Incorporating Prior Knowledge about Genetic Variants into the Analysis of Genetic Association Data: An Empirical Bayes Approach.

Abstract

In a genome-wide association study (GWAS), the probability that a single nucleotide polymorphism (SNP) is not associated with a disease is its local false discovery rate (LFDR). The LFDR for each SNP is relative to a reference class of SNPs. For example, the LFDR of an exonic SNP can vary widely depending on whether it is considered relative to the separate reference class of other exonic SNPs or relative to the combined reference class of all SNPs in the data set. As a result, the analysis of the data based on the combined reference class might indicate that a specific exonic SNP is associated with the disease, while using the separate reference class indicates that it is not associated, or vice versa. To address that, we introduce empirical Bayes methods that simultaneously consider a combined reference class and a separate reference class. Our simulation studies indicate that the proposed methods lead to improved performance. The new maximum entropy method achieves that by depending on the separate class when it has enough SNPs for reliable LFDR estimation and depending solely on the combined class otherwise. We used the new methods to analyze data from a GWAS of 2,000 cases and 3,000 controls. R functions implementing the proposed methods are available on CRAN <https://cran.r-project.org/web/packages/LFDREmpiricalBayes> and Shiny <https://empiricalbayes.shinyapps.io/lfdrempiricalbayesapp>.