Rheumatoid arthritis (RA), like other autoimmune diseases, has a complex genetic 
basis. Rapid technical advances in high-throughput genotyping and analysis have 
now reached a point where genes of low-to-moderate risk can be identified using 
a variety of study designs, including whole genome association studies. The 
availability of large, well-characterized populations of cases and controls are 
critical to the success of these efforts. A functional variant (R620W) of the 
intracellular protein tyrosine phosphatase N22 (PTPN22) has now been 
conclusively shown to confer approximately two-fold risk for seropositive RA as 
well as several other autoimmune disorders. PTPN22 appears to act primarily by 
setting thresholds for T-cell receptor signaling, and the current data suggest 
that the PTPN22 620W allele is likely to be a general risk factor for the 
development of humoral autoimmunity. PTPN22 is expressed widely in hematopoietic 
cells, but other than in T cells, its role is unknown. These results provide 
strong evidence for the longstanding hypothesis that common genes underlie 
different autoimmune phenotypes and emphasize that finding genes of only 
moderate risk can provide important insights into disease pathogenesis.