Detecting association of rare and common variants based on cross-validation prediction error

Despite the extensive discovery of disease-associated common variants, much of the genetic contribution to complex traits remains unexplained. Rare variants may explain additional disease risk or trait variability. Although sequencing technology provides a supreme opportunity to investigate the roles of rare variants in complex diseases, detection of these variants in sequencing-based association studies presents substantial challenges. In this article, we propose novel statistical tests to test the association between rare and common variants in a genomic region and a complex trait of interest based on cross-validation prediction error (PE). We first propose a PE method based on Ridge regression. Based on PE, we also propose another two tests PE-WS and PE-TOW by testing a weighted combination of variants with two different weighting schemes. PE-WS is the PE version of the test based on the weighted sum statistic (WS) and PE-TOW is the PE version of the test based on the optimally weighted combination of variants (TOW). Using extensive simulation studies, we are able to show that (1) PE-TOW and PE-WS are consistently more powerful than TOW and WS, respectively, and (2) PE is the most powerful test when causal variants contain both common and rare variants.