title: A W-test collapsing method for rare-variant association testing in exome sequencing data.
abstract: Advancement in sequencing technology enables the study of association between complex disorder phenotypes and single-nucleotide polymorphisms with rare mutations. However, the rare genetic variant has extremely small variance and impairs testing power of traditional statistical methods. We introduce a W-test collapsing method to evaluate rare-variant association by measuring the distributional differences between cases and controls through combined log of odds ratio within a genomic region. The method is model-free and inherits chi-squared distribution with degrees of freedom estimated from bootstrapped samples of the data, and allows for fast and accurate P-value calculation without the need of permutations. The proposed method is compared with the Weighted-Sum Statistic and Sequence Kernel Association Test on simulation datasets, and showed good performances and significantly faster computing speed. In the application of real next-generation sequencing dataset of hypertensive disorder, it identified genes of interesting biological functions associated to metabolism disorder and inflammation, including the MACROD1, NLRP7, AGK, PAK6, and APBB1. The proposed method offers an efficient and effective way for testing rare genetic variants in whole exome sequencing datasets.
authors.affiliation: Division of Biostatistics, Centre for Clinical Research and Biostatistics, JC School of Public Health and Primary Care, Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR.|Centre for Clinical Trials and Biostatistics, CUHK Shenzhen Research Institute, Shenzhen, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Sun
authors.affiliation: Division of Biostatistics, Centre for Clinical Research and Biostatistics, JC School of Public Health and Primary Care, Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR.|Centre for Clinical Trials and Biostatistics, CUHK Shenzhen Research Institute, Shenzhen, China.
authors.forename: Haoyi
authors.initials: H
authors.lastname: Weng
authors.affiliation: ISOM Department, Biomedical Engineering Division, Hong Kong University of Science and Technology, Kowloon, Hong Kong SAR.
authors.forename: Inchi
authors.initials: I
authors.lastname: Hu
authors.affiliation: Division of Biostatistics, Centre for Clinical Research and Biostatistics, JC School of Public Health and Primary Care, Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR.|Centre for Clinical Trials and Biostatistics, CUHK Shenzhen Research Institute, Shenzhen, China.|Australian National University, Canberra, Australia.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Anesthesia and Intensive Care, Chinese University of Hong Kong, Hong Kong, Hong Kong SAR.
authors.forename: William K K
authors.initials: WK
authors.lastname: Wu
authors.affiliation: Division of Biostatistics, Centre for Clinical Research and Biostatistics, JC School of Public Health and Primary Care, Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR.|Centre for Clinical Trials and Biostatistics, CUHK Shenzhen Research Institute, Shenzhen, China.
authors.forename: Benny Chung-Ying
authors.initials: BC
authors.lastname: Zee
authors.affiliation: Division of Biostatistics, Centre for Clinical Research and Biostatistics, JC School of Public Health and Primary Care, Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR. maggiew@cuhk.edu.hk.|Centre for Clinical Trials and Biostatistics, CUHK Shenzhen Research Institute, Shenzhen, China. maggiew@cuhk.edu.hk.
authors.forename: Maggie Haitian
authors.initials: MH
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D002265:Carboxylic Ester Hydrolases; D056726:Genetic Association Studies; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000473:pathology; D008957:Models, Genetic; D009363:Neoplasm Proteins / Q000235:genetics; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C502448:NLRP7 protein, human; D009363:Neoplasm Proteins; C492429:AGK protein, human; D017853:Phosphotransferases (Alcohol Group Acceptor); D002265:Carboxylic Ester Hydrolases; C476832:MACROD1 protein, human
keywords: exome sequencing; genetic association study; rare-variant testing