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

Identified genetic loci for C-peptide and age at diagnosis (AAD) in individuals with type 1 diabetes (T1D) explain only a small proportion of their variation. Here, we aimed to perform large meta-genome-wide association studies (GWAS) of C-peptide and AAD in T1D and to identify the HLA allele/haplotypes associated with C-peptide and AAD. A total of 7,252 and 7,923 European individuals with T1D were included in C-peptide and AAD GWAS, respectively. HLA-DQB1*06:02, which is strongly protective against T1D, was associated with higher C-peptide. HLA-DQB1*03:02, HLA-DRB1*03:01, and HLA-A*24:02, which increase T1D risk, were independently associated with younger AAD. HLA-DR3-DR4 haplotype combination, the strongest T1D susceptibility factor, was associated with younger AAD. Outside the HLA region, rs115673528 on chromosome 5 (Chr5) (GABRG2) was associated with C-peptide, and an indel, rs111970692, on Chr15 within CTSH, a known T1D locus, was associated with AAD. Genetically predicted CTSH expression, methylation, and protein levels were associated with AAD. Mendelian randomization analysis suggested that higher levels of pro-cathepsin H reduced AAD. In conclusion, some HLA allele/haplotypes associated with T1D also contribute to variability of C-peptide and AAD. Outside HLA, T1D loci were generally not associated with C-peptide or AAD. CTSH could be a potential therapeutic target to delay development/progression of T1D.Article Highlights 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.