Table 2.
Protein-hits for heart failure identified through Mendelian randomization that passed an FDR threshold of 5%
| Protein Gene Name | Number of SNPs | Odds Ratio | 95% CI | P value | pHet† | FDR | MR-Egger Intercept (95% CI); P value | Coloc PP.H4* | Druggability classification (Chemical Modality) | Near known HF gene** |
| ITIH4* | 2 | 1.13 | (1.07, 1.17) | 2.51E-07 | 0.66 | 3.90E-04 | N/A | 0.97 | Non-druggable | No |
| APOC3* | 1 | 1.19 | (1.11, 1.28) | 1.74E-06 | NA | 1.35E-03 | N/A | 0.99 | Advanced Clinical Phase (Oligonucleotide) | No |
| MAPK3 | 3 | 0.95 | (0.93, 0.97) | 6.70E-06 | 0.41 | 3.48E-03 | 0.02 (−0.01, 0.05); 0.43 | 0.52 | Advanced Clinical Phase (Small molecule) | No |
| TNFSF12 | 2 | 0.96 | (0.94, 0.98) | 1.78E-05 | 0.05 | 6.94E-03 | N/A | 0.79 | Clinical Phase 1 (Antibody) | No |
| ABO | 2 | 1.02 | (1.01, 1.03) | 2.89E-05 | 0.11 | 8.99E-03 | N/A | 0.01 | Non-druggable | ABO |
| APOH* | 2 | 0.96 | (0.94, 0.98) | 5.24E-05 | 0.83 | 1.36E-02 | N/A | 0.89 | Non-druggable | No |
| B3GNT8 | 2 | 0.97 | (0.96, 0.99) | 9.35E-05 | 0.96 | 2.08E-02 | N/A | 0.48 | Non-druggable | No |
| NTN4 | 2 | 1.08 | (1.04, 1.13) | 1.10E-04 | 0.68 | 2.14E-02 | N/A | 0.04 | Non-druggable | No |
| DLL1 | 1 | 0.87 | (0.8, 0.93) | 1.53E-04 | NA | 2.65E-02 | N/A | 0.75 | Non-druggable | No |
| MST1 | 3 | 1.02 | (1.01, 1.03) | 1.99E-04 | 0.11 | 3.10E-02 | −0.20 (−0.38, −0.01); 0.29 | 0.37 | Non-druggable | No |
| ENPEP | 4 | 0.96 | (0.94, 0.98) | 3.12E-04 | 0.18 | 4.27E-02 | 0.01 (−0.02, 0.03); 0.62 | 0.74 | Non-druggable | PITX2, FAM241A |
| NAE1 | 1 | 0.82 | (0.74, 0.91) | 3.55E-04 | NA | 4.27E-02 | N/A | 0.6 | Advanced Clinical Phase (Small molecule) | No |
| TNXB | 1 | 1.03 | (1.02, 1.05) | 3.56E-04 | NA | 4.27E-02 | N/A | 0.61 | Non-druggable | No |
| SIRPA | 1 | 0.98 | (0.97, 0.99) | 3.94E-04 | NA | 4.39E-02 | N/A | 0.56 | Non-druggable | No |
| EBI3 | 1 | 0.75 | (0.64, 0.89) | 4.44E-04 | NA | 4.61E-02 | N/A | 0.01 | Non-druggable | No |
| IL27 | 1 | 0.75 | (0.64, 0.89) | 4.44E-04 | NA | 4.61E-02 | N/A | 0.4 | Non-druggable | No |
Gene names are italicized.
Significant MR results, FDR <5%. MR estimates were calculated using Wald ratio for instruments with one variant and inverse-variance weighting and fixed effects for instruments that contained more than one variant. Note that an OR >1 indicates an increase in protein corresponding with an increase in HF risk or vice versa, suggesting that the therapeutic solution may be an inhibitor; an OR <1 indicates either a decrease in protein levels corresponding with an increase in HF risk or an increase in protein levels corresponding with a decrease in HF risk, suggesting the therapeutic solution may be an agonist.
Genes that passed a colocalization threshold of PP.H4 >0.5 (suggestive threshold) are highlighted in bold and PP.H4 >0.8 (strong threshold) are marked with an asterisk.
MR Mendelian randomization, FDR false discovery rate, PP.H4 posterior probability of H4.
*Posterior probability of H4 (one common causal variant) from colocalization of pQTL and GWAS results.
**Previously reported HF GWAS gene for instruments in GWAS loci (within 500 KB up or down from each loci).
†MR pHet were measured by Cochran’s Q-test for heterogeneity across individual-variant MR estimates within a genetic instrument; instruments containing one variant were not tested for heterogeneity.