Meta-analysis of genome-wide linkage studies across autoimmune diseases

Abstract

Autoimmune diseases are chronic disorders initiated by a loss of immunologic tolerance to self-antigens. They cluster within families, and patients may be diagnosed with more than one disease, suggesting pleiotropic genes are involved in the aetiology of different diseases. To identify potential loci, which confer susceptibility to autoimmunity independent of disease phenotype, we pooled results from genome-wide linkage studies, using the genome scan meta-analysis method (GSMA). The meta-analysis included 42 independent studies for 11 autoimmune diseases, using 7350 families with 18 291 affected individuals. In addition to the HLA region, which showed highly significant genome-wide evidence for linkage, we obtained suggestive evidence for linkage on chromosome 16, with peak evidence at 10.0-19.8 Mb. This region may harbour a pleiotropic gene (or genes) conferring risk for several diseases, although no such gene has been identified through association studies. We did not identify evidence for linkage at several genes known to confer increased risk to different autoimmune diseases (PTPN22, CTLA4), even in subgroups of diseases consistently found to be associated with these genes. The relative risks conferred by variants in these genes are modest (<1.5 in most cases), and even a large study like this meta-analysis lacks power to detect linkage. This study illustrates the concept that linkage and association studies have power to identify very different types of disease-predisposing variants.

Figure 1

Evidence for linkage in meta-analysis of 42 genome-wide linkage studies by chromosome (X-axis). Y-axis shows –log₁₀ (P-value) for unweighted and weighted (wts1 and wts2) summed ranks against bin location (30 cM bins), with a single point plotted for each bin, omitting HLA region showing strong linkage. Thresholds for nominal, suggestive and genome-wide significant evidence for linkage are shown.

Figure 2

Linkage to chromosome 16 using different bin widths (20 cM, 30 cM and 40 cM) and shifted 30 cM bins for the weighted GSMA (wts2) on 42 studies. The Y-axis is –log₁₀ (P-value) multiplied by the total number of bins, to give consistent thresholds for genome-wide and suggestive evidence for linkage for all bin widths.

Figure 3

Contribution of each autoimmune disease to the most strongly linked 20 cM bin on 16p13.2-p12.3, with 50 and 75th percentile of ranks for the whole genome shown.