Strategies for Pathway Analysis Using GWAS and WGS Data.

Single-allele study designs, commonly used in genome-wide association studies (GWAS) as well as the more recently developed whole genome sequencing (WGS) studies, are a standard approach for investigating the relationship of common variation within the human genome to a given phenotype of interest. However, single-allele association results published for many GWAS studies represent only the tip of the iceberg for the information that can be extracted from these datasets. The primary analysis strategy for GWAS entails association analysis in which only the single nucleotide polymorphisms (SNPs) with the strongest p-values are declared statistically significant due to issues arising from multiple testing and type I errors. Factors such as locus heterogeneity, epistasis, and multiple genes conferring small effects contribute to the complexity of the genetic models underlying phenotype expression. Thus, many biologically meaningful associations having lower effect sizes at individual genes are overlooked, making it difficult to separate true associations from a sea of false-positive associations. Organizing these individual SNPs into biologically meaningful groups to look at the overall effects of minor perturbations to genes and pathways is desirable. This pathway-based approach provides researchers with insight into the functional foundations of the phenotype being studied and allows testing of various genetic scenarios.