National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
J Med Genet. 2021 May;58(5):289-296. doi: 10.1136/jmedgenet-2020-107350. Epub 2021 Mar 22.
Type 1 diabetes mellitus (T1DM) is defined as an autoimmune disorder and has enormous complexity and heterogeneity. Although its precise pathogenic mechanisms are obscure, this disease is widely acknowledged to be precipitated by environmental factors in individuals with genetic susceptibility. To date, the known susceptibility loci, which have mostly been identified by genome-wide association studies, can explain 80%-85% of the heritability of T1DM. Researchers believe that at least a part of its missing genetic component is caused by undetected rare and low-frequency variants. Most common variants have only small to modest effect sizes, which increases the difficulty of dissecting their functions and restricts their potential clinical application. Intriguingly, many studies have indicated that rare and low-frequency variants have larger effect sizes and play more significant roles in susceptibility to common diseases, including T1DM, than common variants do. Therefore, better recognition of rare and low-frequency variants is beneficial for revealing the genetic architecture of T1DM and for providing new and potent therapeutic targets for this disease. Here, we will discuss existing challenges as well as the great significance of this field and review current knowledge of the contributions of rare and low-frequency variants to T1DM.
1 型糖尿病（T1DM）被定义为一种自身免疫性疾病，具有巨大的复杂性和异质性。尽管其确切的发病机制尚不清楚，但人们普遍认为，这种疾病是由具有遗传易感性的个体中的环境因素引发的。迄今为止，通过全基因组关联研究确定的已知易感基因座，可解释 T1DM 遗传率的 80%-85%。研究人员认为，其缺失的遗传成分至少有一部分是由未检测到的罕见和低频变异引起的。大多数常见变异的效应大小只有小到中等，这增加了对其功能进行剖析的难度，并限制了它们的潜在临床应用。有趣的是，许多研究表明，罕见和低频变异的效应大小更大，在包括 T1DM 在内的常见疾病的易感性方面发挥着更重要的作用，比常见变异的作用更大。因此，更好地认识罕见和低频变异有助于揭示 T1DM 的遗传结构，并为这种疾病提供新的、有效的治疗靶点。在这里，我们将讨论这一领域现存的挑战和重要性，并回顾罕见和低频变异对 T1DM 的贡献的现有知识。
