The missing heritability in type 1 diabetes mellitus

Type 1 diabetes mellitus (T1DM) is a complex autoimmune disease characterized by an absolute deficiency of insulin. It affects more than 20 million people worldwide and imposes an enormous financial burden on patients. The underlying pathogenic mechanisms of T1DM are still obscure, but it is widely accepted that both genetics and the environment play an important role in its onset and development. Previous studies have identified more than 60 susceptible loci associated with T1DM, explaining approximately 80%-85% of the heritability. However, most identified variants confer only small increases in risk, which restricts their potential clinical application. In addition, there is still a so-called “missing heritability” phenomenon. While the gap between known heritability and true heritability in T1DM is relatively small compared to that in other complex traits and disorders, further elucidation of T1DM genetics has the potential to bring novel insights into its etiology and provide new therapeutic targets. Many hypotheses have been proposed to explain the missing heritability, including variants remaining to be found (variants with small effect sizes, rare variants, and structural variants) and interactions (gene–gene and gene–environment interactions e.g., epigenetic effects). In the following review, we will introduce the possible sources of missing heritability and discuss the existing related knowledge in the context of T1DM. This article is protected by copyright. All rights reserved.