Background Type 1 diabetes (T1D) is characterized by the autoimmune destruction of the insulin-producing beta cells, and there is no cure yet for the disease. While islet autoantibodies are well-recognized biomarkers that mark the onset of islet autoimmunity (IA) and are predictors of T1D, few additional biomarkers are available to monitor disease progression. Recent studies have reported the involvement of complement system proteins in the initiation and progression of IA in the study of T1D. However, the genetic factors of complement system proteins at the time of triggering of IA is unknown. Results Through complement system protein quantitative trait locus (pQTL) mapping analysis of 170 participants from the Diabetes Autoimmunity Study in the Young (DAISY), we identified 240 statistically significant pQTLs (false discovery rate, FDR <
0.1) from pooled and IA case-stratified analyses. Replication analysis conducted on 385 IA cases from The Environment Determinants of Diabetes in the Young (TEDDY) study confirmed 68 significant (FDR <
0.05) pQTLs in total for C8A, C8B, CFB, C4A, and MBL2. Furthermore, all replicated pQTLs of CFB and C4A were previously reported to be associated with T1D risk. Conclusions We identified and replicated 68 pQTLs for five complement system proteins (C8A, C8B, CFB, C4A, and MBL2) in the young population. Among them, all replicated pQTLs of CFB and C4A are also associated with T1D risk. Our study provides evidence of complement system proteins as potential protein biomarkers underlying the development and progression of T1D.