T1D, age at diagnosis & genetic risk
Charlotte E. Vollenbrock, Delnaz Roshandel, Kristine E. Lee, Barbara E. Klein, Dick Mul, Melanie M. van der Klauw, Cornelis J. Tack, Marian Rewers, Janet K. Snell-Bergeon, Tina Costacou, Rachel G. Miller, Maria Luiza Caramori, Mike Mauer, Henk-Jan Aanstoot, Bruce H.R. Wolffenbuttel, Andrew D. Paterson, 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.
Type 1 diabetes (T1D) is a genetically complex autoimmune disease that can develop at any age, from early childhood to late adulthood. While genetic factors—especially HLA genotypes—are well known to influence the risk of developing T1D, much less is known about why some individuals develop the disease at a young age whereas others are diagnosed later in life. Age at diagnosis is clinically relevant because earlier onset is associated with a more rapid decline in beta-cell function and a longer lifetime exposure to hyperglycaemia and complications. Understanding the genetic factors that influence age at onset may therefore provide insight into disease mechanisms and help refine risk stratification and prediction models.
The authors performed a large meta–genome-wide association study (meta-GWAS) to identify genetic variants associated with age at diagnosis of T1D. Data from eight cohorts in North America and Europe were combined, including a total of 5,910 individuals with T1D. Three statistical models were used: 1)a basic model analysing age at diagnosis, 2) a model adjusted for HLA-DR3/DR4 genotype categories, and 3) a conditional model to identify independent genetic signals. In addition, previously reported genetic loci for age at diagnosis and known T1D risk variants were tested for association with age at onset.
Key findings:
- Individuals carrying the high-risk HLA-DR3/DR4 genotype were diagnosed on average three years earlier than non-carriers.
- A novel genetic variant in the HLA region (rs76730244) was identified that was associated with younger age at diagnosis, independent of HLA-DR3/DR4 status.
- Six previously reported genetic loci for age at diagnosis were replicated.
- Eleven non-HLA genetic variants known to increase T1D risk were also associated with earlier disease onset.
- Across these loci, alleles that increased T1D risk consistently corresponded to younger age at diagnosis
This study shows that age at diagnosis of T1D is not random but is partly genetically determined. In addition to classical HLA risk genotypes, multiple genetic variants across the genome influence when the disease manifests. These findings support the idea that genetic profiles may help define different biological “endotypes” of T1D, with distinct trajectories of disease progression. In the future, incorporating genetic information into prediction models could improve early identification of individuals at risk of rapid disease development and support more personalised prevention or monitoring strategies.
Concluding, the authors state
"We identified rs76730244 in the HLA region for age at diagnosis of type 1 diabetes, which was independent of the HLA-DR3/DR4 genotype categories. We also confirmed previously identified SNPs and showed that multiple non-HLA loci for type 1 diabetes risk are associated with age at diagnosis." -
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