A type 1 diabetes genetic risk score can discriminate monogenic autoimmunity with diabetes from early-onset clustering of polygenic autoimmunity with diabetes.
AIMS/HYPOTHESIS
Identifying individuals suitable for monogenic autoimmunity testing and gene discovery studies is challenging: early-onset type 1 diabetes mellitus can cluster with additional autoimmune diseases due to shared polygenic risk and islet- and other organ-specific autoantibodies are present in both monogenic and polygenic aetiologies. We aimed to assess whether a type 1 diabetes genetic risk score (GRS) could identify monogenic autoimmune diabetes and be useful to prioritise individuals for gene discovery studies.


METHODS
We studied 79 individuals with diabetes and at least one additional autoimmune disease diagnosed before the age of 5 years. We screened all participants for the seven genes known to cause monogenic autoimmunity that can include diabetes (AIRE, IL2RA, FOXP3, LRBA, STAT1, STAT3, STAT5B). We genotyped the top ten risk alleles for type 1 diabetes, including HLA and non-HLA loci, to generate a type 1 diabetes GRS.


RESULTS
Of the 79 individuals studied, 37 (47%) had mutations in the monogenic autoimmunity genes. The type 1 diabetes GRS was lower in these individuals than in those without mutations in these genes (median 9th vs 49th centile of type 1 diabetes controls, p < 0.0001). Age of diabetes diagnosis and type 1 diabetes GRS combined to be highly discriminatory of monogenic autoimmunity (receiver operating characteristic AUC: 0.88). Most individuals without a mutation in a known gene had a high type 1 diabetes GRS, suggesting that they have polygenic clustering of type 1 diabetes and additional autoimmunity and should not be included in gene discovery studies.


CONCLUSIONS/INTERPRETATION
We have shown that the type 1 diabetes GRS can identify individuals likely to have monogenic autoimmunity, helping both diagnostic testing and novel monogenic autoimmunity gene discovery. Individuals with monogenic autoimmunity have a different clinical course to those with polygenic type 1 diabetes and can respond well to therapies targeting the underlying genetic defect.
['Johnson|Matthew B|MB|', 'Patel|Kashyap A|KA|', 'De Franco|Elisa|E|', 'Houghton|Jayne A L|JAL|', 'McDonald|Timothy J|TJ|', 'Ellard|Sian|S|', 'Flanagan|Sarah E|SE|', 'Hattersley|Andrew T|AT|']
D000483:Alleles D001323:Autoantibodies D001327:Autoimmune Diseases D002675:Child, Preschool D016000:Cluster Analysis D003922:Diabetes Mellitus, Type 1 D005260:Female D020022:Genetic Predisposition to Disease D005838:Genotype D006680:HLA Antigens D006801:Humans D007223:Infant D007231:Infant, Newborn D007515:Islets of Langerhans D008297:Male D009154:Mutation D012372:ROC Curve D012306:Risk D012680:Sensitivity and Specificity
Type 1 diabetes Genetic risk score Gene discovery Monogenic autoimmune diabetes