Table 5. Human variants of BMP2 and GRHL3 are associated with increased risk of fractures.
We performed a phenomewide association study of BMP2 and a downstream effector GRHL3 in 61,062 individuals from DiscovEHR, a cohort linking exome sequence data to electronic health records (EHRs). Using a Bonferroni significance threshold of p<1.86e-7 for 268,192 association results, we observed three significant associations for BMP2 and six significant associations for GRHL3.
| Variant | Gene | Functional Prediction | HGVS amino acid | Phenotype | Odds Ratio (CI) |
P- Value | MAF |
|---|---|---|---|---|---|---|---|
| 20:6770235:T:G | BMP2 | missense | p.Ser37Ala | Post-eruptive color changes of dental hard tissues | 15.44 (6.50–36.64) |
5.33E-10 | 0.01802 |
| 20:6778359:G:A | BMP2 | missense | p.Arg154Gln | Secondary hyperparathyroidism, not elsewhere classified | 18.88 (7.35–48.53) |
1.06E-09 | 0.00033 |
| 1:24336821:A:T | GRHL3 | synonymous | p.Pro202Pro:p.Pro156Pro:p.Pro207Pro:p.Pro202Pro | Fracture of thoracic vertebra | 12.72 (5.59–28.94) |
1.36E-09 | 0.00078 |
| 20:6778291:A:T | BMP2 | missense | p.Arg131Ser | Fracture of lower leg, including ankle | 16.05 (6.44–40.00) |
2.54E-09 | 0.00019 |
| 1:24342967:C:T | GRHL3 | missense | p.Thr454Met:p.Thr408Met:p.Thr459Met:p.Thr454Met | Atresia of bile ducts | 17.11 (6.34–46.18) |
2.07E-08 | 0.03395 |
| 1:24336694:T:C | GRHL3 | missense | p.Val160Ala:p.Val114Ala:p.Val165Ala:p.Val160Ala | Malignant neoplasm of parietal lobe | 8.72 (4.08–18.64) |
2.31E-08 | 0.04732 |
| 1:24344928:A:G | GRHL3 | missense | p.Asn484Ser:p.Asn438Ser:p.Asn489Ser:p.Asn484Ser | Malignant neoplasm of parietal lobe | 8.23 (3.90–17.38) |
3.24E-08 | 0.0484 |
| 1:24339645:C:G | GRHL3 | intronic | NA | Fracture of patella | 13.33 (5.11–34.81) |
1.22E-07 | 0.00109 |
| 1:24342967:C:T | GRHL3 | missense | p.Thr454Met:p.Thr408Met:p.Thr459Met:p.Thr454Met | Atresia of esophagus with tracheo-esophageal fistula | 9.76 (4.16–22.88) |
1.63E-07 | 0.03396 |