Among Multiple Phenotypes by Hierarchical Clustering of Gene-Level Association Statistics
Detecting Shared Genetic Architecture Among Multiple Phenotypes by Hierarchical Clustering of Gene-Level Association Statistics
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DOI：
10.1534/genetics.120.303096
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发表时间：
2020-06-01
期刊：
影响因子：
3.3
通讯作者：
Ramachandran, Sohini
中科院分区：
文献类型：
--
作者：
Mcguirl, Melissa R.;Smith, Samuel Pattillo;Ramachandran, Sohini
新兴的大规模生物银行将基因型数据与表型数据配对，为优先考虑多种表型之间的共享遗传关联提供了新的机会，以进行分子验证。过去的研究，由我们的小组和其他人，已经表明，关联的基因水平测试产生生物学上可解释的遗传结构的特征给定表型。在这里，我们提出了一种新的方法，Ward聚类，利用基因评分（WINGS）来识别内部节点分支长度异常值，用于识别多种表型之间的共享遗传结构。WINGS的目标是确定表型组或“簇”，共享一组核心基因，这些基因在病例中丰富突变。我们通过广泛的模拟研究验证了WINGS，然后将基因水平关联测试与WINGS相结合，以确定来自英国生物银行（UK Biobank）的349,468名欧洲血统个体的81例病例对照和7种定量表型的共享遗传结构。我们确定了八个优先表型集群和恢复多个已发表的基因水平的关联在优先集群。McGuirl等人提出了一种新的方法，Ward聚类，使用基因评分（WINGS）来识别内部节点分支长度异常值，用于识别多种表型之间共享的遗传结构。过去的研究……
Emerging large-scale biobanks pairing genotype data with phenotype data present new opportunities to prioritize shared genetic associations across multiple phenotypes for molecular validation. Past research, by our group and others, has shown gene-level tests of association produce biologically interpretable characterization of the genetic architecture of a given phenotype. Here, we present a new method, Ward clustering to identify Internal Node branch length outliers using Gene Scores (WINGS), for identifying shared genetic architecture among multiple phenotypes. The objective of WINGS is to identify groups of phenotypes, or "clusters," sharing a core set of genes enriched for mutations in cases. We validate WINGS using extensive simulation studies and then combine gene-level association tests with WINGS to identify shared genetic architecture among 81 case-control and seven quantitative phenotypes in 349,468 European-ancestry individuals from the UK Biobank. We identify eight prioritized phenotype clusters and recover multiple published gene-level associations within prioritized clusters.McGuirl et al. present a new method, Ward clustering to identify Internal Node branch length outliers using Gene Scores (WINGS), for identifying shared genetic architecture among multiple phenotypes. Past research...