Abstract:
Both trio and population designs are popular study designs for identifying risk genetic variants in genome-wide association studies (GWASs). The trio design, as a family-based design, is robust to confounding due to population structure, whereas the population design is often more powerful due to larger sample sizes. Here, we propose KnockoffHybrid, a knockoff-based statistical method for hybrid analysis of both the trio and population designs. KnockoffHybrid provides a unified framework that brings together the advantages of both designs and produces powerful hybrid analysis while controlling the false discovery rate (FDR) in the presence of linkage disequilibrium and population structure. Furthermore, KnockoffHybrid has the flexibility to leverage different types of summary statistics for hybrid analyses, including expression quantitative trait loci (eQTL) and GWAS summary statistics. We demonstrate in simulations that KnockoffHybrid offers power gains over non-hybrid methods for the trio and population designs with the same number of cases while controlling the FDR with complex correlation among variants and population structure among subjects. In hybrid analyses of three trio cohorts for autism spectrum disorders (ASDs) from the Autism Speaks MSSNG, Autism Sequencing Consortium, and Autism Genome Project with GWAS summary statistics from the iPSYCH project and eQTL summary statistics from the MetaBrain project, KnockoffHybrid outperforms conventional methods by replicating several known risk genes for ASDs and identifying additional associations with variants in other genes, including the PRAME family genes involved in axon guidance and which may act as common targets for human speech/language evolution and related disorders.
摘要:
三重奏和种群设计都是流行的研究设计,用于在全基因组关联研究(GWAS)中识别风险遗传变异。三重奏设计,作为一个基于家庭的设计,由于人口结构,对混杂来说是稳健的,而总体设计通常由于样本量较大而更强大。这里,我们提议KnockoffHybrid,一种基于仿冒的统计方法,用于对三重奏和种群设计进行混合分析。KnockoffHybrid提供了一个统一的框架,该框架将两种设计的优点结合在一起,并产生强大的混合分析,同时在存在连锁不平衡和种群结构的情况下控制错误发现率(FDR)。此外,KnockoffHybrid可以灵活地利用不同类型的汇总统计数据进行混合分析,包括表达数量性状位点(eQTL)和GWAS汇总统计。我们在模拟中证明,KnockoffHybrid在相同数量的情况下为三重奏和种群设计提供了优于非混合方法的功率增益,同时控制了变量之间的复杂相关性和受试者之间的种群结构。在来自自闭症患者MSSNG的自闭症谱系障碍(ASD)的三个三人组的混合分析中,自闭症测序协会,和孤独症基因组项目,iPSYCH项目的GWAS汇总统计和MetaBrain项目的eQTL汇总统计,KnockoffHybrid通过复制几个已知的ASD风险基因并确定与其他基因变体的其他关联,优于常规方法。包括参与轴突导向的PRAME家族基因,这些基因可能是人类言语/语言进化和相关疾病的共同靶标。