Cucca, F

Groop, P-H

Inshaw, JRJ

Sandholm, N

Sidore, C

Syreeni, A

Todd, JA

Oxford University Research Archive

  212 A genome-wide search for genes affecting the age-at-diagnosis of type 1 diabetes A. Syreeni1,2, J.R.J. Inshaw3, N. Sandholm2,4, C. Sidore5, F. Cucca5,6, J.A. Todd3, P.-H. Groop2,4;  1Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland, 2Folkhälsan Research Center, Biomedicum, Helsinki, Finland, 3JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK, 4Abdominal Center, Nephrology, University of Helsinki, Helsinki University Hospital, Finland, 5Instituto di Ricerca Genetica e Biomedica, CNR, Monserrato, Italy, 6Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, Sassari, Italy.  Background and aims: The age-at-diagnosis of type 1 diabetes varies and the immunological processes leading to type 1 diabetes appear different in individuals diagnosed in early childhood compared to those diagnosed later in life. Only HLA and a few non-HLA loci have, however, been shown to have an effect on age-at-diagnosis of type 1 diabetes. We carried out a genome-wide association study (GWAS) meta-analysis to identify genetic factors affecting age-at-diagnosis. Materials and methods: Our study population comprised 12,451 individuals with type 1 diabetes from four cohorts: The Genetic Resource Investigating Diabetes (GRID) from the UK divided into two cohorts according to the genotyping platform (Illumina 500K Infinium microarray; n = 3,976 and Affymetrix GeneChip Mapping 500K; n = 1,925), Finnish Diabetic Nephropathy (FinnDiane) Study cohort (n = 5,074), and a Sardinian cohort (n = 1,476). Genotyped or imputed single nucleotide polymorphisms (SNPs) or indels were tested for association with natural logarithm transformed age-at-diagnosis using linear regression, adjusting for sex and cohort specific population stratification and genotyping batch variables. For the 7.3 million variants shared between at least two cohorts, the effect sizes and SEs from the individual GWAS were combined with fixed-effects meta-analysis using the METAL software. Results: Multiple independent variants on chromosome 6 were significantly associated with age-at-diagnosis (2 × 10-15 ≤ P < 5 × 10-8), located both in the HLA class I and II regions. No variants outside the HLA region reached a genome-wide significant P value in the meta-analysis; the most significant SNP was rs2941522 (C > T) on chromosome 17p21 near the IKZF3 gene, where the major C allele associated with lower age-at-diagnosis of diabetes (Beta = -0.066, SE = 0.012, P = 6.4 × 10-8). That variant is in linkage disequilibrium with two known type 1 diabetes SNPs (r2= 0.87 for rs2290400 and r2 = 0.83 for rs12453507 in the 1000 Genomes European population), both of which also suggestively associated with age-at-diagnosis (P ≤ 10-5) in our study. All three SNPs are associated with ORMDL3 and GSDMA gene expression levels in whole blood in GTEx V7. Conclusion: Our meta-GWAS proposes that the type 1 diabetes susceptibility region on chromosome 17 is associated with age-at-diagnosis. This locus has also previously been shown to have age-at-diagnosis-specific effects, thus more detailed studies on regulation and function of the genes in this region are warranted. Disclosure: A. Syreeni: None.    

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A genome-wide search for genes affecting the age-at-diagnosis of type 1 diabetes

A genome-wide search for genes affecting the age-at-diagnosis of type 1 diabetes

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