Table 3.
Amassing evidence to identify effector genes
| Signal | Lead OA SNV | EA | EAF | OA | Coding variant and fine map | Fine mapped gene | eQTL colocalization (Gtex/OA tissue) | Cartilage |
Bone |
Blood pQTL MR+coloc | Mouse musculoskeletal phenotype | Human musculoskeletal phenotype | Mouse neuronal phenotype | Human pain disorder | Human pain gene | Score | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Expr. | Abund. | Expr. | |||||||||||||||
| 9 | rs3740129 | A | 0.46 | N | CHST3 | CHST3 (6/1) | CHST3 | CHST3 | CHST3 | 6 | |||||||
| 33 | rs12908498 | C | 0.54 | K | SMAD3 | SMAD3 (1/1) | SMAD3 | SMAD3 | SMAD3 | 6 | |||||||
| 54 | rs143384 | A | 0.59 | K | GDF5 | GDF5 (4/1) | GDF5 | GDF5 | GDF5 | 6 | |||||||
| 14 | rs67924081 | A | 0.74 | K | LTBP3 (1/1) | LTBP3 (+) | LTBP3 | LTBP3 | 5 | ||||||||
| 22 | rs7294636 | A | 0.37 | K | MGP (4/2) | MGP | MGP | MGP | 5 | ||||||||
| 25 | rs7967762 | T | 0.16 | N | WNT10B (+) | WNT10B (+) | WNT10B | WNT10B | WNT10B | 5 | |||||||
| 49 | rs66989638 | A | 0.13 | N | C2orf40 | C2orf40 | C2orf40 (40/21) | C2orf40 | 5 | ||||||||
| 69 | rs1530586 | T | 0.8 | K | FGFR3 (6/4) | FGFR3 | FGFR3 | FGFR3 | 5 | ||||||||
| 72 | rs17615906 | T | 0.84 | N | FBN2 (2/2) | FBN2 | FBN2 | FBN2 | 5 | ||||||||
| 97 | rs62578126 | T | 0.37 | K | LMX1B (3/2) | LMX1B | LMX1B | LMX1B | 5 | ||||||||
| 17 | rs1149620 | A | 0.44 | K | TSKU | TSKU (5/4) | TSKU | 4 | |||||||||
| 25 | rs7967762 | T | 0.16 | N | COL2A1 (1/0) | COL2A1 | COL2A1 | COL2A1 | 4 | ||||||||
| 25 | rs7967762 | T | 0.16 | N | PFKM (2/2) | PFKM (–) | PFKM | 4 | |||||||||
| 25 | rs7967762 | T | 0.16 | N | VDR | VDR | VDR | VDR | 4 | ||||||||
| 28 | rs58973023 | A | 0.49 | N | TNFSF11 (+) | TNFSF11 (+) | TNFSF11 | TNFSF11 | 4 | ||||||||
| 31 | rs11071366 | A | 0.61 | K | ALDH1A2 | ALDH1A2 (–) | ALDH1A2 | ALDH1A2 | 4 | ||||||||
| 33 | rs12908498 | C | 0.54 | K | MAP2K1 | MAP2K1 | MAP2K1 | MAP2K1 | 4 | ||||||||
| 34 | rs12914479 | C | 0.66 | N | IGF1R (1/1) | IGF1R | IGF1R | 4 | |||||||||
| 35 | rs6500609 | C | 0.11 | N | HMOX2 (1/1) | HMOX2 | HMOX2 | 4 | |||||||||
| 42 | rs2716212 | A | 0.62 | K | PRKAR1A (–) | PRKAR1A | PRKAR1A | PRKAR1A | 4 | ||||||||
| 45 | rs75621460 | A | 0.03 | K | TGFB1 | TGFB1 | TGFB1 | TGFB1 | 4 | ||||||||
| 47 | rs4252548 | T | 0.02 | K | IL11 | IL11 | IL11 (+) | IL11 (+) | 4 | ||||||||
| 53 | rs3771501 | A | 0.47 | K | TGFA | TGFA (2/2) | TGFA | 4 | |||||||||
| 55 | rs9981408 | T | 0.23 | K | ERG | ERG (1/1) | ERG | 4 | |||||||||
| 59 | rs2276749 | T | 0.05 | N | VGLL4 | VGLL4 | VGLL4 (1/0) | VGLL4 | 4 | ||||||||
| 93 | rs1330349 | C | 0.59 | K | TNC | TNC (+) | TNC (+) | TNC | 4 | ||||||||
| 100 | rs76340814 | A | 0.05 | N | PTCH1 (5/2) | PTCH1 | PTCH1 | 4 | |||||||||
| 1 | rs11164653 | T | 0.41 | K | COL11A1 | COL11A1 | COL11A1 | 3 | |||||||||
| 3 | 1:150214028 | D | 0.38 | K | CTSK | CTSK | CTSK | 3 | |||||||||
| 3 | 1:150214028 | D | 0.38 | K | SF3B4 | SF3B4 | SF3B4 | 3 | |||||||||
| 5 | rs1327123 | C | 0.35 | N | TSEN15 | TSEN15 (8/5) | 3 | ||||||||||
| 6 | rs2605100 | A | 0.32 | K | IARS2 | IARS2 | IARS2 | 3 | |||||||||
| 7 | rs11588850 | A | 0.82 | N | SNAP47 (3/3) | SNAP47 | 3 | ||||||||||
| 11 | rs3993110 | A | 0.61 | N | TEAD1 | TEAD1 | TEAD1 | 3 | |||||||||
| 18 | rs10831475 | A | 0.81 | N | MTMR2 (+) | MTMR2 | MTMR2 | 3 | |||||||||
| 24 | rs10843013 | A | 0.78 | K | PTHLH | PTHLH | PTHLH | 3 | |||||||||
| 25 | rs7967762 | T | 0.16 | N | WNT1 | WNT1 | WNT1 | 3 | |||||||||
| 30 | rs4380013 | A | 0.19 | K | CYP19A1 | CYP19A1 | CYP19A1 | 3 | |||||||||
| 30 | rs4380013 | A | 0.19 | K | USP8 | USP8 (6/2) | 3 | ||||||||||
| 35 | rs6500609 | C | 0.11 | N | CREBBP | CREBBP | CREBBP | 3 | |||||||||
| 36 | rs9940278 | T | 0.43 | K | FTO | FTO | FTO | 3 | |||||||||
| 36 | rs9940278 | T | 0.43 | K | RPGRIP1L | RPGRIP1L | RPGRIP1L | 3 | |||||||||
| 37 | rs34195470 | A | 0.45 | K | WWP2 | WWP2 (–) | WWP2 | 3 | |||||||||
| 38 | rs216175 | A | 0.83 | K | BHLHA9 | BHLHA9 | BHLHA9 | 3 | |||||||||
| 38 | rs216175 | A | 0.83 | K | SERPINF1 | SERPINF1 | SERPINF1 | 3 | |||||||||
| 39 | rs227732 | T | 0.3 | N | NOG | NOG | NOG | 3 | |||||||||
| 40 | rs9908159 | T | 0.51 | N | NOG | NOG | NOG | 3 | |||||||||
| 41 | rs7212908 | A | 0.8 | K | TBX4 (–) | TBX4 | TBX4 | 3 | |||||||||
| 42 | rs2716212 | A | 0.62 | K | MAP2K6 | MAP2K6 (1/1) | 3 | ||||||||||
| 44 | rs10405617 | A | 0.32 | K | ILF3 (2/1) | ILF3 | 3 | ||||||||||
| 44 | rs10405617 | A | 0.32 | K | SMARCA4 | SMARCA4 | SMARCA4 | 3 | |||||||||
| 45 | rs75621460 | A | 0.03 | K | ERF | ERF | ERF | 3 | |||||||||
| 45 | rs75621460 | A | 0.03 | K | MEGF8 | MEGF8 | MEGF8 | 3 | |||||||||
| 45 | rs75621460 | A | 0.03 | K | SPTBN4 | SPTBN4 | SPTBN4 | 3 | |||||||||
| 46 | rs8112559 | C | 0.89 | N | APOE | APOE | APOE | 3 | |||||||||
| 51 | rs7581446 | T | 0.48 | K | LTBP1 | LTBP1 (1/0) | LTBP1 | 3 | |||||||||
| 55 | rs9981408 | T | 0.23 | K | KCNJ6 | KCNJ6 | KCNJ6 | 3 | |||||||||
| 58 | rs12160491 | A | 0.71 | N | TRIOBP (22/13) | TRIOBP (–) | 3 | ||||||||||
| 69 | rs1530586 | T | 0.8 | K | IDUA | IDUA | IDUA | 3 | |||||||||
| 69 | rs1530586 | T | 0.8 | K | TACC3 (9/6) | TACC3 | 3 | ||||||||||
| 73 | rs10062749 | T | 0.27 | N | NR3C1 | NR3C1 | NR3C1 | 3 | |||||||||
| 74 | rs3884606 | A | 0.52 | K | FGF18 | FGF18 (+) | FGF18 | 3 | |||||||||
| 74 | rs3884606 | A | 0.52 | K | SH3PXD2B | SH3PXD2B | SH3PXD2B | 3 | |||||||||
| 76 | rs56132153 | A | 0.61 | N | PIK3R1 (–) | PIK3R1 | PIK3R1 | 3 | |||||||||
| 77 | rs9396861 | A | 0.61 | N | RNF144B | RNF144B (2/1) | 3 | ||||||||||
| 78 | rs79220007 | T | 0.93 | K | HFE | HFE | HFE | 3 | |||||||||
| 81 | rs17288390 | T | 0.65 | K | CLIC5 | CLIC5 | CLIC5 | 3 | |||||||||
| 81 | rs17288390 | T | 0.65 | K | RUNX2 | RUNX2 | RUNX2 | 3 | |||||||||
| 82 | rs9475400 | T | 0.1 | K | HCRTR2 | HCRTR2 | HCRTR2 | 3 | |||||||||
| 83 | rs12209223 | A | 0.11 | K | MYO6 (+) | MYO6 | MYO6 | 3 | |||||||||
| 84 | rs116934101 | A | 0.27 | N | CUX1 | CUX1 (+) | CUX1 | 3 | |||||||||
| 86 | rs143083812 | T | 0.0011 | K | SMO | SMO | SMO | 3 | |||||||||
| 87 | rs571734653 | A | 3.00E-04 | N | CHRM2 | CHRM2 | CHRM2 | 3 | |||||||||
| 88 | rs7787744 | A | 0.67 | N | NOS3 | NOS3 | NOS3 | 3 | |||||||||
| 89 | rs111844273 | A | 0.02 | K | TWIST1 | TWIST1 | TWIST1 | 3 | |||||||||
| 92 | rs72760655 | A | 0.33 | K | COL27A1 (–) | COL27A1 | COL27A1 | 3 | |||||||||
| 93 | rs1330349 | C | 0.59 | K | COL27A1 (–) | COL27A1 | COL27A1 | 3 | |||||||||
| 96 | rs10983775 | T | 0.54 | N | TLR4 | TLR4 | TLR4 | 3 | |||||||||
| 98 | rs10465114 | A | 0.22 | N | LMX1B | LMX1B | LMX1B | 3 | |||||||||
| S1 | rs10453201 | T | 0.22 | N | ENHO (–) | ENHO | ENHO | 3 | |||||||||
Abbreviations: Lead OA SNV, rsID of the lead variant; EA, effect allele; EAF, effect allele frequency; OA, if the signal is new (N) or previously reported (K); Coding variant and FineMap, gene in which the lead SNV or a SNV in high LD (R2 ≥0.8) has a moderate to high severity consequence (STAR Methods) and is present in the 95% credible set (CS); Fine-mapped gene, all SNVs in the 95% CS reside within the transcript of the gene; eQTL colocalization, gene colocalized in at least 1 GTEx tissue, the number of GTEx tissues in parentheses followed by the number of these tissues also enriched in tissue enrichment analysis, which is suggestive of a role in osteoarthritis pathology; Cartilage Differential Expr, gene was differentially expressed (+ indicates increased, – indicates decreased) in high-grade compared to low-grade osteoarthritic cartilage; Cartilage Differential Abund, gene that codes for a protein that was differentially expressed (+ indicates increased, – indicates decreased) in high-grade compared to low-grade osteoarthritic cartilage; Bone Differential Expr, gene was differentially expressed in subchondral bone; Blood pQTL MR+coloc, gene is on the causal path and also colocalized; Human musculoskeletal phenotype, gene linked to a musculoskeletal phenotype according to the nosology and classification of genetic skeletal disorders (Mortier et al., 2019); Mouse musculoskeletal/Neuronal phenotype, indicates if a musculoskeletal (skeleton, limb/digit/tail, and muscle) or neuronal phenotype (“nervous system phenotype” included in the MGI mouse phenotype ontology) is observed in any mouse knockout from https://www.hugedomains.com/domain_profile.cfm?d=boneandcartilage&e=com and the MGI Mouse Genome Informatics from http://www.informatics.jax.org/; Human pain disorder, gene is linked to a pain or neuropathy disorder according to OMIM (https://www.omim.org/); Human Pain Gene, gene is linked to pain in the Human Pain Genetics Database (HPGD) (http://humanpaingenetics.org/hpgdb; Score, cumulative score for each gene based on the supporting fine-mapping and functional analysis. Genes are identified by Ensembl GeneName. See also Tables S9 and S10.