Fig. 5
Comparison between summary-PrediXcan and SMR. a Depicts how SMR tests the mediating role of gene expression level \(T_g\). The top eQTL is linked to the phenotype as an instrumental variable in a Mendelian Randomization approach. b Shows the significance of SMR vs. the significance of Summary-PrediXcan. As expected, SMR associations tend to be smaller than S-PrediXcan ones. c and d show that the SMR statistics significance is bounded by GWAS and eQTL p-values. The p-values (−log10) of the SMR statistics are plotted against the GWAS p-value of the top eQTL SNP (c), and the gene’s top eQTL p-value (d). e Shows a QQ plot for simulated values of \(T_{\mathrm{SMR}}\). Under the null hypothesis of significant eQTL signal and no GWAS association, we generated random values for \(Z_{\mathrm{GWAS}}^2\) and \(Z_{\mathrm{eQTL}}^2\) following the simulations from ref. 16. \(T_{\mathrm{SMR}}\) statistic was calculated from these values, and compared to a \(\chi _1^2\) distribution to illustrate this statistics’ deflation. f shows the sample mean of \(T_{\mathrm{SMR}}\) from 1000 simulations, centered close to 0.93, instead of the expected value of 1 for a \(\chi _1^2\)-distributed variable. g shows the proportion of non-colocalized significant associations to total significant associations in PrediXcan and SMR. h Shows the proportion of colocalized significant associations (shared eQTL and GWAS signals). As expected, SMR shows a higher proportion of colocalized and non-colocalized associations than PrediXcan. This is caused by SMR’s high eQTL significance threshold, that rules out most of the genes with low colocalization power (P0 + P1 + P2 > 0.5). For some of the associations, GWAS and eQTL p-values were more significant than shown since they were thresholded at 10−50 to improve visualization. Phenotype abbreviations are as follows: FNBD Femoral Neck Bone Density, LSBD Lumbar Spine Bone Density, BMI Body Mass Index, HEIGHT Height, LDL Low-Density Lipoprotein Cholesterol, HDL High-Density Lipoprotein Cholesterol, TRYG Tryglicerides, CROHN Crohn’s Disease, INFBOWEL Inflammatory Bowel’s Disease, ULCERC Ulcerative Colitis, HBA1C Hemogoblin Levels, HOMA-IR HOMA Insulin Response, SCZ Schizophrenia, RA Rheumatoid Arthritis, COLLEGE College Completion, EDUCYEARS Education Years
