Association of genetic variation with age at diagnosis in type 1 diabetes.

PubMed ID: 41545229

Author(s): Vollenbrock CE, Roshandel D, Lee KE, Klein BE, Mul D, van der Klauw MM, Tack CJ, Rewers M, Snell-Bergeon JK, Costacou T, Miller RG, Caramori ML, Mauer M, Aanstoot HJ, Wolffenbuttel BHR, Paterson AD; DCCT/EDIC Research Group; DCCT/EDIC Research Group. Association of genetic variation with age at diagnosis in type 1 diabetes. BMJ Open Diabetes Res Care. 2026 Jan 16;14(1):e003877. doi: 10.1136/bmjdrc-2023-003877. PMID 41545229

Journal: Bmj Open Diabetes Research & Care, Volume 14, Issue 1, Jan 2026

INTRODUCTION Type 1 diabetes is an autoimmune disease with a strong genetic basis. The aim of this study was to identify additional single-nucleotide polymorphisms (SNPs) for type 1 diabetes age at diagnosis and to replicate previously identified loci.

RESEARCH DESIGN AND METHODS Meta genome-wide association studies of age at diagnosis from eight cohorts (n=5910 in total) were performed in three models. Model 1 was age at diagnosis with no covariates. Model 2 was age at diagnosis adjusted for DR3/DR4 genotype categories. Model 3 was similar to model 2, including the most significant SNP from model 2 (coded additively). Models 1 and 2 were also performed for major histocompatibility complex (MHC) imputed data. In addition, we tested previously identified loci for age at diagnosis and type 1 diabetes risk for association with age at diagnosis in model 1.

RESULTS In model 1, we identified a genome-wide significant locus (rs2856721, p=3.3×10-11) in the MHC region whose effect was attenuated in model 2 (p=0.03). In model 2, we identified another locus in the MHC region, rs76730244, p=4.9×10-9, which was associated with age at diagnosis adjusted for DR3/DR4 genotypes. Model 3 and analysis of the MHC region did not reveal novel loci. Among 14 previously identified SNPs for age at diagnosis, 6 were confirmed; in addition, 11 out of 78 non-HLA loci for type 1 diabetes risk were associated with age at diagnosis.

CONCLUSIONS We identified rs76730244 in the MHC region for age at diagnosis of type 1 diabetes, which was independent of the HLA-DR3/DR4 genotype categories. We also confirmed 6 previously identified SNPs and showed that 11 non-HLA loci for type 1 diabetes risk are associated with age at diagnosis.