Genetics Coming of Age in Type 1 Diabetes

Abstract

Decades of studies demonstrate that ∼50% of risk for type 1 diabetes (T1D) is heritable (1). The first loci linked to T1D were the HLA genes that have the largest effect size of any T1D susceptibility locus, followed by linkage of the insulin VNTR to T1D (2,3). Linkage studies have given way to genome-wide association studies (GWAS) that have identified >50 loci that contribute risk for developing T1D (4). Most of these loci impart modest relative risk for T1D (odds ratio ≤2.0) and together with HLA account for ∼80% of the heritability of T1D (5). The question remains: have GWAS delivered in terms of our ability to understand the causes of T1D and thus identify therapeutic targets or predict disease course? GWAS have revealed several important aspects of T1D disease etiology. First, the majority of genes associated with T1D function in the immune system, underscoring the immune basis of disease initiation and progression (6). Second, GWAS have identified pathways that are important in disease pathogenesis, such as variants in the interleukin-2 (IL-2) signaling pathway ( IL2 , IL2RA , and PTPN2 loci) that are associated with disease (4,7,8). Third, T1D GWAS studies have identified a shared genetic architecture with other autoimmune diseases (e.g., PTPN22 , CTLA4 , SH2B3 , TYK2 , and CLEC16A loci), indicating common pathogenic mechanisms and the possibility of repurposing therapies for T1D that are in use for other autoimmune diseases. Additionally, genotype-phenotype studies have provided important windows into disease pathogenesis by revealing alterations in B-cell and T-cell development, tolerance checkpoints, regulatory T-cell fitness, …