We used bi-directional Mendelian randomization (MR) to investigate the relationships between four traits genetically correlated with major depression: years of education (EDY)62, body mass index (BMI)29, coronary artery disease (CAD)63, and schizophrenia19. These traits were selected because all of the following were true: phenotypically associated with MDD, significant rg with MDD, and >30 independent genome-wide significant associations from large GWA. We report GSMR64 results but obtained qualitatively similar results with other MR methods (Supplementary Table 13 and Supplementary Fig. 4). MR analyses provided evidence for a 1.12-fold increase in major depression per standard deviation of BMI (PGSMR=1.2×10−7) and a 0.84-fold decrease in major depression per standard deviation of EDY (PGSMR=2.3×10−6). There was no evidence of reverse causality of major depression for BMI (PGSMR=0.53) or EDY (PGSMR=0.11). For BMI there was some evidence of pleiotropy, as six BMI SNPs were excluded by the HEIDI-outlier test including SNPs near OLFM4 and NEGR1. Thus, these results are consistent with EDY and BMI as either causal risk factors or correlated with causal risk factors for major depression. These results provide hypotheses for future research to understand these potentially directional relationships.
