Mapping of multiple susceptibility variants within the MHC region for 7 immune-mediated diseases

Abstract

The human MHC represents the strongest susceptibility locus for autoimmune diseases. However, the identification of the true predisposing gene(s) has been handicapped by the strong linkage disequilibrium across the region. Furthermore, most studies to date have been limited to the examination of a subset of the HLA and non-HLA genes with a marker density and sample size insufficient for mapping all independent association signals. We genotyped a panel of 1,472 SNPs to capture the common genomic variation across the 3.44 megabase (Mb) classic MHC region in 10,576 DNA samples derived from patients with systemic lupus erythematosus, Crohn's disease, ulcerative colitis, rheumatoid arthritis, myasthenia gravis, selective IgA deficiency, multiple sclerosis, and appropriate control samples. We identified the primary association signals for each disease and performed conditional regression to identify independent secondary signals. The data demonstrate that MHC associations with autoimmune diseases result from complex, multilocus effects that span the entire region.

Fig. 1.

Summary of primary and secondary signals for all 7 diseases. Top primary association signals (red) and putative independent secondary signals (blue) are shown for each disease along with their location within the region. Independent secondary signals were defined as those with residual conditional association p-values < 0.001, following logistic regression analysis for the top primary association signal and showing pair-wise correlation (r²) lower than 0.2 with other neighboring signals. The correlation neighborhood or extent of correlation around each marker, at an r² > 0.8, is illustrated by black lines. Numbers attached to each signal refer to additional information on span and location of the correlation neighborhoods (see Table S4).