We report the largest and most diverse genetic study of type 1 diabetes (T1D) to date (61,427 participants), yielding 78 genome-wide significant ( P < 5 × 10 −8 ) regions, including 36 novel. We define credible sets of T1D-associated variants and show they are enriched in immune cell-accessible chromatin, particularly CD4 + effector T cells. Using chromatin accessibility profiling of CD4 + T cells from 115 individuals, we map chromatin accessibility quantitative trait loci (caQTLs) and identify five regions where T1D risk variants colocalize with caQTLs. We highlight rs72928038 in BACH2 as a candidate causal T1D variant leading to decreased enhancer accessibility and BACH2 expression in T cells. Finally, we prioritize potential drug targets by integrating genetic evidence, functional genomic maps, and immune protein-protein interactions, identifying 12 genes implicated in T1D that have been targeted in clinical trials for autoimmune diseases. These findings provide an expanded genomic landscape for T1D.

The reconciliation between Mendelian inheritance of discrete traits and the genetically based correlation between relatives for quantitative traits was Fisher’s infinitesimal model of a large number of genetic variants, each with very small effects, whose causal effects could not be individually identified. The development of genome-wide genetic association studies (GWAS) raised the hope that it would be possible to identify single polymorphic variants with identifiable functional effects on complex traits. It soon became clear that, with larger and larger GWAS on more and more complex traits, most of the significant associations had such small effects, that identifying their individual functional effects was essentially hopeless. Polygenic risk scores that provide an overall estimate of the genetic propensity to a trait at the individual level have been developed using GWAS data. These provide useful identification of groups of individuals with substantially increased risks, which can lead to recommendations of medical treatments or behavioral modifications to reduce risks. However, each such claim will require extensive investigation to justify its practical application. The challenge now is to use limited genetic association studies to find individually identifiable variants of significant functional effect that can help to understand the molecular basis of complex diseases and traits, and so lead to improved disease prevention and treatment. This can best be achieved by 1) the study of rare variants, often chosen by careful candidate assessment, and 2) the careful choice of phenotypes, often extremes of a quantitative variable, or traits with relatively high heritability.

Immunohistological analyses of pancreata from patients with type 1 diabetes suggest distinct autoimmune islet b-cell pathology between those diagnosed at <7 years (<7 group) and those diagnosed at age ‡13 years (‡13 group), with both Band T-lymphocyte islet inflammation common in children in the <7 group, whereas B cells are rare in the ‡13 group. Based on these observations, we sought to identify differences in genetic susceptibility between these prespecified age-at-diagnosis groups to inform on the etiology of the most aggressive form of type 1 diabetes that initiates in the first years of life. RESEARCH DESIGN AND METHODS Using multinomial logistic regression models, we tested if known type 1 diabetes loci (17 within the HLA and 55 non-HLA loci) had significantly stronger effect sizes in the <7 group compared with the ‡13 group, using genotype data from 27,071 individuals (18,485 control subjects and 3,121 case subjects diagnosed at <7 years, 3,757 at 7-13 years, and 1,708 at ‡13 years). RESULTS Six HLA haplotypes/classical alleles and six non-HLA regions, one of which functions specifically in b-cells (GLIS3) and the other five likely affecting key T-cell (IL2RA, IL10, IKZF3, and THEMIS), thymus (THEMIS), and B-cell development/functions (IKZF3 and IL10) or in both immune and b-cells (CTSH), showed evidence for stronger effects in the <7 group. CONCLUSIONS A subset of type 1 diabetes-associated variants are more prevalent in children diagnosed under the age of 7 years and are near candidate genes that act in both pancreatic band immune cells. Type 1 diabetes is a multifactorial disease in which the insulin-producing b-cells of pancreatic islets are destroyed or rendered dysfunctional by an autoimmune process that often initiates in the first few months of life, causing a prediabetic, nonsymptomatic state in up to 0.4% of children (1). However, the actual diagnosis often