%0 Journal Article %A Jamie R.J. Inshaw %A Antony J. Cutler %A Daniel J.M. Crouch %A Linda S. Wicker %A John A. Todd %T Specific type 1 diabetes risk genes underpin age-at-diagnosis and indicate joint defects in immunity, beta-cell fragility and responses to viral infections in early-onset disease %D 2019 %R 10.1101/577304 %J bioRxiv %P 577304 %X Objective Immunohistological analyses of pancreata from patients with type 1 diabetes suggest a stratification of islet pathology of both B and T lymphocyte islet inflammation common in children diagnosed at <7 years (<7 group), whereas B cells are rare in those diagnosed age ≥13 (≥13 group). Based on these observations, we sought to identify differences in genetic susceptibility between these age-at-diagnosis groups, to inform on the aetiology of the most aggressive form of type 1 diabetes that initiates in the first years of life.Research Design and Methods Using multinomial logistic regression models, we tested if known type 1 diabetes loci (17 within the HLA region and 55 non-HLA regions) had significantly stronger effect sizes in the <7 group compared to the ≥13 group, using genotype data from 27,075 individuals (18,488 controls, 3,109 cases diagnosed at <7, 3,754 at 7-13 and 1,724 at ≥13).Results Six HLA haplotypes/classical alleles and seven non-HLA regions, one of which functions specifically in beta cells (GLIS3), and the other six likely affecting key T cell (IL2RA, IL10, SIRPG, IKZF3, THEMIS), thymus (THEMIS) and B cell development/functions (IKZF3, IL10) or in both immune and beta cells (CTSH) had stronger effects in the <7 group.Conclusions In newborn children with the greatest load of certain risk alleles, dysregulated response of immune and beta cells to environmental stresses such as virus infection, combine to cause a rapid loss of insulin production, driving down the age of type 1 diabetes diagnosis. %U https://www.biorxiv.org/content/biorxiv/early/2019/04/18/577304.full.pdf