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. 2025 Feb 1;74(2):223-233.
doi: 10.2337/db24-0340.

Genetics of C-Peptide and Age at Diagnosis in Type 1 Diabetes

Delnaz Roshandel  1 , Athina Spiliopoulou  2   3 , Stuart J McGurnaghan  3 , Andrii Iakovliev  2 , Debby Lipschutz  2 , Caroline Hayward  3 , Shelley B Bull  4   5 , Barbara E K Klein  6 , Kristine E Lee  6 , Gregory L Kinney  7 , Marian Rewers  8 , Tina Costacou  9 , Rachel G Miller  9 , Paul M McKeigue  2 , Andrew D Paterson  1   5 , Helen M Colhoun  3
Affiliations

Genetics of C-Peptide and Age at Diagnosis in Type 1 Diabetes

Delnaz Roshandel et al. Diabetes. .

Abstract

Identified genetic loci for C-peptide and type 1 diabetes (T1D) age at diagnosis (AAD) explain only a small proportion of their variation. We aimed to identify additional genetic loci associated with C-peptide and AAD. Some HLA allele/haplotypes associated with T1D also contributed to variability of C-peptide and AAD, whereas outside the HLA region, T1D loci were mostly not associated with C-peptide or AAD. Genetic variation within CTSH can affect AAD. There is still residual heritability of C-peptide and AAD outside of HLA that could benefit from larger meta-genome-wide association studies.

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Conflict of interest statement

Duality of Interest. H.M.C. receives honoraria from Novo Nordisk; is a member of advisory boards for Novo Nordisk and Bayer AG; receives or has recently received research funding from Diabetes UK, JDRF, IQVIA, and the European Union Commission; and P.M.M. holds shares in Roche Pharmaceuticals and Bayer AG. No other conflicts of interest relevant to this article were reported.

Figures

None
Graphical abstract
Figure 1
Figure 1
C-Peptide meta-GWAS. A: Manhattan plot. B: Q-Q plot. C: HLA locus (TOPMed imputation). D: GABRG2 locus. E: HLA region (HLA imputation). F: HLA region conditional to HLA-DQB1*06:02. The plots in A–D were made using LocusZoom (https://my.locuszoom.org/). The LD is based on the European population from the 1000 Genomes LD panel derived from deep whole-genome sequencing (50). The coordinates are based on GRCh38. The plots in E and F were made using HLAManhattan in HLA-TAPAS (https://github.com/immunogenomics/HLA-TAPAS) (31). HLA haplotypes, AA changes, and SNPs/indels are in red, yellow, and gray, respectively. The coordinates are based on GRCh37.
Figure 2
Figure 2
AAD meta-GWAS. A: Manhattan plot. B: Q-Q plot. C: CTSH locus. D: HLA-DR-DQ locus. E: HLA-A locus. F: HLA region (HLA imputation). G: HLA region conditional to HLA-DQB1*03:02. H: HLA region conditional to HLA-DQB1*03:02 and HLA-DRB1*03:01. I: HLA region conditional to HLA-DQB1*03:02, HLA-DQB1*03:02, and HLA-A*24:02:01:01. The plots in A–E were made using LocusZoom (https://my.locuszoom.org/). The LD is based on the European population from 1000 Genomes LD panel derived from deep whole-genome sequencing (50). The coordinates are based on GRCh38. The plots in F and G were made using HLAManhattan in HLA-TAPAS (https://github.com/immunogenomics/HLA-TAPAS) (31). HLA haplotypes, AA changes/indels are in red, yellow, and gray, respectively. The coordinates are based on GRCh37.
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