Meta-analysis of four rheumatoid arthritis genome-wide linkage studies: confirmation of a susceptibility locus on chromosome 16.

OBJECTIVE Susceptibility to rheumatoid arthritis (RA) is likely to involve several genes of weak effect, and consequently, individual studies may have insufficient power to detect linkage. Four major RA genome-wide linkage studies have been carried out, but apart from the well-established HLA susceptibility locus, none of the reported significant regions of linkage has been replicated. We applied a genome-search meta-analysis to 4 RA genome searches to assess linkage across studies, using published results. METHODS For each study, 120 genomic bins of approximately 30 cM were defined and ranked according to the maximum evidence for linkage within each bin. Ranks were summed across studies and each bin was assessed empirically by the magnitude of summed rank, using a permutation test. A high summed rank indicated a region in which evidence for linkage was consistent across several studies. RESULTS In addition to the HLA locus (P < 0.00002), the strongest evidence for an RA susceptibility locus was found on chromosome 16 (P = 0.004). This locus was not identified as statistically significant in any of the 4 individual RA genome searches. In total, 12 regions achieved a significant (P < 0.05) summed rank, compared with the 6 bins expected by random chance. Four of these regions (on chromosomes 6p, 16cen, 6q, and 12p) reached a significance value of P < 0.01, suggesting that a subset of these regions contains RA susceptibility loci. CONCLUSION Using a meta-analysis approach, we have identified existing and novel putative RA susceptibility loci. These results can provide a basis for further positional and functional candidate-gene studies, and may prove useful in other complex rheumatic diseases.