Connecting Genomics and Proteomics to Identify Protein Biomarkers for Adult and Youth-Onset Type 2 Diabetes: A Two-Sample Mendelian Randomization Study

Type 2 diabetes shows an increasing prevalence in both adults and children. Identification of biomarkers for both youth and adult-onset type 2 diabetes is crucial for development of screening tools or drug targets. Here, using two-sample Mendelian randomization (MR), we identified 22 circulating proteins causally linked to adult type 2 diabetes and 11 proteins with suggestive evidence for association with youth-onset type 2 diabetes. Among these, co-localization analysis further supported a role in type 2 diabetes for C-type Mannose Receptor 2 (MR OR=0.85, 95% CI 0.79 – 0.92 per genetically predicted standard deviation (SD) increase in protein level), MANS domain containing 4 (MR OR=0.90, 95% CI 0.88 – 0.92), Sodium/potassium-transporting ATPase subunit Beta-2 (MR OR=1.10, 95% CI 1.06 – 1.15), Endoplasmic Reticulum Oxidoreductase 1 Beta (MR OR=1.09, 95% CI 1.05 – 1.14), Spermatogenesis-Associated Protein 20 (MR OR=1.12, 95% CI 1.06 – 1.18), Haptoglobin (MR OR=0.96, 95% CI 0.94 – 0.98), and Alpha 1-3-N-Acetylgalactosaminyltransferase and Alpha 1-3-Galactosyltransferase (MR OR=1.04, 95% CI 1.03 – 1.05). Our findings support a causal role in type 2 diabetes for a set of circulating proteins, which represent promising type 2 diabetes drug targets.