title: An evolutionary framework for association testing in resequencing studies.
abstract: Sequencing technologies are becoming cheap enough to apply to large numbers of study participants and promise to provide new insights into human phenotypes by bringing to light rare and previously unknown genetic variants. We develop a new framework for the analysis of sequence data that incorporates all of the major features of previously proposed approaches, including those focused on allele counts and allele burden, but is both more general and more powerful. We harness population genetic theory to provide prior information on effect sizes and to create a pooling strategy for information from rare variants. Our method, EMMPAT (Evolutionary Mixed Model for Pooled Association Testing), generates a single test per gene (substantially reducing multiple testing concerns), facilitates graphical summaries, and improves the interpretation of results by allowing calculation of attributable variance. Simulations show that, relative to previously used approaches, our method increases the power to detect genes that affect phenotype when natural selection has kept alleles with large effect sizes rare. We demonstrate our approach on a population-based re-sequencing study of association between serum triglycerides and variation in ANGPTL4.
authors.affiliation: Department of Health Studies, University of Chicago, Chicago, Illinois, United States of America. cking@health.bsd.uchicago.edu
authors.forename: C Ryan
authors.initials: CR
authors.lastname: King
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Rathouz
authors.forename: Dan L
authors.initials: DL
authors.lastname: Nicolae
mesh_terms: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics; D003198:Computer Simulation; D019143:Evolution, Molecular; D056726:Genetic Association Studies; D056084:Genetic Fitness; D014644:Genetic Variation; D006801:Humans; D016018:Least-Squares Analysis; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods*; D013781:Texas
chemical_list: C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins