title: Improved power by collapsing rare and common variants based on a data-adaptive forward selection strategy.
abstract: Genome-wide association studies have been used successfully to detect associations between common genetic variants and complex diseases, but common single-nucleotide polymorphisms (SNPs) detected by these studies explain only 5-10% of disease heritability. Alternatively, the common disease/rare variants hypothesis suggests that complex diseases are often caused by multiple rare variants with moderate to high effects. Under this hypothesis, the analysis of the cumulative effect of rare variants may thus help us discover the missing genetic variations. Collapsing all rare variants across a functional region is currently a popular method to find rare variants that may have a causal effect on certain diseases. However, the power of tests based on collapsing methods is often impaired by misclassification of functional variants. We develop a data-adaptive forward selection procedure that selectively chooses only variants that improve the association signal between functional regions and the disease risk. We apply our strategy to the Genetic Analysis Workshop 17 unrelated individuals data with quantitative traits. The type I error rate and the power of different collapsing functions are evaluated. The substantially higher power of the proposed strategy was demonstrated. The new method provides a useful strategy for the association study of sequencing data by taking advantage of the selection of rare variants.
authors.affiliation: Department of Mathematical Sciences, Michigan Technological University, 1400 Townsend Drive, Houghton, MI 49931, USA. rjiang@mtu.edu.
authors.forename: Yilin
authors.initials: Y
authors.lastname: Dai
authors.forename: Ling
authors.initials: L
authors.lastname: Guo
authors.forename: Jianping
authors.initials: J
authors.lastname: Dong
authors.forename: Renfang
authors.initials: R
authors.lastname: Jiang