Twin and family studies suggest that systemic lupus erythematosus (SLE) has a substantial genetic susceptibility component [1–3]. Whole-genome scans of SLE families with affected sibling pairs have now been published, and, despite the relatively small sizes of the individual studies and the ethnic heterogeneity of the populations studied, there appears to be a surprising degree of overlap between findings [4–8]. All the studies have reported linkage to regions of the long arm of chromosome 1. In volume 3 issue 5 of this journal, Graham et al. described their approach to following up this linkage data for one of these regions, mapping to 1q41–42 .
Linkage analysis identifies genomic regions that are shared, identical-by-descent, by siblings affected by disease more often than would be expected by chance alone. However, linkage typically extends for 10 cM or more and such a region could contain 500 genes. Variation in any one of these genes could be responsible for the observed linkage. Association is the nonrandom cosegregation of alleles and assumes that populations are descended from a small founder group and that repeated recombinations over generations reduce the shared chromosomal segments to very small regions. Therefore, in order to detect an association, the marker and disease gene must be in linkage disequilibrium . Because linkage disequilibrium extends for shorter distances (~60 Kbp from common coding variants in the North American population) , demonstration of association refines the region likely to harbour the disease gene. Linkage disequilibrium mapping can be carried out either by directly testing potential candidate genes or by using microsatellite markers mapping to a region of linkage. Going directly to candidate genes is fraught with danger. Virtually any gene could be a candidate, and sometimes functional genes appear to have an obscure role, e.g. APOE gene polymorphism and Alzheimer's disease .
The alternative approach taken by Graham et al. was to try to refine the ~16 cM region of linkage likely to harbour the disease gene by first investigating association with a number of microsatellite markers mapping to the region in 210 families with affected sibling pairs and 122 families with three affected members. Using extensions of the family-based association method, the transmission disequilibrium test (TDT) , they found strong evidence for association with one marker, D1S490, by all the TDT methods used. Haplotype analysis not only can increase the power to detect association but also can be used to localise the genetic region harbouring the disease gene. Association with three haplotypes spanning ~9 cM was demonstrated using two-marker approaches. When three-marker haplotypes were investigated, however, association with two different combinations of markers, spanning just 3 cM, was demonstrated. The equivalent physical distance is ~2.3 Mb. Reassuringly, linkage to the 1q41–42 region was largely accounted for by families carrying either of two risk haplotypes spanning the five markers. Even though the results presented in the study provide consistent and compelling evidence to support association to the region using a number of tests, it must be remembered that no correction has been applied for multiple testing, and confirmation of these findings in other data sets is required.