Table 1.
Fourteen Prioritized Candidates for Transcription‐Regulatory BMD‐Causal Variants (Tier‐1 SNPs) in Five Bone‐Related Genes
| Gene | Tier‐1 SNP for BMD association | I/P or Imp SNP | Distance of SNP to gene TSS (kb) | Alleles (Ref/Alt) | BMD‐increasing allele (Freq EUR) a | Chromatin state b at the SNP in ostb | Predicted TF binding c | |
|---|---|---|---|---|---|---|---|---|
| Ref allele | Alt allele | |||||||
| BICC1 | rs112597538 | I/P | −0.1 | T/C | Unknown (0.50) | Str prom | SREBF1/2 | None |
| rs1896245 | I/P, Imp | 3.2 | T/G | Alt (0.50) | Str enh/prom | SATB1 | None | |
| rs1896243 | I/P, Imp | 3.5 | C/T | Alt (0.50) | Str enh | None | TCF3 | |
| rs11006188 | Imp | 60.6 | G/C | Ref (0.60) | Str enh | SMAD, GLIS3 | NR2F6 | |
| rs1982173 | Imp | 61.2 | G/T | Ref (0.60) | Str enh | RBPJ | None | |
| NPR3 | rs1173771 | I/P | 104.3 | A/G | Alt (0.58) | Str enh | SATB1 | None |
| rs7733331 | I/P | 118.1 | T/C | Alt (0.58) | Str enh | GTF2I | None | |
| LGR4 | rs10835153 | I/P, Imp | −181 | A/T | Ref (0.41) | Str enh | None | BPTF |
| HMGA2 | rs80019710 | Imp | −231.1 | C/T | Alt (0.05) | Str enh | None | HMGA1 |
| rs17101510 | I/P, Imp | −231 | C/T | Alt (0.02) | Str enh | None | YY1 | |
| rs12296417 | I/P, Imp | −230.5 | T/A | Alt (0.02) | Str enh | None | SATB1, ZBTB20 | |
| DAAM2 | rs2504105 | I/P, Imp | 62.4 | A/G | Ref (0.40) | Str enh/prom | SMAD | None |
| rs2504104 | I/P, Imp | 62.4 | A/G | Ref (0.40) | Str enh/prom | None | RUNX2/1, CBFB | |
| rs2504103 | I/P, Imp | 62.5 | C/G | Ref (0.40) | Str enh/prom | None | NFIC | |
Note: 14 Tier‐1 SNPs (prioritized candidates for regulatory osteoporosis‐risk SNPs) and their five associated genes determined from 38 BMD GWAS.
Abbreviations: Alt, alternate allele; BMD, bone mineral density; GWAS, genome‐wide association study; I/P, index or proxy SNP; Imp, imputed SNP; ostb, osteoblasts; Ref, reference allele; SNP, single‐nucleotide polymorphism; Str enh, strong enhancer chromatin; Str prom, strong promoter chromatin; TF, transcription factor; TSS, transcription start site.
The BMD‐increasing alleles and their frequency in the European population.
From Roadmap 18‐State/Auxiliary Hidden Markov Model, States 1, 3, 8, or 9.
Predictions of allele‐specific TF binding sites by hand curation of data from the TRANSFAC database and database‐verification of TF expression in ostb.