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Methods Mol Biol. 2013;1019:519-41. doi: 10.1007/978-1-62703-447-0_25.

Incorporating prior knowledge to increase the power of genome-wide association studies.

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Department of Biostatistics, University of Washington, Seattle, WA, USA.


Typical methods of analyzing genome-wide single nucleotide variant (SNV) data in cases and controls involve testing each variant's genotypes separately for phenotype association, and then using a substantial multiple-testing penalty to minimize the rate of false positives. This approach, however, can result in low power for modestly associated SNVs. Furthermore, simply looking at the most associated SNVs may not directly yield biological insights about disease etiology. SNVset methods attempt to address both limitations of the traditional approach by testing biologically meaningful sets of SNVs (e.g., genes or pathways). The number of tests run in a SNVset analysis is typically much lower (hundreds or thousands instead of millions) than in a traditional analysis, so the false-positive rate is lower. Additionally, by testing SNVsets that are biologically meaningful finding a significant set may more quickly yield insights into disease etiology.In this chapter we summarize the short history of SNVset testing and provide an overview of the many recently proposed methods. Furthermore, we provide detailed step-by-step instructions on how to perform a SNVset analysis, including a substantial number of practical tips and questions that researchers should consider before undertaking a SNVset analysis. Lastly, we describe a companion R package (snvset) that implements recently proposed SNVset methods. While SNVset testing is a new approach, with many new methods still being developed and many open questions, the promise of the approach is worth serious consideration when considering analytic methods for GWAS.

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