Sex-Specific causal dynamic between Insulin resistance and MDD, a bidirectional Mendelian randomization study.

Aims/hypothesisObservational studies have shown a bidirectional association between major depressive disorder (MDD), Insulin resistance (IR), and related diseases, which varies between sexes and ancestries. We conducted a sex-specific two-sample bidirectional Mendelian randomization (MR) study to assess the causal associations of MDD with Insulin resistance measured through the TG: HDL-C ratio and vice versa using Caucasian and East Asian data. MethodsWe extracted summary-level data for MDD and insulin resistance from corresponding published large genome-wide association studies of individuals of European descent and partially replicated the analyses using available summary data from studies of individuals of East Asian descent. The random-effects inverse-variance weighted method and MRlap method were used for the main analyses for non-overlapping and overlapping samples, respectively. ResultsGenetic liability to MDD was significantly associated with insulin resistance both generally and sex-specifically, while the causal effect of Insulin resistance on MDD is only consistently significant in females. We did not find any significant causal association between IR and MDD using East Asian data, though the beta estimates suggest potentially ancestry-related differences in the direction of effect. Conclusions/interpretationThe present study strengthened the evidence that MDD is a potential risk factor for insulin resistance and that insulin resistance plays a sex--and ancestry-specific role in MDD pathology. Together, these findings could contribute to further our understanding of the comorbidity between MDD and IR-related diseases, allowing for more individualized treatment and diagnosis.