Meta-Qtest: Meta-analysis of quadratic test for rare variants

Background: In genome-wide association studies (GWASs), meta-analysis has been widely used to improve statistical power by combining the results of different studies. Meta-analysis can detect phenotype associated variants that are failed to be detected in single studies. Especially, in biomedical sciences, meta-analysis is often necessary not only for improving statistical power, but also for reducing unavoidable limitation in data collection. As next-generation sequencing (NGS) technology has been developed, meta-analysis of rare variants is proceeding briskly along with meta-analysis of common variants in GWASs. However, meta-analysis on a single variant that is commonly used in common variant association test is improper for rare variants. A sparse signal of rare variant undermines the association signal and its large number causes multiple testing problem. To over-come these problems, we propose a meta-analysis method at the gene-level rather than variant level. Results: Among many methods that have been developed, we used the unified quadratic tests (Q-tests); Q-test is more powerful than or as powerful as other tests such as Sequence Kernel Association Tests (SKAT). Since there are three different versions of Q-test (QTest1, QTest2, QTest3), each assumes different relationships among multiple rare variants, we extended them into meta-study accordingly. For meta-analysis, we consider two types of approaches, the one is to combine regression coefficients and the other is to combine test statistics from each single study. We extend the Q-test for meta-analysis, proposing Meta Quadratic Test (Meta-Qtest). Meta Q-test avoids the limitations of MetaSKAT. It does not only consider genetic heterogeneity among studies as MetaSKAT but also reflects diverse real situations; since we extend three different Q-tests into meta-analysis respectively, flexible Meta Q-test suggests way to deal with gene-level rare variant meta-analysis efficiently From the results of real data analysis of blood pressure trait, our meta-analysis could successfully discovered genes, KCNA5 and CABIN1 that are already well known for relevance with hypertension disease and they are not detected in MetaSKAT. Conclusion: As exemplified by an application to T2D Genes projects data set, Meta-Qtest more effectively identified genes associated with hypertension disease than MetaSKAT did.