Fourth, in the most extensive analysis of the genetic “connections” of major depression with a wide range of disorders, diseases, and human traits, we found significant positive genetic correlations with measures of body mass and negative genetic correlations with years of education, while showing no evidence of genetic correlation with IQ. MR analysis results are consistent with both BMI and years of education being causal, or correlated with causal, risk factors for major depression, and our results provide hypotheses and motivation for more detailed prospective studies, as currently available data may not provide insight about the fundamental driver or drivers of causality. The underlying mechanisms are likely more complex as it is difficult to envision how genetic variation in educational attainment or body mass alters risk for MDD without invoking an additional mechanistic component. While the significant MR analyses need further investigations to fully understand, the negative MR results provide important evidence that there is not a direct causal relationship between MDD and subsequent changes in body mass or education years. If such associations are observed in epidemiological or clinical samples, then it is likely not MDD but something correlated with MDD that drives the association.
