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. In this study, 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, colocalization analysis further supported a role in type 2 diabetes for C-type mannose receptor 2 (MR odds ratio [OR] 0.85 [95% CI 0.79–0.92] per genetically predicted SD increase in protein level), MANS domain containing 4 (MR OR 0.90 [95% CI 0.88–0.92]), sodium/potassium-transporting ATPase subunit β2 (MR OR 1.10 [95% CI 1.06–1.15]), endoplasmic reticulum oxidoreductase 1β (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 α1–3-N-acetylgalactosaminyltransferase and α1–3-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.