Table 2. List of robust exome-by-phenome-wide significant gene-phenotype associations.
List of genes among 97 pLOF-based gene burdens with phenotype associations at P < 10−6 in the PMBB discovery cohort that were most robust according to the DiCE approach, which integrates successful replication of the association with clinical and experimental evidence. For replication studies, gene–phenotype associations were evaluated for their robustness by interrogating REVEL-informed missense-based gene burdens and single variants in the same discovery PMBB cohort, and pLOF-based gene burdens, REVEL-informed missense-based gene burdens and single variants in an independent cohort of African Americans in the PMBB (the PMBB2 cohort), as well as in BioMe, DiscovEHR and the UKB. Targeted single variants that showed successful replication in the PMBB, PMBB2 and UKB were additionally analyzed in BioVU. Each gene–phecode association is labeled with the corresponding P value from logistic regression analyses in the discovery phase in the PMBB, as well as the number of total replications and existence of clinical/experimental evidence, fully detailed in Supplementary Table 17. Only associations with at least two total check marks in Supplementary Table 17, where each successful mode of replication in a particular biobank (for example, pLOF burden in BioMe) or the existence of clinical/experimental evidence is labeled with a checkmark, were deemed robust and therefore included here. Previously known associations were considered to represent positive controls. Positive control (above line) and new associations (below line) are each ranked alphabetically by gene name.
| Gene | Phecode Description | Discovery P | Replications (N) | Clinical/Experimental Evidence |
|---|---|---|---|---|
| BRCA2 | Breast cancer | 1.72E-07 | 4 | ✓ |
| CFTR | Bronchiectasis | 2.27E-07 | 10 | ✓ |
| Pseudomonal pneumonia | 4.21E-11 | 5 | ✓ | |
| Cystic fibrosis | 1.05E-15 | 1 | ✓ | |
| CYP2D6 | Opiates and related narcotics causing adverse effects in therapeutic use | 1.50E-09 | 3 | ✓ |
| MYBPC3 | Hypertrophic cardiomyopathy | 3.49E-15 | 5 | ✓ |
| TTN | Cardiomyopathy | 7.83E-13 | 10 | ✓ |
| Cardiac conduction disorders | 6.45E-09 | 10 | ✓ | |
| Cardiac dysrhythmias | 1.77E-08 | 12 | ✓ | |
|
| ||||
| ABCA10 | Benign neoplasm of brain, cranial nerves, meninges | 7.26E-08 | 2 | |
| Abnormal results of function study of pulmonary system | 1.54E-07 | 3 | ||
| BBS10 | Hypertrophic cardiomyopathy | 2.89E-08 | 1 | ✓ |
| CES5A | Abnormal coagulation profile | 8.10E-08 | 5 | |
| CILP | Aortic ectasia | 4.29E-08 | 3 | ✓ |
| CTC1 | Temporomandibular joint disorders | 3.76E-07 | 3 | |
| DNAH6 | Lack of coordination | 7.93E-10 | 2 | |
| DNHD1 | Aseptic necrosis of bone | 2.67E-07 | 4 | |
| EFCAB5 | Prolapse of vaginal walls | 3.19E-08 | 3 | |
| EPPK1 | Phlebitis and thrombophlebitis of lower extremities | 9.19E-08 | 3 | |
| FER1L6 | Muscular wasting and disuse atrophy | 7.18E-07 | 3 | ✓ |
| FLG2 | Stiffness of joint | 1.76E-07 | 2 | |
| MYCBP2 | Spasm of muscle | 2.08E-07 | 2 | ✓ |
| PPP1R13L | Primary open angle glaucoma | 7.29E-07 | 2 | ✓ |
| RGS12 | Type 1 diabetes | 6.48E-08 | 5 | ✓ |
| RTKN2 | Orthostatic hypotension | 7.24E-07 | 5 | |
| SCNN1D | Cardiac conduction disorders | 4.52E-07 | 5 | |
| TGM6 | Lipoma | 2.77E-07 | 4 | |
| TRDN | Acquired toe deformities | 3.90E-07 | 3 | |
| WDR87 | Ventral hernia | 1.70E-07 | 4 | |
| ZNF175 | Tinnitus | 3.24E-10 | 3 | ✓ |
| ZNF334 | Microscopic hematuria | 1.69E-07 | 3 | |