Genetics of rheumatoid arthritis: time for a change!

To review recent progress in the genetics of rheumatoid arthritis (RA) and discuss the implications for understanding the pathogenesis of the disease as well as clinical application.

Protection against anticitrullinated protein antibody (ACPA) positive RA was shown to be associated wit DRB1*1301. Genome-wide association studies (GWASs) added about 10 new loci to the list of already more than 20 loci associated with RA, so the list is now over 30. Typing for the known risk loci is not helpful for prediction of the risk for RA. It is remarkable how few functional studies have been published.

Known genetic factors explain 50-60% of the genetic variance for susceptibility to ACPA-positive and 30-50% for ACPA-negative RA. Searching for the remaining missing or hidden heritability is in all probability not going to yield much for prediction and/or targeted intervention. Therefore, I conclude that if you want to find more genes you should have a lot of patience, time and money, stop with convential GWAS and invest in large-scale sequencing of selected patients and controls. I have a better suggestion, however: use the information that is already available to perform functional studies in order to understand the mechanism of the known associations!