Table 1.
Results of the meta-analysis of CREAM and 23andMe for the previously-identified loci and a subset of the newly-identified loci, and replication in UK Biobank
| a Replication of the HapMap II index variants for refractive error per locus in the Stage 3 meta-analysis
| ||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SNP | Chr | Position | Nearest Loci And Gene(s) |
Effect Allele |
Other Allele |
EAF EUR |
EAF ASN |
Z-score | Direction | P value | HetISq | HetPVal | Sample Size (N) |
HapMap II Discovery (2013) |
Category | P value Replication |
| rs10500355 | 16 | 7459347 | RBFOX1 | A | T | 0.354 | 0.133 | −13.73 | −− | 6.49E-43 | 9.1 | 2.93E-07 | 160,139 | Kiefer et al. & Verhoeven et al. | I | 2.50E-48 |
| rs11145465 | 9 | 71766593 | TJP2 | A | C | 0.212 | NA | −9.55 | −− | 1.35E-21 | 46.3 | 0.1722 | 153,174 | Kiefer et al. & Verhoeven et al. | I | 1.00E-10 |
| rs11178469 | 12 | 71275137 | PTPRR | T | C | 0.752 | 0.638 | −7.40 | −− | 1.33E-13 | 0 | 0.6989 | 160,139 | Verhoeven et al. | II (CREAM) | 2.60E-04 |
| rs11602008 | 11 | 40149305 | LRRC4C | A | T | 0.822 | 0.749 | 13.98 | ++ | 2.12E-44 | 22.5 | 1.56E-10 | 157,505 | Kiefer et al. | II (23andMe) | 2.90E-47 |
| rs12193446 | 6 | 129820038 | BC035400, LAMA2 | A | G | 0.906 | NA | −19.43 | −− | 4.21E-84 | 16.8 | 5.72E-15 | 150,269 | Kiefer et al. & Verhoeven et al. | I | 4.60E-106 |
| rs1550094 | 2 | 233385396 | CHRNG, PRSS56 | A | G | 0.701 | 0.705 | 12.74 | ++ | 3.64E-37 | 26.3 | 0.003 | 159,422 | Kiefer et al. & Verhoeven et al., Kiefer et al. | I | 4.10E-59 |
| rs1649068 | 10 | 60304864 | BICC1 | A | C | 0.475 | 0.504 | −9.44 | −− | 3.77E-21 | 0 | 0.712 | 160,144 | Verhoeven et al. | I | 7.50E-11 |
| rs17382981 | 10 | 94953258 | CYP26A1,MYOF | T | C | 0.417 | 0.190 | −6.31 | −− | 2.72E-10 | 67.9 | 0.077 | 155,332 | Verhoeven et al. | II (CREAM) | 4.10E-07 |
| rs17428076 | 2 | 172851936 | HAT1, METAP1D | C | G | 0.768 | 0.854 | −8.18 | −− | 2.77E-16 | 0 | 0.003 | 160,151 | Kiefer et al. | II (23andMe) | 7.50E-08 |
| rs1858001 | 1 | 207488004 | C4BPA,CD55 | C | G | 0.676 | 0.415 | 7.28 | ++ | 3.45E-13 | 59.6 | 0.020 | 160,149 | Verhoeven et al. | II (CREAM) | 6.70E-20 |
| rs1954761 | 11 | 105596885 | GRIA4 | T | C | 0.371 | 0.377 | −8.40 | −− | 4.57E-17 | 0 | 0.911 | 160,122 | Verhoeven et al. | I | 1.20E-16 |
| rs2155413 | 11 | 84634790 | DLG2 | A | C | 0.482 | 0.655 | −7.76 | −− | 8.85E-15 | 0 | 2.99E-04 | 159,504 | Kiefer et al. | II (23andMe) | 1.10E-17 |
| rs235770 | 20 | 6761765 | BMP2 | T | C | 0.372 | 0.388 | −5.93 | −− | 3.11E-09 | 0 | 0.547 | 157,521 | Verhoeven et al. | II (23andMe) | 4.80E-11 |
| rs2573081 | 2 | 178828507 | PDE11A | C | G | 0.524 | 0.538 | 8.21 | ++ | 2.18E-16 | 47.6 | 0.167 | 160,126 | Kiefer et al. | II (23andMe) | 1.60E-29 |
| rs2753462 | 14 | 60850703 | JB175233, C14orf39 | C | G | 0.296 | 0.568 | −6.49 | −− | 8.37E-11 | 73.9 | 0.050 | 157,352 | Verhoeven et al. | II (CREAM) | 2.00E-15 |
| rs2855530 | 14 | 54421917 | BMP4 | C | G | 0.507 | 0.474 | −8.58 | −− | 9.87E-18 | 41.7 | 0.190 | 160,092 | Kiefer et al. | I | 4.80E-22 |
| rs2908972 | 17 | 11407259 | SHISA6 | A | T | 0.415 | 0.484 | −11.13 | −− | 9.46E-29 | 23 | 0.254 | 160,123 | Kiefer et al. & Verhoeven et al. | I | 6.10E-29 |
| rs3138141 | 12 | 56115778 | BLOC1S1-RDH5,RDH5 | A | C | 0.214 | 0.147 | 13.80 | ++ | 2.46E-43 | 3.2 | 5.05E-07 | 157,531 | Kiefer et al. & Verhoeven et al. | I | 2.30E-56 |
| rs4687586 | 3 | 53837971 | CACNA1D | C | G | 0.691 | NA | −6.55 | −− | 5.86E-11 | 0 | 0.605 | 150,217 | Verhoeven et al. | III | 1.60E-08 |
| rs4793501 | 17 | 68718734 | KCNJ2, BC039327 | T | C | 0.575 | 0.444 | −7.21 | −− | 5.53E-13 | 0 | 0.592 | 160,150 | Verhoeven et al. | II (CREAM) | 3.70E-12 |
| rs524952 | 15 | 35005886 | GOLGA8B, GJD2 | A | T | 0.475 | 0.507 | −17.08 | −− | 2.28E-65 | 67.2 | 0.015 | 160,150 | Kiefer et al. & Verhoeven et al. | I | 1.60E-103 |
| rs56075542 | 2 | 146882415 | BC040861, PABPC1P2 | T | G | 0.552 | 0.472 | −8.99 | −− | 2.39E-19 | 13.9 | 0.001 | 159,478 | Kiefer et al. | II (23andMe) | 1.30E-18 |
| rs62070229 | 17 | 31227593 | MYO1D, TMEM98 | A | G | 0.807 | 0.874 | 8.58 | ++ | 9.64E-18 | 0 | 0.416 | 156,570 | Verhoeven et al. | I | 1.30E-18 |
| rs6495367 | 15 | 79375347 | RASGRF1 | A | G | 0.408 | 0.399 | −10.20 | −− | 1.95E-24 | 0 | 0.667 | 160,144 | Kiefer et al. & Verhoeven et al. | I | 7.20E-37 |
| rs7042950 | 9 | 77149837 | RORB | A | G | 0.732 | 0.392 | 6.80 | ++ | 1.07E-11 | 0 | 0.912 | 160,153 | Verhoeven et al. | III | 2.90E-18 |
| rs72621438 | 8 | 60178580 | SNORA51, CA8 | C | G | 0.642 | 0.609 | −13.14 | −− | 2.03E-39 | 38.4 | 0.006 | 160,128 | Kiefer et al. & Verhoeven et al. | I | 1.80E-49 |
| rs745480 | 10 | 85986554 | LRIT2,LRIT1 | C | G | 0.511 | 0.418 | 8.31 | ++ | 9.26E-17 | 67.3 | 0.081 | 159,504 | Kiefer et al. | II (23andMe) | 8.20E-18 |
| rs7624084 | 3 | 141093285 | ZBTB38 | T | C | 0.568 | 0.633 | −8.81 | −− | 1.24E-18 | 18.5 | 0.018 | 160,151 | Kiefer et al. | II (23andMe) | 6.50E-17 |
| rs7662551 | 4 | 80537638 | LOC100506035, PCAT4 | A | G | 0.723 | 0.558 | 8.53 | ++ | 1.47E-17 | 19.4 | 0.265 | 160,147 | Verhoeven et al. | I | 6.00E-12 |
| rs7692381 | 4 | 81903049 | C4orf22, BMP3 | A | G | 0.763 | 0.630 | 9.40 | ++ | 5.55E-21 | 0 | 0.013 | 160,134 | Kiefer et al. | I | 7.50E-13 |
| rs7744813 | 6 | 73643289 | KCNQ5 | A | C | 0.591 | 0.602 | −14.56 | −− | 5.43E-48 | 35 | 0.001 | 160,091 | Kiefer et al. & Verhoeven et al. | I | 1.00E-75 |
| rs7829127 | 8 | 40726394 | ZMAT4 | A | G | 0.792 | 0.897 | −10.91 | −− | 1.02E-27 | 15.9 | 2.77E-04 | 160,132 | Kiefer et al. & Verhoeven et al. | II (23andMe) | 3.10E-22 |
| rs7895108 | 10 | 79061458 | KCNMA1 | T | G | 0.351 | 0.118 | −8.87 | −− | 7.56E-19 | 32.8 | 0.021 | 160,140 | Kiefer et al. | II (23andMe) | 1.10E-27 |
| rs79266634 | 16 | 7309047 | RBFOX1 | C | G | 0.093 | 0.115 | −5.93 | −− | 3.00E-09 | 0 | 0.561 | 156,268 | Kiefer et al. & Verhoeven et al. | III | 1.50E-08 |
| rs837323 | 13 | 101175664 | PCCA | T | C | 0.512 | 0.762 | 6.32 | ++ | 2.65E-10 | 35.6 | 0.213 | 160,142 | Verhoeven et al. | II (23andMe) | 5.30E-16 |
| rs9517964 | 13 | 100717833 | ZIC2,PCCA | T | C | 0.589 | 0.786 | 8.42 | ++ | 3.68E-17 | 0 | 0.020 | 160,121 | Kiefer et al. | II (23andMe) | 3.40E-20 |
| b Subset of the new loci harboring the smallest p-values for refractive error in the Stage 3 meta-analysis | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SNP | Chr | Position | Nearest Loci And Gene(s) |
Effect Allele |
Other Allele |
EAF EUR |
EAF ASN | Z-score | Direction | P value | HetISq | HetPVal | Sample Size (N) |
Category | P value Replication |
| rs36024104 | 14 | 42294993 | LRFN5 | A | G | 0.823 | NA | 9.09 | ++ | 9.86E-20 | 15.9 | 0.01414 | 152,585 | II (23andMe) | 2.20E-12 |
| rs7456039 | 7 | 6901710 | CCZ1B, LOC100131257 | C | G | 0.183 | NA | 8.82 | ++ | 1.18E-18 | 42.1 | 3.79E-12 | 121,337 | II (23andMe) | 6.50E-01 |
| rs1556867 | 1 | 164213686 | 5S_rRNA, PBX1 | T | C | 0.264 | 0.494 | −8.81 | −− | 1.29E-18 | 71.1 | 0.06266 | 160,155 | II (23andMe) | 4.20E-17 |
| rs12667032 | 7 | 154406581 | DPP6 | A | G | 0.152 | 0.317 | 7.99 | ++ | 1.31E-15 | 82.3 | 1.02E-11 | 130,790 | II (23andMe) | 2.10E-01 |
| rs2225986 | 1 | 200311910 | LINC00862 | A | T | 0.381 | 0.169 | −7.96 | −− | 1.68E-15 | 40.2 | 0.196 | 160,152 | II (23andMe) | 7.50E-17 |
| rs1207782 | 6 | 22059967 | LINC00340 | T | C | 0.577 | 0.265 | −7.92 | −− | 2.47E-15 | 0 | 0.8946 | 160,149 | I | 4.90E-13 |
| rs72826094 | 10 | 114801488 | TCF7L2 | A | T | 0.799 | 0.838 | 7.88 | ++ | 3.20E-15 | 64.5 | 0.09323 | 156,825 | II (23andMe) | 4.90E-02 |
| rs297593 | 2 | 157363743 | GPD2 | T | C | 0.286 | 0.257 | −7.82 | −− | 5.45E-15 | 0 | 0.5285 | 159,461 | II (23andMe) | 7.80E-11 |
| rs5442 | 12 | 6954864 | GNB3 | A | G | 0.068 | NA | −7.82 | −− | 5.48E-15 | 8.8 | 0.03693 | 146,217 | II (23andMe) | 1.20E-33 |
| rs10880855 | 12 | 46144855 | ARID2 | T | C | 0.507 | 0.464 | −7.78 | −− | 7.35E-15 | 0 | 0.9683 | 160,144 | I | 4.80E-08 |
| rs12405776 | 1 | 242431557 | PLD5 | T | C | 0.220 | 0.521 | 7.75 | ++ | 9.52E-15 | 64.9 | 3.56E-10 | 153,784 | II (23andMe) | 1.50E-01 |
| rs2150458 | 21 | 47377296 | PCBP3, COL6A1 | A | G | 0.455 | 0.641 | 7.74 | ++ | 1.04E-14 | 55.7 | 0.1329 | 160,151 | II (23andMe) | 1.80E-13 |
| rs12898755 | 15 | 63574641 | APH1B | A | G | 0.245 | 0.456 | 7.53 | ++ | 4.98E-14 | 7.9 | 0.2974 | 159,506 | II (23andMe) | 1.40E-16 |
| rs7122817 | 11 | 117657679 | DSCAML1 | A | G | 0.507 | 0.662 | 7.51 | ++ | 5.73E-14 | 73.8 | 0.05077 | 160,147 | II (23andMe) | 1.10E-10 |
| rs10511652 | 9 | 18362865 | SH3GL2, ADAMTSL1 | A | G | 0.416 | 0.445 | 7.36 | ++ | 1.91E-13 | 44.8 | 0.1782 | 160,149 | II (23andMe) | 3.50E-18 |
| rs11101263 | 10 | 49414181 | FRMPD2 | T | C | 0.258 | 0.105 | −7.33 | −− | 2.33E-13 | 0 | 0.3477 | 160,155 | II (23andMe) | 2.20E-13 |
| rs11118367 | 1 | 219790221 | LYPLAL1 | T | C | 0.482 | 0.630 | −7.29 | −− | 3.16E-13 | 0 | 0.8576 | 160,141 | III | 1.20E-13 |
| rs9395623 | 6 | 50757699 | TFAP2D, TFAP2B | A | T | 0.315 | 0.381 | 7.25 | ++ | 4.16E-13 | 0 | 0.9579 | 160,151 | III | 2.20E-10 |
| rs284816 | 8 | 53362145 | ST18, FAM150A | A | G | 0.163 | 0.198 | −7.21 | −− | 5.52E-13 | 0 | 0.9242 | 160,140 | III | 1.60E-08 |
| rs12965607 | 18 | 47391025 | MYO5B | T | G | 0.857 | 0.923 | 7.07 | ++ | 1.52E-12 | 20.8 | 0.01674 | 157,604 | II (23andMe) | 8.10E-16 |
| rs7747 | 4 | 80827062 | ANTXR2 | T | C | 0.202 | 0.093 | 7.03 | ++ | 2.05E-12 | 5.4 | 0.01267 | 150,327 | II (23andMe) | 7.70E-16 |
| rs12451582 | 17 | 54734643 | NOG, C17orf67 | A | G | 0.369 | 0.308 | 7.02 | ++ | 2.22E-12 | 0 | 0.5925 | 160,155 | II (23andMe) | 8.80E-18 |
| rs80253120 | 17 | 14138507 | CDRT15 | T | C | 0.626 | 0.723 | 6.97 | ++ | 3.25E-12 | 58.6 | 0.12 | 156,054 | II (23andMe) | 7.20E-11 |
| 22:23069851:I | 22 | 23069851 | DKFZp667J0810 | ATG | A | 0.084 | 0.1582 | 6.95 | −+ | 3.56E-12 | 98.5 | 4.80E-16 | 120,481 | II (23andMe) | 9.30E-01 |
| rs7968679 | 12 | 9313304 | PZP | A | G | 0.700 | 0.894 | 6.95 | ++ | 3.65E-12 | 0 | 0.01951 | 160,076 | II (23andMe) | 4.20E-10 |
| rs11202736 | 10 | 90142203 | RNLS | A | T | 0.717 | 0.762 | −6.92 | −− | 4.53E-12 | 0 | 0.4007 | 160,150 | II (23andMe) | 9.40E-07 |
| rs11088317 | 21 | 16574122 | NRIP1, USP25 | T | C | 0.287 | 0.299 | −6.90 | −− | 5.38E-12 | 72.5 | 0.05657 | 160,116 | II (23andMe) | 6.50E-06 |
| rs10853531 | 18 | 42824449 | SLC14A2 | A | G | 0.200 | 0.182 | 6.88 | ++ | 5.89E-12 | 0 | 0.6755 | 160,104 | III | 2.60E-10 |
| rs72655575 | 8 | 60556509 | SNORA51, CA8 | A | C | 0.201 | 0.124 | 6.87 | ++ | 6.54E-12 | 0 | 0.8811 | 156,566 | I | 7.10E-07 |
| rs12998513 | 2 | 242879499 | CXXC11,AK097934 | A | G | 0.880 | 0.676 | −6.86 | +− | 7.15E-12 | 65.2 | 4.51E-14 | 117,611 | II (23andMe) | 7.80E-01 |
| rs1790165 | 11 | 131928971 | NTM | A | C | 0.411 | 0.283 | 6.85 | ++ | 7.17E-12 | 0 | 0.003708 | 160,131 | II (23andMe) | 1.80E-10 |
| rs511217 | 11 | 30029948 | METTL15, KCNA4 | A | T | 0.738 | 0.729 | −6.79 | −− | 1.10E-11 | 0 | 0.3626 | 160,143 | II (23andMe) | 1.40E-17 |
| rs1150687 | 6 | 28162469 | ZNF192P1, TRNA_Ser | T | C | 0.619 | 0.504 | 6.78 | ++ | 1.17E-11 | 56.2 | 0.131 | 159,448 | II (23andMe) | 3.10E-10 |
| rs56055503 | 16 | 80532694 | MAF, DYNLRB2 | A | G | 0.751 | 0.539 | −6.72 | −− | 1.83E-11 | 0 | 0.8407 | 160,145 | II (23andMe) | 8.00E-06 |
| rs9681162 | 3 | 8194734 | AK124857, LMCD1-AS1 | T | C | 0.680 | 0.437 | 6.70 | ++ | 2.10E-11 | 63 | 0.1002 | 160,152 | II (23andMe) | 6.30E-13 |
| rs11589487 | 1 | 61342229 | AK097193, BC030753 | A | G | 0.445 | 0.089 | 6.67 | ++ | 2.64E-11 | 34.6 | 0.2163 | 160,143 | II (23andMe) | 2.20E-10 |
We identified 140 loci for refractive error with genome-wide significance (P < 5 × 10−8) on the basis the meta-analyses of the genome-wide single-variant linear regressions performed in 160,420 participants of mixed ancestries (CREAM-ASN, CREAM-EUR and 23andMe). Shown are the replication of the previously found loci from HapMap II and a subset of the new loci harboring the smallest P values. For each locus, represented by an index variant (the variant with smallest p-value in that locus), Effect Allele, Other Allele, effect allele frequencies per ancestry (EAF AZN and EAF EUR), effect size (Z-score), direction of the effect (Direction), the P value, heterogeneity I square (HetISq), heterogeneity P value (HetPval), Sample Size (N), Category (I = both GWS in Stage 1 and 2, 2=one of two cohorts (CREAM or 23andMe) GWS, 3= both not GWS in Stage 1 or 2) and P value of the replication in UK Biobank are shown (Full table: Supplementary Table 2). Chr, chromosome; EAF, effect allele frequency; ASN, Asian; EUR, European; GWS, genome wide significant.