Interpreting Meta-Analyses of Genome-Wide Association Studies

Abstract

Meta-analysis is an increasingly popular tool for combining multiple genome-wide association studies in a single analysis to identify associations with small effect sizes. The effect sizes between studies in a meta-analysis may differ and these differences, or heterogeneity, can be caused by many factors. If heterogeneity is observed in the results of a meta-analysis, interpreting the cause of heterogeneity is important because the correct interpretation can lead to a better understanding of the disease and a more effective design of a replication study. However, interpreting heterogeneous results is difficult. The standard approach of examining the association p-values of the studies does not effectively predict if the effect exists in each study. In this paper, we propose a framework facilitating the interpretation of the results of a meta-analysis. Our framework is based on a new statistic representing the posterior probability that the effect exists in each study, which is estimated utilizing cross-study information. Simulations and application to the real data show that our framework can effectively segregate the studies predicted to have an effect, the studies predicted to not have an effect, and the ambiguous studies that are underpowered. In addition to helping interpretation, the new framework also allows us to develop a new association testing procedure taking into account the existence of effect.

Author Summary

Genome-wide association studies are an effective means of identifying genetic variants that are associated with diseases. Although many associated loci have been identified, those loci account for only a small fraction of the genetic contribution to the disease. The remaining contribution may be accounted by loci with very small effect sizes, so small that tens of thousands of samples are needed to identify them. Since it is costly to conduct a study collecting such a large sample, a practical alternative is to combine multiple independent studies in a single analysis called meta-analysis. However, many factors, such as genetic or environmental factors, can differ between the studies combined in a meta-analysis. These factors can cause the effect size of the causal variant to differ between the studies, a phenomenon called heterogeneity. If heterogeneity exists in the data of a meta-analysis, interpreting the meta-analysis results is an important but difficult task. In this paper, we propose a method that helps such interpretation, in addition to a new association testing procedure that is powerful when heterogeneity exists.