The two signals on chromosome 12 (at 12q13 and 12q24) map to regions of extensive linkage disequilibrium covering more than ten genes (Fig. 5). Several of these represent functional candidates because of their presumed roles in immune signalling, considered to be a major feature of T1D-susceptibility. These include ERBB3 (receptor tyrosine-protein kinase erbB-3 precursor) at 12q13 and SH2B3/LNK (SH2B adaptor protein 3), TRAFD1 (TRAF-type zinc finger domain containing 1) and PTPN11 (protein tyrosine phosphatase, non-receptor type 11) at 12q24. For these signal regions in particular, extensive resequencing, further genotyping and targeted functional studies will be essential steps in identifying which gene, or genes, are causal95. Of those listed, PTPN11 is a particularly attractive candidate given a major role in insulin and immune signalling96. It is also a member of the same family of regulatory phosphatases as PTPN22, already established as an important susceptibility gene for T1D and other autoimmune diseases94,97. Indeed, the 12q24 variant most associated with T1D also features in both the CD and RA scans, generating a combined signal for all autoimmune cases of 9.3×10-10 (Supplementary Table 11).
