Abstract A051: Phenome-wide exploration of genetically predicted T-cadherin-mediated adiponectin changes highlights cardioprotective effects and potential safety signals

Introduction: We have previously shown that T-cadherin-mediated increases in circulating adiponectin levels may represent a putative therapeutic target to lower obesity-associated increase in cardiovascular disease (CVD) risk. Here, we utilize a phenome-wide approach to identify T-cadherin-mediated adiponectin’s body-wide effects, potential safety signals, as well as populations/conditions that may derive concomitant benefit. Methods: We followed a cis-Mendelian randomization (MR) and phenome-wide MR approach. We constructed a cis-genomic instrument, selecting genome-wide significant, independent (r 2 ≤0.1) variants near the gene that encodes T-cadherin, CDH13 , from a GWAS of circulating adiponectin levels (n=~38,600). Using this instrument, we performed MR on 1,289 well-powered (≥1,000 cases) clinical outcomes in 500,348 individuals from the FinnGen consortium. The false discovery rate was used to identify robust associations, and effect size estimates were expressed as per standard deviation of circulating adiponectin levels. ChatGPT was used to generate part of the code for the analysis. Results: The cis-instrument consisted of 8 genomic variants (mean F=120.7, R 2 = 2.48%). Higher genetically proxied, CDH13 -mediated circulating adiponectin levels were associated with lower risk of all stroke and coronary artery disease (0.62, 95% CI: 0.39-0.98 and 0.33, 95% CI: 0.18-0.61, respectively). In the phenome-wide MR analysis, notable associations with higher genetically predicted, CDH13 -mediated adiponectin levels included lower risk of CVD (coronary atherosclerosis, coronary revascularization, major heart disease event, heart failure and coronary heart disease, cardiac arrhythmias) and mental health disorders (schizophrenia, nonorganic psychotic disorders). In contrast, higher genetically predicted, CDH13 -mediated adiponectin levels were associated with higher risk of intestinal malabsorption, abrasion of teeth, mental/neurological disorders (social phobias, phobic anxiety disorders, mononeuropathies), pregnancy-related conditions (pre-eclampsia/eclampsia), as well as higher weight and BMI (all p-FDR<0.05). Conclusion: While T-cadherin-mediated changes in circulating adiponectin may serve as a promising therapeutic target for CVD outcomes, specific co-existing conditions may warrant close monitoring. Whether the target’s vasculoprotective effects outweigh its suggestive fat-storing capacity warrants further research.