title: A Powerful Pathway-Based Adaptive Test for Genetic Association with Common or Rare Variants.
abstract: In spite of the success of genome-wide association studies (GWASs), only a small proportion of heritability for each complex trait has been explained by identified genetic variants, mainly SNPs. Likely reasons include genetic heterogeneity (i.e., multiple causal genetic variants) and small effect sizes of causal variants, for which pathway analysis has been proposed as a promising alternative to the standard single-SNP-based analysis. A pathway contains a set of functionally related genes, each of which includes multiple SNPs. Here we propose a pathway-based test that is adaptive at both the gene and SNP levels, thus maintaining high power across a wide range of situations with varying numbers of the genes and SNPs associated with a trait. The proposed method is applicable to both common variants and rare variants and can incorporate biological knowledge on SNPs and genes to boost statistical power. We use extensively simulated data and a WTCCC GWAS dataset to compare our proposal with several existing pathway-based and SNP-set-based tests, demonstrating its promising performance and its potential use in practice.
authors.affiliation: Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: weip@biostat.umn.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Pan
authors.affiliation: Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Il-Youp
authors.initials: IY
authors.lastname: Kwak
authors.affiliation: Division of Biostatistics and Human Genetics Center, University of Texas School of Public Health, Houston, TX 77030, USA. Electronic address: peng.wei@uth.tmc.edu.
authors.forename: Peng
authors.initials: P
authors.lastname: Wei
mesh_terms: D003198:Computer Simulation; D005796:Genes / Q000235:genetics*; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008957:Models, Genetic; D020412:Multifactorial Inheritance; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
keywords: GRASS; PLINK; SNP; SPU; SSU tests; aSPU test; genome-wide association studies (GWASs)