CEP128 is a crucial risk locus for autoimmune thyroid diseases.

Autoimmune thyroid disease (AITD) mainly includes Graves' disease (GD) and Hashimoto's thyroiditis (HT), and its pathogenesis is not clearly defined. This study was designed to explore risk loci for AITD. Genome-wide genetic data were analyzed to identify important risk loci for GD, and a case-control study with 845 AITD patients and 694 healthy controls was also conducted. The functional role of possible risk loci for GD was explored by analyzing the correlations of Centrosomal protein 128 (CEP128) expression level with intrathyroidal immune cells and key genes for candidate immune cells in GD thyroid tissues. CEP128 was identified as an important risk locus for GD in the genome-wide genetic analysis, and it was located near TSHR without obvious linkage disequilibrium with TSHR. Two tag single-nucleotide variants in CEP128 including a missense variant rs327463 were substantially related to genetic predisposition to GD and HT in the case-control study. CEP128 rs327463 was substantially related to GD under the allele model (OR = 1.31, 95%CI 1.08-1.59, P = 0.006) and the dominant model (OR = 1.37, 95%CI 1.09-1.72, P = 0.008), and it was related to HT under the recessive model (OR = 1.85, P = 0.031) and the homozygous model (OR = 1.91, P = 0.025). Moreover, CEP128 was substantially correlated with the frequencies of T-follicular helper (Tfh) cell and M1 macrophages in GD tissues. Gene set enrichment analysis suggested that CEP128 was related to several common immune pathways involved in GD pathogenesis, such as interferon-γ mediated signaling pathway and toll-like receptor signaling pathway. This study highlight the crucial role of CEP128 in the pathogenesis of GD, and polymorphisms in CEP128 contribute to genetic predisposition to both GD and HT.