title: Assessing methods for assigning SNPs to genes in gene-based tests of association using common variants.
abstract: Gene-based tests of association are frequently applied to common SNPs (MAF>5%) as an alternative to single-marker tests. In this analysis we conduct a variety of simulation studies applied to five popular gene-based tests investigating general trends related to their performance in realistic situations. In particular, we focus on the impact of non-causal SNPs and a variety of LD structures on the behavior of these tests. Ultimately, we find that non-causal SNPs can significantly impact the power of all gene-based tests. On average, we find that the "noise" from 6-12 non-causal SNPs will cancel out the "signal" of one causal SNP across five popular gene-based tests. Furthermore, we find complex and differing behavior of the methods in the presence of LD within and between non-causal and causal SNPs. Ultimately, better approaches for a priori prioritization of potentially causal SNPs (e.g., predicting functionality of non-synonymous SNPs), application of these methods to sequenced or fully imputed datasets, and limited use of window-based methods for assigning inter-genic SNPs to genes will improve power. However, significant power loss from non-causal SNPs may remain unless alternative statistical approaches robust to the inclusion of non-causal SNPs are developed.
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, Washington, United States of America.
authors.forename: Ashley
authors.initials: A
authors.lastname: Petersen
authors.forename: Carolina
authors.initials: C
authors.lastname: Alvarez
authors.forename: Scott
authors.initials: S
authors.lastname: DeClaire
authors.forename: Nathan L
authors.initials: NL
authors.lastname: Tintle
mesh_terms: D000465:Algorithms; D002879:Chromosomes, Human, Pair 10; D003198:Computer Simulation; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008957:Models, Genetic; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011951:Receptors, Complement / Q000235:genetics*
chemical_list: D011951:Receptors, Complement; C414427:VSIG4 protein, human