{"doi":"10.2337/db24-0340","title":"Genetics of C-Peptide and Age at Diagnosis in Type 1 Diabetes","abstract":"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.","journal":"Diabetes","year":2024,"id":466749,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.8098,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":595905,"name":"Athina Spiliopoulou","orcid":"0000-0002-5929-6585","position":1,"is_corresponding":false},{"id":854886,"name":"Stuart J. McGurnaghan","orcid":"0000-0002-3292-4633","position":2,"is_corresponding":false},{"id":1298866,"name":"Andrii Iakovliev","orcid":"0000-0003-4031-0073","position":3,"is_corresponding":false},{"id":1298867,"name":"Debby Lipschutz","orcid":"0000-0003-2845-3557","position":4,"is_corresponding":false},{"id":5331,"name":"Caroline Hayward","orcid":"0000-0002-9405-9550","position":5,"is_corresponding":false},{"id":331673,"name":"Shelley B. Bull","orcid":"0000-0002-3280-7154","position":6,"is_corresponding":false},{"id":54595,"name":"Barbara E.K. Klein","orcid":"0000-0003-2379-976X","position":7,"is_corresponding":false},{"id":1299288,"name":"Kris E. Lee","orcid":null,"position":8,"is_corresponding":false},{"id":24982,"name":"Gregory L. Kinney","orcid":"0000-0002-5218-4986","position":9,"is_corresponding":false},{"id":95828,"name":"Marian Rewers","orcid":"0000-0003-3829-9207","position":10,"is_corresponding":false},{"id":439760,"name":"Tina Costacou","orcid":"0000-0001-9303-3810","position":11,"is_corresponding":false},{"id":382894,"name":"Rachel G. Miller","orcid":"0000-0003-1845-8477","position":12,"is_corresponding":false},{"id":595906,"name":"Paul McKeigue","orcid":"0000-0002-5217-1034","position":13,"is_corresponding":false},{"id":1531,"name":"Andrew D. Paterson","orcid":"0000-0002-9169-118X","position":14,"is_corresponding":false},{"id":594596,"name":"Helen M. Colhoun","orcid":"0000-0002-8345-3288","position":15,"is_corresponding":false},{"id":283018,"name":"Delnaz Roshandel","orcid":"0000-0002-4902-8587","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-19T02:05:06.743102Z","pmid":"39556808","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}