Gene-set and pathway analyses have also been used to investigate genetic influences on complex traits by utilizing associations that are not GWS, based on the principle that genes belonging to the same molecular and cellular pathways work together to influence disease susceptibility. Although the effects of single genes may be too small to detect individually, they may be detectable when their effects are aggregated (Wang et al., 2011). Gene-set analysis identifies genes that contain an excess of SNPs with low P-values, in contrast to traditional GWAS analysis, which tests for association with individual SNPs. This reduces the multiple testing burden from ∼1 million tests to ∼20,000 tests. Pathway analysis, an extension of gene-set analysis, models the relationships between genes in a set to gain insights into the underlying biology of a phenotype. Although the terms “gene-set” and “pathway” analysis are often used synonymously, we limit the term “gene-set analysis” to those that do not incorporate pathway-level information.
