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.