title: Evolutionary meta-analysis of association studies reveals ancient constraints affecting disease marker discovery.
abstract: Genome-wide disease association studies contrast genetic variation between disease cohorts and healthy populations to discover single nucleotide polymorphisms (SNPs) and other genetic markers revealing underlying genetic architectures of human diseases. Despite scores of efforts over the past decade, many reproducible genetic variants that explain substantial proportions of the heritable risk of common human diseases remain undiscovered. We have conducted a multispecies genomic analysis of 5,831 putative human risk variants for more than 230 disease phenotypes reported in 2,021 studies. We find that the current approaches show a propensity for discovering disease-associated SNPs (dSNPs) at conserved genomic positions because the effect size (odds ratio) and allelic P value of genetic association of an SNP relates strongly to the evolutionary conservation of their genomic position. We propose a new measure for ranking SNPs that integrates evolutionary conservation scores and the P value (E-rank). Using published data from a large case-control study, we demonstrate that E-rank method prioritizes SNPs with a greater likelihood of bona fide and reproducible genetic disease associations, many of which may explain greater proportions of genetic variance. Therefore, long-term evolutionary histories of genomic positions offer key practical utility in reassessing data from existing disease association studies, and in the design and analysis of future studies aimed at revealing the genetic basis of common human diseases.
authors.forename: Joel T
authors.initials: JT
authors.lastname: Dudley
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
authors.forename: Maxwell
authors.initials: M
authors.lastname: Sanderford
authors.forename: Atul J
authors.initials: AJ
authors.lastname: Butte
authors.forename: Sudhir
authors.initials: S
authors.lastname: Kumar
mesh_terms: D000818:Animals; D019143:Evolution, Molecular; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012372:ROC Curve
chemical_list: D005819:Genetic Markers