An adaptive test for meta‐analysis of rare variant association studies

Abstract

Single genome-wide studies may be underpowered to detect trait-associated rare variants with moderate or weak effect sizes. As a viable alternative, meta-analysis is widely used to increase power by combining different studies. The power of meta-analysis critically depends on the underlying association patterns and heterogeneity levels, which are unknown and vary from locus to locus. However, existing methods mainly focus on one or only a few combinations of the association pattern and heterogeneity level, thus may lose power in many situations. To address this issue, we propose a general and unified framework by combining a class of tests including and beyond some existing ones, leading to high power across a wide range of scenarios. We demonstrate that the proposed test is more powerful than some existing methods in simulation studies, then show their performance with the NHLBI Exome-Sequencing Project (ESP) data.One gene (B4GALNT2) was found by our proposed test, but not by others, to be statistically significantly associated with plasma triglyceride. The signal was driven by African-ancestry subjects but it was previously reported to be associated with coronary artery disease among European-ancestry subjects. We implemented our method in an R package aSPUmeta, publicly available at https://github. com/ytzhong/metaRV and will be on CRAN soon. K E Y W O R D SaSPU, genetic heterogeneity, statistical power, whole-exome sequencing, whole-genome sequencing *Tianzhong Yang and Junghi Kim contributed equally to this work.

Integrating DNA sequencing and transcriptomic data for association analyses of low-frequency variants and lipid traits

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