Utility of Diabetes Type–Specific Genetic Risk Scores for the Classification of Diabetes Type Among Multiethnic Youth

Abstract

<b>Objective</b>: Genetic risk scores (GRS) aid classification of diabetes type in white European adult populations. We aimed to assess the utility of GRS in classification of diabetes type among racially/ethnically diverse youth in the U.S.<br><p> <br> </p> <p><b>Research Design and Methods</b>: We generated type 1 (T1D) and type 2 diabetes (T2D) specific GRS in 2045 individuals from the SEARCH for Diabetes in Youth study. We assessed the distribution of genetic risk stratified by diabetes type defined by autoantibody positive or negative (DAA+/-) and insulin sensitive (IS) or insulin resistant (IR) and self-reported race/ethnicity (white, black, Hispanic and other).<br> <br> </p> <p><b>Results</b>: T1D and T2D GRS were strong independent predictors of etiologic type. The T1D GRS was highest in the diabetes autoantibody positive insulin sensitive group and lowest in the diabetes autoantibody negative insulin resistant group, with the inverse relationship observed with the T2D GRS. Discrimination was similar across all racial/ethnic groups but showed between race/ethnicity differences in score distribution. Clustering by combined genetic risk showed diabetes autoantibody positive insulin resistant and diabetes autoantibody negative insulin sensitive individuals show a greater probability of T1D than T2D. In diabetes autoantibody negative individuals, genetic probability of T1D identified individuals most likely to progress to absolute insulin deficiency.<br> <br> </p> <p><b>Conclusion</b>: Diabetes type specific GRS are consistent predictors of diabetes type across racial/ethnic groups in a U.S. youth cohort, but future work needs to account for differences in GRS distribution by ancestry. T1D and T2D GRS may have particular utility for classification of diabetes autoantibody negative children.</p>