INS and Insulin resistance: Our findings indicate that certain variables related to insulin resistance and ectopic fat may exert causal influence on SH3BP4 methylation, as suggested by significant cross-twin cross-trait association in Model 2 (body fat percentage Bcotwin = 0.170, p = 0.074; intra-abdominal fat Bcotwin = 0.235, p = 0.031; HOMA-IR Bcotwin = 0.278, p = 0.002; Matsuda Bcotwin = − 0.253, p = 0.006; fasting insulin Bcotwin = 0.235, p = 0.004) that attenuated towards null after conditioning on twin’s own corresponding measures (Fig. 5b).