metaFARVAT: An Efficient Tool for Meta-Analysis of Family-Based, Case-Control, and Population-Based Rare Variant Association Studies

Front Genet. 2019 Jun 19;10:572. doi: 10.3389/fgene.2019.00572. eCollection 2019.

Abstract

Family-based designs have been shown to be powerful in detecting the significant rare variants associated with human diseases. However, very few significant results have been found owing to relatively small sample sizes and the fact that statistical analyses often suffer from high false-negative error rates. These limitations can be avoided by combining results from multiple studies via meta-analysis. However, statistical methods for meta-analysis with rare variants are limited for family-based samples. In this report, we propose a tool for the meta-analysis of family-based rare variant associations, metaFARVAT. metaFARVAT is based on a quasi-likelihood score for each variant. These scores are combined to generate burden test, variable-threshold test, sequence kernel association test (SKAT), and optimal SKAT statistics. The proposed method tests homogeneous and heterogeneous effects of variants among different studies and can be applied to both quantitative and dichotomous phenotypes. Simulation results demonstrated the robustness and efficiency of the proposed method in different scenarios. By applying metaFARVAT to data from a family-based study and a case-control study, we identified a few promising candidate genes, including DLEC1, which is associated with chronic obstructive pulmonary disease.

Keywords: chronic obstructive pulmonary disease; family-based design; meta-analysis; metaFARVAT; rare variant association analysis.