Susceptibility to most complex diseases is controlled by many genes, each having a small effect on the disease. One example is rheumatoid arthritis (RA), a common complex multifactorial autoimmune disease. Several studies have been carried out to detect the genetic basis of RA, and more than 30 genomic regions have shown evidence of linkage to the disease. Most of these genomic regions did not reach a genome-wide significant threshold value of linkage, with P values between 0.05 and 0.001 [1-5]. Thus, these loci only have a small effect on RA. Small genetic contributions could also be seen from the susceptibility genes of RA identified so far, including HLA-DR4, PADI4, PTPN22 and FCRL3 [6-9]. Except for HLA-DR4, which is strongly associated with RA, all the other susceptibility genes have only a small effect on the disease. In the mouse model of RA, small genetic contributions are also often observed. For example, in a previous study, we carried out a genome screen to identify the quantitative trait loci (QTL) in collagen-induced arthritis (CIA), which is a widely used animal model of RA. Only one QTL, Cia2, was identified for the phenotype of CIA severity, but this QTL contributes to only 16% of the phenotype variations for CIA susceptibility in F2 progeny [10]. This suggests that there must be other susceptibility genes whose contributions were not big enough to reach the stringent significance threshold value of linkage analysis.