How Can We Explain Very Low Odds Ratios in GWAS? I. Polygenic Models.
Genome-wide association studies of common diseases often identify a number of disease-related SNPs that reach highly significant p values but at the same time show very low disease odds ratios (ORs), most <1.5 and many <1.2. Despite their statistical significance, associations involving very low ORs explain little about the genetic contribution to the disease and nothing about disease inheritance. A commonly accepted explanation for very low ORs involves a model of polygenic inheritance, i.e., where the disease being studied is caused by a large number of interacting genes, each gene contributing only a small increment to disease risk. Here we demonstrate the perhaps counterintuitive result that, within a reasonable range of disease population prevalences (≤10%), a pure polygenic model is incompatible with very low ORs, unless very large numbers (hundreds or even thousands) of polygenic loci are involved.
Battelle Center for Mathematical Medicine, The Research Institute, Nationwide Children's Hospital, and Department of Pediatrics, The Ohio State University, Columbus, OH, USA.
Susan E
SE
Hodge
David A
DA
Greenberg
D030342:Genetic Diseases, Inborn / Q000235:genetics; D055106:Genome-Wide Association Study / Q000592:standards*; D006801:Humans; D008957:Models, Genetic; D020412:Multifactorial Inheritance; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide
Case-control association analysis; Complex disorder; GWAS; Genetic heterogeneity; Genome-wide scan; Linkage disequilibrium; Odds ratios; Polygenic inheritance; Statistical genetics