a covering method for detecting genetic associations between rare variants and common phenotypes覆盖方法检测基因罕见变异之间的联系和共同的表型.pdfVIP

A Covering Method for Detecting Genetic Associations between Rare Variants and Common Phenotypes 1,2 3 3 3 4 3,4 Gaurav Bhatia *, Vikas Bansal , Olivier Harismendy , Nicholas J. Schork , Eric J. Topol , Kelly Frazer , Vineet Bafna1,5 1 Department of Computer Science and Engineering, University of California San Diego, La Jolla, California, United States of America, 2 Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts, United States of America, 3 Scripps Translational Science Institute, La Jolla, California, United States of America, 4 Department of Pediatrics, University of California San Diego, La Jolla, California, United States of America, 5 Institute for Genomic Medicine, University of California San Diego, La Jolla, California, United States of America Abstract Genome wide association (GWA) studies, which test for association between common genetic markers and a disease phenotype, have shown varying degrees of success. While many factors could potentially confound GWA studies, we focus on the possibility that multiple, rare variants (RVs) may act in concert to influence disease etiology. Here, we describe an algorithm for RV analysis, RARECOVER. The algorithm combines a disparate collection of RVs with low effect and modest penetrance. Further, it does not require the rare variants be adjacent in location. Extensive simulations over a range of assumed penetrance and population attributable risk (PAR) values illustrate the power of our approach over other published methods, including the collapsing and weighted-collapsing strategies. To showcase the method, we apply