High-density SNP analysis of 642 Caucasian families with rheumatoid arthritis identifies two new linkage regions on 11p12 and 2q33.

We have completed a genome wide linkage scan using >5700 informative single-nucleotide polymorphism (SNP) markers (Illumina IV SNP linkage panel) in 642 Caucasian families containing affected sibling pairs with rheumatoid arthritis (RA), ascertained by the North American Rheumatoid Arthritis Consortium. The results show striking new evidence of linkage at chromosomes 2q33 and 11p12 with logarithm of odds (LOD) scores of 3.52 and 3.09, respectively. In addition to a strong and broad linkage interval surrounding the major histocompatibility complex (LOD>16), regions with LOD>2.5 were observed on chromosomes 5 and 10. Additional linkage evidence (LOD scores between 1.46 and 2.35) was also observed on chromosomes 4, 7, 12, 16 and 18. This new evidence for multiple regions of genetic linkage is partly explained by the significantly increased information content of the Illumina IV SNP linkage panel (75.6%) compared with a standard microsatellite linkage panel utilized previously (mean 52.6%). Stratified analyses according to whether or not the sibling pair members showed elevated anticyclic citrullinated peptide titers indicates significant variation in evidence for linkage among strata on chromosomes 4, 5, 6 and 7. Overall, these new linkage data should reinvigorate efforts to utilize positional information to identify susceptibility genes for RA.