CCN3/NOV as a potential therapeutic target for diverticular disease: A proteome-wide Mendelian randomization study

Genome-wide association studies (GWAS) identified over 100 susceptibility loci and candidate causal genes for diverticular disease (DD) at the transcriptional level. However, effective therapeutics or preventions based on underlying disease mechanisms remain to be elucidated. In this study, we explored potential causal genes for DD at the protein level. We used 2 GWAS summary statistics of DD; 1 was obtained from the United Kingdom Biobank (UKBB) with 31,917 cases and 419,135 controls, and the other from the FinnGen consortium with 30,649 cases and 301,931 controls. For the primary analysis, we employed proteome-wide Mendelian randomization (MR) studies using 738 cis-acting protein quantitative trait loci (pQTLs) for 735 plasma proteins from the 5 published studies. For external validation, we conducted 2-sample MR analyses using plasma pQTLs of the screened proteins from another study by deCODE genetics. Moreover, we performed a series of sensitivity analyses including reverse MR and Bayesian colocalization tests. The primary MR identified 4 plasma proteins that were associated with DD risk including CCN3/NOV (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.97-0.99; P = 1.2 × 10-11 for UKBB. OR, 0.73; 95% CI, 0.66-0.81; P = 7.2 × 10-10 for FinnGen). The validation MR well replicated the primary result of CCN3/NOV (OR, 0.95; 95% CI, 0.93-0.96; P = 1.9 × 10-11 for UKBB. OR, 0.43; 95% CI, 0.33-0.56; P = 7.0 × 10-10 for FinnGen). Sensitivity analyses supported the causal association. We prioritized plasma CCN3/NOV protein as a protective factor for DD for follow-up functional studies to elucidate the disease mechanisms and therapeutics.