: This study aimed to estimate the association between overweight and type 2 diabetes mellitus (T2DM) in twins, and further to explore whether genetic and early-life environmental factors account for this association.

: This study included 31,197 twin individuals from the Chinese National Twin Registry (CNTR). Generalized estimating equation (GEE) models were applied for unmatched case-control analysis. Conditional logistic regressions were used in co-twin matched case-control analysis. Logistic regressions were fitted to examine the differences in odds ratios (ORs) from the GEE models and conditional logistic regressions. Bivariate genetic model was used to explore the genetic and environmental correlation between body mass index (BMI) and T2DM.

: In the GEE model, overweight was associated with a higher T2DM risk (OR=2.71, 95% confidence interval (CI): 1.96∼3.73), compared with participants with normal BMI. In the multi-adjusted conditional logistic regression, the association was still significant (OR=2.60, 95% CI: 1.15∼5.87). The ORs from the unmatched and matched analyses were different (P = 0.042). Particularly, overweight could increase T2DM risk in monozygotic (MZ) twins, and the difference in ORs between the unmatched and matched designs was significant (P = 0.014). After controlling for age and sex, the positive BMI-T2DM association was partly due to a significant genetic correlation (rA= 0.31, 95% CI: 0.20∼0.41).

: Our findings suggest that genetics and early-life environments might account for the observed overweight-T2DM association. Genetic correlation between BMI and T2DM further provides evidence for the influence of overlap genes on their association.