Background <p>Discovery of autoantibodies in steroid-sensitive nephrotic syndrome (SSNS) has transformed our understanding of SSNS as an immune-mediated disease; however, mechanisms underlying autoantibody production are unknown. Current treatments for SSNS are non-targeted and cause serious adverse effects. We sought to identify circulating proteins with a causal relationship to SSNS, which likely reflect underlying immune derangements, using an unbiased two-sample Mendelian randomization (MR) and colocalization approach to inform novel drug targets for disease.</p> Methods <p>Summary-level data from eight large independent proteome-wide association studies were used to estimate the causal effect of 1540 proteins on SSNS risk by Mendelian randomization (MR) using <i>cis</i> genetic determinants (protein quantitative trait loci, pQTL). Genetic colocalization, gene expression, and affinity binding analyses were performed to further investigate loci identified by MR.</p> Results <p>Two proteins, apolipoprotein M (APOM) and Tenascin XB (TNXB), were causally linked to SSNS by MR and colocalization analysis. Increases in APOM and TNXB levels were associated with decreased risk of SSNS (p = 1.37 × 10⁻⁵;[OR] = 0.40;95%[CI] = 0.27–0.61 for APOM, and p = 2.95 × 10⁻⁴;[OR] = 0.49;95%[CI] = 0.33–0.72 for TNXB). Colocalization with SSNS occurred at HLA-DRB1 (98%) and HLA-DQA1 (80%) for APOM and TNXB, respectively. Binding affinity and gene expression analysis showed that APOM peptides have strong affinity for HLA-DRB1, that APOM has a biologically plausible causal relationship with SSNS, and that there are approved drugs targeting the APOM pathway.</p> Conclusions <p>We identified APOM and TNXB as novel blood proteins associated with SSNS in children. These proteins are promising targets for the development or repurposing of drugs as novel treatments for SSNS.</p> Graphical abstract <p></p>