Type 1 Diabetes Genetic Risk Scores: History, Application and Future Directions

To review the genetics of type 1 diabetes (T1D) and T1D genetic risk scores, focusing on their development, research and clinical applications, and future directions.

More than 90 genetic loci have been linked to T1D risk, with approximately half of the genetic risk attributable to the human leukocyte antigen (HLA) locus, along with non-HLA loci that have smaller effects to disease risk. The practical use of T1D genetic risk scores simplifies the complex genetic information, within the HLA and non-HLA regions, by combining the additive effect and interactions of single nucleotide polymorphisms (SNPs) associated with risk. Genetic risk scores have proven to be useful in various aspects, including classifying diabetes (e.g., distinguishing between T1D vs. neonatal, type 2 or other diabetes types), predicting the risk of developing T1D, assessing the prognosis of the clinical course (e.g., determining the risk of developing insulin dependence and glycemic control), and research into the heterogeneity of diabetes (e.g., atypical diabetes). However, there are gaps in our current knowledge including the specific sets of genes that regulate transition between preclinical stages of T1D, response to disease modifying therapies, and other outcomes of interest such as persistence of beta cell function. Several T1D genetic risk scores have been developed and shown to be valuable in various contexts, from classification of diabetes to providing insights into its etiology and predicting T1D risk across different stages of T1D. Further research is needed to develop and validate T1D genetic risk scores that are effective across all populations and ancestries. Finally, barriers such as cost, and training of medical professionals have to be addressed before the use of genetic risk scores can be incorporated into routine clinical practice.