Follow-up analysis of genome-wide association data identifies novel loci for type 1 diabetes

OBJECTIVE—Two recent genome-wide association (GWA) studies have revealed novel loci for type 1 diabetes, a common multifactorial disease with a strong genetic component. To fully utilize the GWA data that we had obtained by genotyping 563 type 1 diabetes probands and 1,146 control subjects, as well as 483 case subject–parent trios, using the Illumina HumanHap550 BeadChip, we designed a full stage 2 study to capture other possible association signals.RESEARCH DESIGN AND METHODS—From our existing datasets, we selected 982 markers with P < 0.05 in both GWA cohorts. Genotyping these in an independent set of 636 nuclear families with 974 affected offspring revealed 75 markers that also had P < 0.05 in this third cohort. Among these, six single nucleotide polymorphisms in five novel loci also had P < 0.05 in the Wellcome Trust Case-Control Consortium dataset and were further tested in 1,303 type 1 diabetes probands from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) plus 1,673 control subjects.RESULTS—Two markers (rs9976767 and rs3757247) remained significant after adjusting for the number of tests in this last cohort; they reside in UBASH3A (OR 1.16; combined P = 2.33 × 10⁻⁸) and BACH2 (1.13; combined P = 1.25 × 10⁻⁶).CONCLUSIONS—Evaluation of a large number of statistical GWA candidates in several independent cohorts has revealed additional loci that are associated with type 1 diabetes. The two genes at these respective loci, UBASH3A and BACH2, are both biologically relevant to autoimmunity.Type 1 diabetes is a multifactorial disease with a strong genetic component that results from autoimmune destruction of the pancreatic β-cells. The major type 1 diabetes susceptibility locus, mapping to the HLA class II genes at 6p21 (1) and encoding highly polymorphic antigen-presenting proteins, accounts for almost 50% of the genetic risk for type 1 diabetes (2). Several other loci with more modest effects are known, but they do not account for the remaining portion of the risk.The recent development of high-throughput single nucleotide polymorphism (SNP) genotyping array technologies has enabled us (3) and others (4) to perform high-density genome-wide association (GWA) studies in search of the remaining type 1 diabetes loci. We recently reported the outcome of our GWA for type 1 diabetes in a large pediatric type 1 diabetic cohort of European descent (3); in addition to confirming previously identified loci, we observed highly significant and replicated association with KIAA0350 (now renamed CLEC16A [C-type lectin domain family 16 member A]). Subsequent follow-up of our data also revealed a locus on 12q13 (5). In parallel and independently, the Wellcome Trust Case Control Consortium (WTCCC) (4) also demonstrated replicated (6) association to the same linkage disequlibrium blocks at 16p13 and 12q13, along with two additional loci on 12q24 and 18p11.The results that we have reported thus far were of loci that achieved statistical significance on the basis of the results of the GWA genotyping (stage 1) or replication in additional cohorts (stage 2) of only a small number of the most promising loci. Here, we describe the results of a full evaluation of all statistical candidates from the GWA phase.