A gene-based test of association through an orthogonal decomposition of genotype scores.

The burden test and the sequence kernel association test (SKAT) are two popular methods for detecting association with rare variants. Treated as two different sources of association information, they are adaptively combined to form an optimal SKAT (SKAT-O) method for optimal power. We show that the burden test is part of rather than independent of the SKAT. We introduce a new test statistic that is the sum of the burden statistic and a statistic asymptotically independent of the burden statistic. The performance of this new test statistic is demonstrated through extensive simulation studies and applications to a Genetic Analysis Workshop 17 data set and the Ocular Hypertension Treatment Study data.