To further evaluate whether the cis-regulated brain protein expression mediates the association between the genetic variants and depression for each of these 24 genes, we applied summary data-based Mendelian randomization (SMR)18 on the same discovery dataset. Results from SMR suggest that was the case for all 24 genes, at least at nominally significant level, and for 5 genes at FDR q<0.05 (Table 1; Supplementary Table 2). Next, we performed the Heterogeneity in Dependent Instrument (HEIDI)18 test to distinguish pleiotropy/causality from linkage for these 24 genes. HEIDI results suggest that 4 of the 24 genes were likely significant due to linkage disequilibrium, 1 was undetermined, and 19 were consistent with either pleiotropy or causality (Table 1, Supplementary Table 2). Taken together, results from FUSION, SMR, and HEIDI suggest that 19 genes likely contribute to depression pathogenesis via their cis-regulated brain protein abundance (Table 1).
