A Genome-Wide Assessment of the Genetic Basis of Type 1 Diabetes and Its Biology.

The strong familial clustering of autoimmune type 1 diabetes in families remains only partially explained. The six confirmed genes or chromosome regions with convincing statistical support (P < 10[sup-9]) in large, and multiple, populations, namely the major histocompatibility complex (MHC), the insulin gene (INS), CTLA4, PTPN22, IL2RA/CD25, and the interferon-induced helicase 1 gene region (IFIH1/MDA5), can explain only about 50% of familial aggregation. Nonetheless, their identification has provided many insights into the biology and pathways of type I diabetes, often closely mirroring findings in the spontaneous animal models of the disease. Recent expansions in sample collections, including the Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory (JDRF/WT DIL) British T1D case sample (n = 8,000), and advances in affordable, genome-wide, high throughput single nucleotide polymorphism (SNP) genotyping technologies (Affymetrix), has allowed an association analysis of 500,000 SNPs across the genome in 2,000 type 1 diabetes cases and 3,000 controls as part of the Wellcome Trust Case-Control Consortium (WTCCC). Attesting to the quality of the SNP map, positive results were obtained for all six susceptibility loci reported previously. However, follow-up genotyping studies of 14 other chromosome regions showing P < 10[sup-5] in the WTCCC scan in over 6,000 cases and 6,000 controls, and in approximately 2,000 families, supported in a convincing way (P < l0[sup-15] and odds ratios approximately 1.2) three new regions associated with type 1 diabetes in both the family and case-control samples, on chromosomes 16p13 (rs12708716), 12q13 (rs11171739) and 12q24 (rs17696736). The chromosome 12 loci map to regions of linkage disequilibrium containing many genes, although the chromosome 16p13 locus maps to a region containing two functional candidate genes, MHC2TA, which regulates HLA class II expression and the suppressor of cytokine signalling gene, SOCS1, and the third gene of unknown function, KIAA0350. These results illustrate how powerful the genome-wide association approach is in the systematic characterisation of the genetic basis of type 1 diabetes. [ABSTRACT FROM AUTHOR]