Insights into causal associations between type 2 diabetes and common human diseases: a phenotype-wide bi-directional Mendelian randomization analysis

Background and aims: There is substantial evidence showing the significant comorbidity between Type 2 Diabetes (T2D) and various diseases. However, there is still a need to develop a detailed understanding of the pairwise causal associations within the comorbidity networks of T2D. Methods and results: A phenotype-wide two-sample bidirectional Mendelian randomization (MR) analysis was performed to investigate the causal relationships between T2D (N = 933,970) from the DIAMANTE dataset and 892 common diseases (N = 99,936–377,277) from the FinnGen database (R10). A total of 892 disease phenotypes were selected from the FinnGen database, filtered from 2272 phenotypes by retaining only those with over 2000 cases and excluding duplicates or phenotypes with specific labels. Inverse variance weighting was the primary method used, supplemented by weighted median and MR-Egger approaches for sensitivity analyses. In the MR analysis, a total of 41 diseases were causally associated with T2D risk (average b: 0.124). This included 9 neurological diseases (average b: 0.178), 8 psychiatric and behavioral diseases (average b: 0.003), 7 circulatory diseases (average b: 0.120), and 5 digestive system diseases (average b: 0.002). Our reverse MR analysis showed that T2D was causally linked to the risk of 120 disease phenotypes (average b: 0.103). This included 35 circulatory diseases (average b: 0.118), 24 genitourinary system diseases (average b: 0.132), 15 skin, muscle, bone, and connective tissue diseases (average b: 0.067), 11 endocrine system diseases (average b: 0.114), 10 digestive system diseases (average b: 0.109), among others. Bidirectional causality was observed between T2D and 16 diseases. Most MR analyses showed little evidence of heterogeneity and pleiotropy. Conclusions: Our findings highlight the broad yet well-defined spectrum of causal effects that T2D exerts on other human diseases. Conversely, analyses investigating the impact of other diseases on T2D show a narrow scope with a greater magnitude of effect.