Summary data-based Mendelian Randomization18 (SMR, downloaded from https://cnsgenomics.com/software/smr on May 22, 2019) was used to test whether the depression PWAS-significant genes (from the FUSION approach) were associated with depression via their cis-regulated brain protein expression. We used Plink54 to estimate protein quantitative trait loci (pQTL) in the discovery proteomic dataset by linear regression. Next, we used the pQTL results and the discovery depression GWAS summary statistics to perform SMR18. We used the conservative unadjusted p-value ≤ 0.05 from Heterogeneity in Dependent Instrument (HEIDI) to suggest that presence of linkage likely influences the main SMR findings. In addition, we performed SMR using the depression GWAS summary statistics from all 807,553 participants from Howard et al10 and the pQTL results from joining both the ROS/MAP and Banner proteomic profiles to determine mediation and pleiotropy/causality for the significant genes from the proteome-wide meta-analysis of the discovery and replication PWAS.
