MAGMA: Generalized Gene-Set Analysis of GWAS Data

Abstract

By aggregating data for complex traits in a biologically meaningful way, gene and gene-set analysis constitute a valuable addition to single-marker analysis. However, although various methods for gene and gene-set analysis currently exist, they generally suffer from a number of issues. Statistical power for most methods is strongly affected by linkage disequilibrium between markers, multi-marker associations are often hard to detect, and the reliance on permutation to compute p-values tends to make the analysis computationally very expensive. To address these issues we have developed MAGMA, a novel tool for gene and gene-set analysis. The gene analysis is based on a multiple regression model, to provide better statistical performance. The gene-set analysis is built as a separate layer around the gene analysis for additional flexibility. This gene-set analysis also uses a regression structure to allow generalization to analysis of continuous properties of genes and simultaneous analysis of multiple gene sets and other gene properties. Simulations and an analysis of Crohn’s Disease data are used to evaluate the performance of MAGMA and to compare it to a number of other gene and gene-set analysis tools. The results show that MAGMA has significantly more power than other tools for both the gene and the gene-set analysis, identifying more genes and gene sets associated with Crohn’s Disease while maintaining a correct type 1 error rate. Moreover, the MAGMA analysis of the Crohn’s Disease data was found to be considerably faster as well.

Author Summary

Gene and gene-set analysis are statistical methods for analysing multiple genetic markers simultaneously to determine their joint effect. These methods can be used when the effects of individual markers is too weak to detect, which is a common problem when studying polygenic traits. Moreover, gene-set analysis can provide additional insight into functional and biological mechanisms underlying the genetic component of a trait. Although a number of methods for gene and gene-set analysis are available however, they generally suffer from various statistical issues and can be very time-consuming to run. We have therefore developed a new method called MAGMA to address these issues, and have compared it to a number of existing tools. Our results show that MAGMA detects more associated genes and gene-sets than other methods, and is also considerably faster. The way the method is set up also makes it highly flexible. This makes it suitable as a basis for more general statistical analyses aimed at investigating more complex research questions.