Eli A Stahl, Daniel Wegmann, Gosia Trynka, Javier Gutierrez-Achury, Ron Do, Benjamin F Voight, Peter Kraft, Robert Chen, Henrik J Kallberg, Fina A S Kurreeman, Sekar Kathiresan, Cisca Wijmenga, Peter K Gregersen, Lars Alfredsson, Katherine A Siminovitch, Jane Worthington, Paul I W de Bakker, Soumya Raychaudhuri, Robert M Plenge

The genetic architectures of common, complex diseases are largely uncharacterized. We modeled the genetic architecture underlying genome-wide association study (GWAS) data for rheumatoid arthritis and developed a new method using polygenic risk-score analyses to infer the total liability-scale variance explained by associated GWAS SNPs. Using this method, we estimated that, together, thousands of SNPs from rheumatoid arthritis GWAS explain an additional 20% of disease risk (excluding known associated loci). We further tested this method on datasets for three additional diseases and obtained comparable estimates for celiac disease (43% excluding the major histocompatibility complex), myocardial infarction and coronary artery disease (48%) and type 2 diabetes (49%). Our results are consistent with simulated genetic models in which hundreds of associated loci harbor common causal variants and a smaller number of loci harbor multiple rare causal variants. These analyses suggest that GWAS will continue to be highly productive for the discovery of additional susceptibility loci for common diseases.