Genetic risk in extremely early onset type 1 diabetes

Identifying individuals at risk of early onset type 1 diabetes (diagnosed <2 years) would be highly beneficial in reducing risk of severe diabetic ketoacidosis (DKA) for those with extreme autoimmunity. We aimed to investigate whether genetic variation contributes to heterogeneity in age of type 1 diabetes onset, focusing on those diagnosed <2 years and ages previously defined by histological differences. We carried out association testing on 6773 individuals with type 1 diabetes and tested for heterogeneity in Human Leukocyte Antigen (HLA) variants across stratified age groups (594 diagnosed <2 years, 2241 diagnosed 2-7 years, 3094 diagnosed 7-13 years, 844 diagnosed 13+ years). We used a 67 SNP type 1 diabetes genetic risk score (T1D-GRS) to quantify aggregated genetic risk and assessed its utility in screening for type 1 diabetes <2 years. We observed higher T1D-GRSs as age of onset decreased in type 1 diabetes and found that DR3-DQ2 homozygosity was most strongly associated with <2 years onset (log-OR=4.27). The T1D-GRS showed high discriminative ability for <2 years onset type 1 diabetes onset (AUC=0.94) and correctly identified 88% of type 1 diabetes cases at the 85th population centile. We have shown higher genetic risk for very early onset T1D and suggest T1D-GRSs in newborn screening is likely to be particularly sensitive to those with younger type 1 diabetes onset.