Unravelling the contribution of MODY genes in type 1 diabetes susceptibility through a polygenic approach

Introduction: Monogenic and polygenic diabetes are usually considered distinct diseases, however recent data support the hypothesis of a genetic continuum between MODY and polygenic forms of diabetes, such as type 1 diabetes (T1D). Objectives: In the present study, a polygenic approach was used to assess the contribution of MODY genes on T1D susceptibility. Methods: 383 T1D young individuals (mean age:13.9±3.4, 52% females) and 187 healthy controls (mean age:12.8±3.4, 56% females) were recruited. Participants were genotyped using Illumina Infinium Global Screening Array. A Polygenic Score (PGS) based on Single Nucleotide Polymorphisms (SNPs) in 16 genes responsible for MODY was developed and its association with T1D and related clinical characteristics (i.e., age at diagnosis, glycated haemoglobin, autoantibody positivity) was tested by regression analysis. Results: The PGS obtained by a Bayesian regression approach using 334 SNPs performed best. This PGS was associated with a higher risk of developing T1D (beta=5.14, p-value=0.001). In a sub-sample of 107 T1D individuals, PGS was also associated with a higher presence of Zinc transporter 8 autoantibodies (ZnT8-ab) s (beta=12.58, p-value=0.01). Analysis of clinical characteristics of ZnT8-ab in T1D showed older age at diagnosis in T1D with positive ZnT8-ab (median: 8.8, IQR: 3.7) compared to T1D with negative ZnT8-ab (median 7.6; IQR: 5.9) (p-value=0.0007). Moreover, diabetic ketoacidosis at diagnosis was less common among T1D with positive ZnT8-ab in comparation with T1D with negative ZnT8-ab (10% versus 39%, p-value=0.025). No association between PGS and other T1D clinical characteristics emerged. Conclusions: Our study showed a polygenic contribution of MODY variants in T1D susceptibility and ZnT8 autoimmunity, confirming the existence of shared genetic characteristics between different forms of diabetes.