Type 1 Diabetes Genetic Risk Score: A Novel Tool to Discriminate Monogenic and Type 1 Diabetes

Abstract

Distinguishing patients with monogenic diabetes from those with type 1 diabetes (T1D) is important for correct diagnosis, treatment, and selection of patients for gene discovery studies. We assessed whether a T1D genetic risk score (T1D-GRS) generated from T1D-associated common genetic variants provides a novel way to discriminate monogenic diabetes from T1D. The T1D-GRS was highly discriminative of proven maturity-onset diabetes of young (MODY) (n = 805) and T1D (n = 1,963) (receiver operating characteristic area under the curve 0.87). A T1D-GRS of >0.280 (>50th T1D centile) was indicative of T1D (94% specificity, 50% sensitivity). We then analyzed the T1D-GRS of 242 white European patients with neonatal diabetes (NDM) who had been tested for all known NDM genes. Monogenic NDM was confirmed in 90, 59, and 8% of patients with GRS <5th T1D centile, 50-75th T1D centile, and >75th T1D centile, respectively. Applying a GRS 50th T1D centile cutoff in 48 NDM patients with no known genetic cause identified those most likely to have a novel monogenic etiology by highlighting patients with probable early-onset T1D (GRS >50th T1D centile) who were diagnosed later and had less syndromic presentation but additional autoimmune features compared with those with proven monogenic NDM. The T1D-GRS is a novel tool to improve the use of biomarkers in the discrimination of monogenic diabetes from T1D.

Figure 1. T1D genetic risk score is higher in T1D than in confirmed MODY and non-diabetic controls.

A) Dot-plot of T1D genetic risk score from 1963 T1D patients, 805 MODY (subtype of monogenic diabetes) and 2938 non-diabetic controls. Blue bar highlights the median T1D genetic risk score for each group. Upper red horizontal line shows genetic risk score equivalent to 50^th centile for T1D cohort and lower red horizontal line shows genetic risk score equivalent to 5^th centile for T1D cohort. The control and T1D patients came from WTCCC (10). B) ROC curve (AUC=0.87) for T1D genetic risk score to discriminate MODY (n=805) and T1D (n=1963).

Figure 2. T1D genetic risk score identified proven and probable monogenic neonatal diabetes.

A) T1D genetic risk score identified proven monogenic neonatal diabetes. 242 White-European patients with neonatal diabetes (diagnosed before 6 months of age) who had comprehensive genetic testing for all 23 neonatal diabetes genes were grouped by their T1D-GRS (11). The subgroups of T1D-GRS are based on centiles of T1D cohort. The black bars show the percentage of monogenic diabetes with a positive genetic test, (proven monogenic NDM, n=194) from low to high score groups (left to right). The white bar represents the percentage of patients with negative genetic test thus the etiology of their diabetes is unknown (NDMX, n=48). Total number of patients is also shown for each group. B) T1D genetic risk score identified probable monogenic neonatal diabetes and probable T1D in NDMX. The T1D-GRS distribution of NDM patients with unknown etiology (negative genetic test, n=48) showed bimodal distribution with peaks at <5^th T1D centile and >75^th T1D centile with the nadir around 50^th T1D centile. T1D-GRS 50^th T1D centile categorized this group as probable T1D (T1D-GRS >50^th T1D centile, n=21) and probable monogenic diabetes due to mutations in as yet undiscovered disease genes (T1D-GRS ≤ 50^th T1D centile, n=27).