GWAS are based on the common disease–common variant (CDCV) hypothesis (4), which states that relatively common genetic variants (MAF > 5%) of relatively low penetrance are important contributors to the genetic susceptibility to common diseases. Well-powered GWAS, which capture a substantial majority of common variation in the genome, have been now conducted for many common diseases. However, for the majority of these diseases, common variants explain only a small proportion of heritability (5), due to small individual effect sizes. It has been estimated that only 13% of all identified susceptibility loci have odds ratios (OR) above 2, and only 1% have OR above 10 (6). For example, if we consider a total estimated sibling recurrence risk ratio (λs) of 5–10 for rheumatoid arthritis (RA) (7), 15 for type 1 diabetes (T1D) (8), 17–35 for Crohn's disease (CD) (9) and 3 for type 2 diabetes (T2D) (10), their established susceptibility loci would contribute ∼33–47%, 55.6%, 10–12.6% and 11.9% of the total heritability, respectively (Table 1). Table 1.Established susceptibility loci for RA, T1D, CD and T2DChromosomeSNPPositionRegion/geneRAFORλsReferenceRheumatoid arthritis 1p36rs38907452553624TNFSFR140.681.121.003(16) 1p13rs2476601114377568PTPN220.101.941.068(16) 1p13rs11586238117263138CD2, CD580.241.131.003(16) 1q23rs12746613161467042FCGR2A0.121.131.002(16)
