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PLoS Comput Biol. 2016 Jan 25;12(1):e1004714. doi: 10.1371/journal.pcbi.1004714. eCollection 2016 Jan.

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

Author information

1
Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
2
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
3
Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.

Abstract

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.

PMID:
26808494
PMCID:
PMC4726509
DOI:
10.1371/journal.pcbi.1004714
[Indexed for MEDLINE]
Free PMC Article

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