Identification of Novel T1D Risk Loci and Their Association With Age and Islet Function at Diagnosis in Autoantibody-Positive T1D Individuals: Based on a Two-Stage Genome-Wide Association Study.

Abstract

Type 1 diabetes (T1D) is a highly heritable disease with much lower incidence but more adult-onset cases in the Chinese population. Although genome-wide association studies (GWAS) have identified >60 T1D loci in Caucasians, less is known in Asians. We performed the first two-stage GWAS of T1D using 2,596 autoantibody-positive T1D case subjects and 5,082 control subjects in a Chinese Han population and evaluated the associations between the identified T1D risk loci and age and fasting C-peptide levels at T1D diagnosis. We observed a high genetic correlation between children/adolescents and adult T1D case subjects (r g = 0.87), as well as subgroups of autoantibody status (r g ≥ 0.90). We identified four T1D risk loci reaching genome-wide significance in the Chinese Han population, including two novel loci, rs4320356 near BTN3A1 (odds ratio [OR] 1.26, P = 2.70 × 10-8) and rs3802604 in GATA3 (OR 1.24, P = 2.06 × 10-8), and two previously reported loci, rs1770 in MHC (OR 4.28, P = 2.25 × 10-232) and rs705699 in SUOX (OR 1.46, P = 7.48 × 10-20). Further fine mapping in the MHC region revealed five independent variants, including another novel locus, HLA-C position 275 (omnibus P = 9.78 × 10-12), specific to the Chinese population. Based on the identified eight variants, we achieved an area under the curve value of 0.86 (95% CI 0.85-0.88). By building a genetic risk score (GRS) with these variants, we observed that the higher GRS were associated with an earlier age of T1D diagnosis (P = 9.08 × 10-11) and lower fasting C-peptide levels (P = 7.19 × 10-3) in individuals newly diagnosed with T1D. Our results extend current knowledge on genetic contributions to T1D risk. Further investigations in different populations are needed for genetic heterogeneity and subsequent precision medicine.