Follow-Up Analysis of Genome-Wide Association Data Identifies Novel Loci for Type 1 Diabetes

Abstract

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.

Comparative Genetic Analysis of Type 1 Diabetes and Inflammatory Bowel Disease

“…The SNPs with lowest nominal P-values were taken forward for further genotyping in an additional British cohort of approximately 6,000 cases, 7,000 controls and 2,800 families. As a result, the IL2-IL21 association strengthened further and they found strong evidence for the following loci: BACH2 (as we described previously (Grant et al, 2009)), a 10p15 region harboring the protein kinase C, theta gene (PRKCQ), a 15q24 region harboring nine genes including cathepsin H (CTSH) and a 22q13 region harboring the C1q and tumor necrosis factor related protein 6 (C1QTNF6) and somatostatin receptor 3 (SSTR3). Additional studies are required to elucidate the culprit genes and their mechanism at the 15q24 and 22q13 loci.…”

“…In order to get the most from such an endeavor, GWAS investigators have chosen to combine datasets from different investigative groups in order to carry out meta-analyses. We used this datamining approach to determine additional novel loci associated with T1D (Grant et al, 2009) conferring increasingly modest risks in the region of 1.1 to 1.2. Through subsequent rounds of testing in an independent cohort of nuclear T1D families from Montreal, the Children's Hospital of Philadelphia and the Type 1 Diabetes Genetics Consortium (T1DGC), followed by the WTCCC dataset and the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study cohort, we observed convincing association with the genes encoding ubiquitin-associated and SH3 domain-containing protein A (UBASH3A) and BTB and broad complex-tramtrack-bric-abrac (BTB) and cap 'n' collar (CNC) homology 2 (BACH2).…”

Anti-inflammatory genes associated with multiple sclerosis: A gene expression study

“…These findings identified BACH2 as a key regulator of CD4+ T-cell differentiation that prevents inflammatory disease by controlling the balance between tolerance and immunity (Roychoudhuri et al, 2013). Consistently, BACH2 variants were linked to several autoimmune diseases including vitiligo, celiac disease, type 1 diabetes (Grant et al, 2009) and recently MS (IMSGC, 2011;IMSGC, 2013).…”

“…Interestingly, all these genes are involved in the immune system regulation with predominant antiinflammatory role and in the development of autoimmune diseases (Hollinger et al, 2002;Yao et al 2009;Sanduja et al, 2011;Roychoudhuri et al, 2013;Hunt et al, 2008;Medici et al, 2014;Perdigones et al, 2010;Grant et al, 2009). …”

“…This approach highlighted 5 matching genes namely as tumor necrosis factor alpha-induced protein 3 (TNFAIP3), BTB and CNC Homology 1 basic leucine zipper transcription factor 2 (BACH2), prostaglandin E receptor 4 (Subtype EP4) (PTGER4), regulator of G-protein signaling 1 (RGS1), and zinc finger protein 36-C3H-type-like 1 (ZFP36L1). Interestingly, all these transcripts were previously reported as involved in the immune system regulation, mainly with an anti-inflammatory role (Hollinger et al, 2002;Murn et al, 2008;Yao et al 2009;Esaki et al, 2010;Sanduja et al, 2011;Roychoudhuri et al, 2013) and associated to several autoimmune diseases (Hunt et al, 2008;Medici et al, 2014;Perdigones et al, 2010;Grant et al, 2009). …”