Common and unique susceptibility loci in Graves and Hashimoto diseases: results of whole-genome screening in a data set of 102 multiplex families

Abstract

The autoimmune thyroid diseases (AITDs), comprising Graves disease (GD) and Hashimoto thyroiditis (HT), develop as a result of a complex interaction between predisposing genes and environmental triggers. Previously, we identified six loci that showed evidence for linkage with AITD in a data set of 56 multiplex families. The goals of the present study were to replicate/reject the previously identified loci before fine mapping and sequencing the candidate genes in these regions. We performed a whole-genome linkage study in an expanded data set of 102 multiplex families with AITD (540 individuals), through use of 400 microsatellite markers. Seven loci showed evidence for linkage to AITD. Three loci, on chromosomes 6p, 8q, and 10q, showed evidence for linkage with both GD and HT (maximum multipoint heterogeneity LOD scores [HLOD] 2.0, 3.5, and 4.1, respectively). Three loci showed evidence for linkage with GD: on 7q (HLOD 2.3), 14q (HLOD 2.1), and 20q (LOD 3.3, in a subset of the families). One locus on 12q showed evidence of linkage with HT, giving an HLOD of 3.4. Comparison with the results obtained in the original data set showed that the 20q (GD-2) and 12q (HT-2) loci continued to show evidence for linkage in the expanded data set; the 6p and 14q loci were located within the same region as the previously identified 6p and 14q loci (AITD-1 and GD-1, respectively), but the Xq (GD-3) and 13q (HT-1) loci were not replicated in the expanded data set. These results demonstrated that multiple genes may predispose to GD and HT and that some may be common to both diseases and some are unique. The loci that continue to show evidence for linkage in the expanded data set represent serious candidate regions for gene identification.

Figure 1

A, Whole-genome analysis for loci linked with both GD and HT (AITD). The X-axis shows the relative marker positions on each chromosome, and the Y-axis shows the two-point LOD score obtained for each marker on every chromosome. Three loci, on chromosomes 6p, 8q, and 10q (marked by asterisks [*]), gave two-point LOD scores >2. B, The differences between the two-point LOD scores obtained in the expanded data set and those obtained in the original data set. The X-axis shows the relative marker positions on each chromosome, and the Y-axis shows Z_total−Z_orig for each marker. Two loci, on chromosomes 8q and 10q, showed a notable increase in LOD scores. One marker on 2q also showed an increase in LOD score, but the Z_total at this locus remained <2.

Figure 2

Multipoint analysis for chromosomes 6, 8, and 10. The X-axis shows the relative marker position in centimorgans, and the Y-axis shows the multipoint HLOD score. The maximum multipoint HLOD scores were 2.0 for the 6p locus, 3.5 for the 8q locus, and 4.1 for the 10q locus.