Fast and Rigorous Computation of Gene and Pathway Scores from SNP-Based Summary Statistics

Integrating single nucleotide polymorphism (SNP) p-values from genome-wide association studies (GWAS) across genes and pathways is a strategy to improve statistical power and gain biological insight. Here, we present Pascal (Pathway scoring algorithm), a powerful tool for computing gene and pathway scores from SNP-phenotype association summary statistics. For gene score computation, we implemented analytic and efficient numerical solutions to calculate test statistics. We examined in particular the sum and the maximum of chi-squared statistics, which measure the strongest and the average association signals per gene, respectively. For pathway scoring, we use a modified Fisher method, which offers not only significant power improvement over more traditional enrichment strategies, but also eliminates the problem of arbitrary threshold selection inherent in any binary membership based pathway enrichment approach. We demonstrate the marked increase in power by analyzing summary statistics from dozens of large meta-studies for various traits. Our extensive testing indicates that our method not only excels in rigorous type I error control, but also results in more biologically meaningful discoveries.Author Summary: Genome-wide association studies (GWAS) typically generate lists of trait- or disease-associated SNPs. Yet, such output sheds little light on the underlying molecular mechanisms and tools are needed to extract biological insight from the results at the SNP level. Pathway analysis tools integrate signals from multiple SNPs at various positions in the genome in order to map associated genomic regions to well-established pathways, i.e., sets of genes known to act in concert. The nature of GWAS association results requires specifically tailored methods for this task. Here, we present Pascal (Pathway scoring algorithm), a tool that allows gene and pathway-level analysis of GWAS association results without the need to access the original genotypic data. Pascal was designed to be fast, accurate and to have high power to detect relevant pathways. We extensively tested our approach on a large collection of real GWAS association results and saw better discovery of confirmed pathways than with other popular methods. We believe that these results together with the ease-of-use of our publicly available software will allow Pascal to become a useful addition to the toolbox of the GWAS community.