Table 2.
Lead variants for 27 significant association loci in the genome-wide association study meta-analysis of otosclerosis
| Rsid | Chr | Position | Effect allele | Non-effect allele | EAF | Nearest Gene | Consequence | Meta-analysis OR (95% CI) | P-value | FinnGen OR (95% CI) | UKBB OR (95% CI) | EstBB OR (95% CI) | Q p-value | I2 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| rs77249084 | 8 | 116560300 | G | A | 0.3 | EIF3H | Regulatory region | 1.31 (1.24–1.38) | 1.78E–23 | 1.44 (1.33–1.56) | 1.21 (1.09–1.34) | 1.22 (1.1–1.34) | 0.0074 | 0.8 |
| rs11868207 | 17 | 68679579 | C | T | 0.23 | FAM20A (LINC01482) | Intergenic (Intronic) | 1.34 (1.26–1.42) | 1.25E–22 | 1.46 (1.33–1.6) | 1.29 (1.16–1.43) | 1.24 (1.11–1.38) | 0.056 | 0.65 |
| rs12270054 | 11 | 65555077 | T | C | 0.22 | LTBP3 | Intronic | 0.75 (0.71–0.8) | 4.29E–20 | 0.68 (0.61–0.74) | 0.76 (0.69–0.85) | 0.86 (0.77–0.97) | 0.0074 | 0.8 |
| rs10592836 | 14 | 103471816 | C | CAAT | 0.34 | MARK3 | Intronic | 1.25 (1.19−1.32) | 2.79E–18 | 1.35 (1.25–1.46) | 1.2 (1.09–1.32) | 1.16 (1.06–1.28) | 0.032 | 0.71 |
| rs71900142 | 10 | 30775253 | G | GCTTCTGGCTTAAGC | 0.41 | ZNF438 | Intergenic | 0.82 (0.78–0.86) | 1.20E–15 | 0.75 (0.7–0.81) | 0.88 (0.81–0.97) | 0.86 (0.78–0.94) | 0.015 | 0.76 |
| rs7995158 | 13 | 110459370 | G | A | 0.55 | COL4A2 (COL4A2-AS2) | 3’ UTR (Intronic) | 0.82 (0.79–0.86) | 1.81E–15 | 0.83 (0.78–0.89) | 0.79 (0.72–0.86) | 0.85 (0.78–0.93) | 0.47 | 0 |
| rs39375 | 7 | 103837624 | C | A | 0.41 | RELN | Intronic | 1.21 (1.15–1.27) | 3.21E–14 | 1.27 (1.18–1.37) | 1.14 (1.04–1.25) | 1.18 (1.08–1.29) | 0.15 | 0.47 |
| rs791903 | 6 | 33734868 | C | G | 0.5 | IP6K3 | Intronic | 0.83 (0.8–0.88) | 1.15E–13 | 0.84 (0.79–0.91) | 0.82 (0.75–0.89) | 0.84 (0.76–0.92) | 0.85 | 0 |
| rs753138805 | 4 | 87845066 | G | GGAAA | 0.0033 | MEPE | Frameshift | 9.80E–14 | 21.5 (9.6–48.4) | NA | NA | NA | NA | |
| rs181831514 | 4 | 87901594 | T | C | 0.0024 | MEPE | Intergenic | 12.3 (6.09–24.9) | 2.87E–12 | 19.66 (8.92–43.33) | NA | 2.04 (0.43–9.62) | 0.011 | 0.85 |
| rs4917 | 3 | 186619924 | C | T | 0.64 | AHSG | Missense | 0.84 (0.8–0.88) | 3.35E–12 | 0.86 (0.8–0.92) | 0.77 (0.7–0.85) | 0.88 (0.8–0.97) | 0.12 | 0.52 |
| rs13192457 | 6 | 44887654 | A | C | 0.44 | SUPT3H | Intronic | 1.21 (1.14–1.28) | 4.80E–11 | 1.3 (1.21–1.39) | 1.07 (0.98–1.18) | NA | 0.0013 | 0.9 |
| rs4636903 | 16 | 54995451 | T | C | 0.12 | IRX5 | Intergenic | 1.28 (1.19–1.39) | 7.32E–11 | 1.35 (1.2–1.52) | 1.36 (1.18–1.56) | 1.14 (0.99–1.31) | 0.12 | 0.52 |
| rs67284550 | 16 | 1480948 | T | C | 0.42 | PTX4 | Downstream gene | 1.17 (1.12–1.23) | 1.43E–10 | 1.25 (1.16–1.34) | 1.13 (1.03–1.24) | 1.09 (1–1.2) | 0.055 | 0.66 |
| rs11683921 | 2 | 111714056 | G | T | 0.38 | ANAPC1 | Intronic | 1.17 (1.11–1.23) | 3.23E–10 | 1.21 (1.12–1.3) | 1.13 (1.03–1.24) | 1.15 (1.05–1.27) | 0.49 | 0 |
| rs553652 | 11 | 96200151 | A | G | 0.92 | MAML2 | Intronic | 1.3 (1.2–1.42) | 9.24E–10 | 1.35 (1.2–1.52) | 1.31 (1.08–1.6) | 1.21 (1.04–1.42) | 0.55 | 0 |
| rs73172296 | 13 | 42525753 | A | G | 0.11 | TNFSF11 | Intergenic | 1.26 (1.17–1.36) | 1.18E–09 | 1.25 (1.13–1.4) | 1.42 (1.2–1.68) | 1.19 (1.03–1.36) | 0.27 | 0.23 |
| rs485107 | 8 | 8723898 | G | C | 0.53 | CLDN23 | Intergenic | 1.16 (1.1–1.21) | 2.20E–09 | 1.17 (1.09–1.26) | 1.15 (1.05–1.26) | 1.14 (1.04–1.25) | 0.92 | 0 |
| rs2762049 | 13 | 50248227 | C | G | 0.39 | KCNRG (DLEU1) | Intergenic (Intronic) | 1.16 (1.1–1.22) | 2.34E–09 | 1.19 (1.11–1.28) | 1.12 (1.02–1.23) | 1.15 (1.05–1.26) | 0.58 | 0 |
| rs4877080 | 9 | 89398813 | A | T | 0.28 | SEMA4D | Intronic | 0.83 (0.78–0.88) | 3.60E–09 | 0.84 (0.78–0.91) | 0.81 (0.73–0.89) | NA | 0.52 | 0 |
| rs201694067 | 1 | 219593023 | T | TGA | 0.33 | ZC3H11B | Intergenic | 1.19 (1.12–1.26) | 4.30E–09 | 1.18 (1.09–1.27) | NA | 1.22 (1.11–1.34) | 0.54 | 0 |
| rs6066825 | 20 | 48723580 | G | A | 0.32 | PREX1 | Intronic | 1.16 (1.1–1.22) | 1.20E–08 | 1.17 (1.08–1.27) | 1.25 (1.14–1.37) | 1.06 (0.96–1.17) | 0.066 | 0.63 |
| rs66487118 | 19 | 10142669 | A | G | 0.3 | DNMT1 | Intronic | 1.16 (1.1–1.23) | 1.76E–08 | 1.14 (1.05–1.24) | 1.26 (1.15–1.39) | 1.1 (0.99–1.21) | 0.12 | 0.53 |
| rs8105161 | 19 | 41333726 | C | T | 0.16 | TGFB1 | Intronic | 0.83 (0.78–0.89) | 2.71E–08 | 0.81 (0.74–0.89) | 0.85 (0.75–0.97) | 0.86 (0.76–0.96) | 0.71 | 0 |
| rs2118612 | 15 | 67108152 | T | C | 0.79 | SMAD3 | Intronic | 0.85 (0.8–0.9) | 3.34E–08 | 0.84 (0.77–0.92) | 0.81 (0.73–0.91) | 0.89 (0.79–0.99) | 0.59 | 0 |
| rs4464751 | 6 | 73707844 | T | G | 0.54 | CD109 | Intronic | 1.14 (1.09–1.2) | 3.58E–08 | 1.15 (1.07–1.24) | 1.18 (1.07–1.29) | 1.1 (1.01–1.2) | 0.58 | 0 |
| rs80339979 | 9 | 99889430 | G | GA | 0.64 | STX17 (STX17-AS1) | Intergenic (Intronic) | 1.15 (1.09–1.21) | 3.66E–08 | 1.1 (1.03–1.19) | 1.16 (1.05–1.27) | 1.22 (1.11–1.34) | 0.26 | 0.27 |
| rs6066131 | 20 | 46941020 | C | T | 0.45 | EYA2 | Intronic | 1.14 (1.09–1.2) | 4.91E–08 | 1.17 (1.09–1.26) | 1.13 (1.03–1.24) | 1.11 (1.01–1.21) | 0.57 | 0 |
A total of 3,504 cases and 861,198 controls from FinnGen, Estonian Biobank and UK Biobank were included in the meta-analysis. A Bonferroni-corrected two-sided genome-wide p-value threshold of 5×10−8 was used to establish significance, accounting for multiple comparisons. For all loci, the nearest protein-coding gene is shown. RNA and antisense genes overlapping the lead variant are additionally shown in parentheses. In addition to the 27 lead variants from the meta-analysis, data (in italic) are presented for the frameshift variant rs753138805 in MEPE which was observed only in FinnGen and was not included in the meta-analysis. The p-value for Cochran’s Q test and the I2 statistic are reported for each lead variant. Chr chromosome, EA effect allele, EAF effect allele frequency, NEA non-effect allele, OR odds ratio, CI confidence interval.