Table 2.
Selecteda DNA methylation marks significantly associated with cancer risk identified in genomic regions within 1 Mb of known cancer risk variants but representing independent association signals
| CpG | Cytoband | Closest gene | Classification | Za | OR (95% CI)a | Pa | Rb | Nearest GWAS variants | Distance (Mb) | Pa adjusted for GWAS variants | Coloc PP.H4 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Breast cancer | |||||||||||
| cg09938876 | 1p36.23 | UTS2 | TSS1500 | 5.60 | 1.22 (1.14-1.31) | 2.10 × 10−8 | 0.34 | rs707475 | -0.003 | 3.96 × 10-9 | 0.14 |
| cg11557886 | 5p12 | MRPS30 | Intronic | -15.58 | 0.63 (0.59-0.66) | 9.64 × 10-55 | 0.45 | rs10941679 | 0.105 | 8.49 × 10−10 | 0.29 |
| cg25021969 | 6q14.1 | BCKDHB; TENT5A | Intergenic | -5.99 | 0.76 (0.69-0.83) | 2.15 × 10-9 | 0.29 | rs12207986 | 0.081 | 1.24 × 10−7 | 0.17 |
| cg24428144 | 12p11.22 | PTHLH; LOC729291 | Intergenic | -17.48 | 0.73 (0.70-0.75) | 2.17 × 10-68 | 0.41 | rs7297051 | 0.006 | 1.81 × 10−7 | 0.13 |
| cg11385249 | 19p13.11 | MYO9B | Intronic | -5.24 | 0.88 (0.84-0.92) | 1.58 × 10−7 | 0.45 | rs67397200 | 0.186 | 2.19 × 10−7 | 0.63 |
| Colorectal cancer | |||||||||||
| cg19593490 | 6p22.1 | HCG9 | Exonic | -5.52 | 0.90 (0.87-0.94) | 3.38 × 10−8 | 0.68 | rs1476570 | 0.133 | 2.70 × 10-42 | 0.99 |
| cg13115165 | 10q22.3 | ZMIZ1 | Intronic | -5.99 | 0.63 (0.54-0.73) | 2.07 × 10-9 | 0.35 | rs1782645 | -0.003 | 1.15 × 10−7 | 0.99 |
| cg25472918 | 11q22.1 | TRPC6; ANGPTL5 | Intergenic | 5.52 | 1.07 (1.04-1.09) | 3.30 × 10−8 | 0.42 | rs2155065 | 0.015 | 2.48 × 10−8 | 0.88 |
| cg12149513 | 12q22 | TMCC3; MIR492 | Intergenic | 5.91 | 1.10 (1.06-1.13) | 3.50 × 10-9 | 0.50 | rs11108175 | -0.861 | 2.33 × 10-42 | 1.00 |
| cg27204212 | 20q13.13 | LINC01271; PTPN1 | Intergenic | 9.67 | 2.55 (2.11-3.08) | 4.08 × 10-22 | 0.37 | rs6095946 | 0.002 | 1.25 × 10−10 | 0.98 |
| Lung cancer | |||||||||||
| cg23681745 | 2q33.1 | CFLAR | Intronic | 5.80 | 1.09 (1.06-1.13) | 6.76 × 10-9 | 0.31 | rs3769821 | -0.119 | 7.06 × 10-9 | 0.96 |
| cg21687591 | 3q26.2 | MYNN | Intronic | 6.38 | 1.11 (1.07-1.15) | 1.76 × 10−10 | 0.35 | rs2293607 | 0.010 | 1.68 × 10−10 | 0.99 |
| cg22662645 | 3q28 | TP63 | TSS200 | 9.51 | 1.70 (1.52-1.90) | 1.99 × 10-21 | 0.17 | rs13314271 | 0.008 | 6.09 × 10−10 | 0.21 |
| cg25518571 | 5p15 | TERT | Intronic | -14.19 | 0.59 (0.54-0.63) | 1.03 × 10-45 | 0.27 | rs7705526 | 0.000 | 2.51 × 10−8 | 0.19 |
| cg08293075 | 6p21.32 | PBX2 | Intronic | 5.89 | 1.28 (1.18-1.40) | 3.96 × 10-9 | 0.26 | rs34102154 | 0.416 | 4.59 × 10-9 | 0.11 |
| Ovarian cancer | |||||||||||
| cg26405475 | 3q25.31 | SSR3; TIPARP-AS1 | Intergenic | -7.41 | 0.80 (0.75-0.85) | 1.27 × 10-13 | 0.24 | rs62274041 | 0.112 | 1.89 × 10−7 | 0.22 |
| cg16467921 | 8q24.21 | MYC; PVT1 | Intergenic | -5.38 | 0.69 (0.60-0.79) | 7.25 × 10−8 | 0.47 | rs9886651 | 0.017 | 2.13 × 10−7 | 0.98 |
| Prostate cancer | |||||||||||
| cg27467234 | 3q26.2 | LRRC34 | TSS1500 | -7.89 | 0.91 (0.89-0.93) | 3.04 × 10-15 | 0.40 | rs2293607 | 0.049 | 1.76 × 10-9 | 0.99 |
| cg12473775 | 11q13.2 | RHOD | Intronic | -5.82 | 0.63 (0.53-0.73) | 5.97 × 10-9 | 0.54 | rs11227678 | 0.018 | 2.03 × 10−7 | 0.75 |
| cg19252671 | 12p13.1 | CDKN1B | Exonic | -6.08 | 0.84 (0.80-0.89) | 1.18 × 10-9 | 0.34 | rs2066827 | 0.000 | 5.29 × 10−8 | 0.94 |
| cg15958104 | 17p13.3 | RPH3AL | 5’UTR | -5.46 | 0.86 (0.82-0.91) | 4.74 × 10−8 | 0.61 | rs684232 | 0.420 | 7.62 × 10-12 | 1.00 |
| cg04105270 | 17q12 | HNF1B | TSS1500 | -38.18 | 0.55 (0.53-0.57) | 5.69 × 10-319 | 0.61 | rs11263763 | 0.003 | 3.41 × 10-9 | 0.99 |
OR odds ratio per standard deviation (SD) increase in genetically predicted DNA methylation levels, CI confidence interval, GWAS genome-wide association studies, Mb mega base, TSS transcription start site, UTR untranslated region, PP.H4 posterior probability that both the CpG site and cancer risk are associated and share a single causal variant.
a Of the 4461 significant CpG-associations identified in the present study, 254 remained significant after adjusting for the nearest GWAS-identified variants, in which 162 CpGs are located in 52 loci that are < 1 Mb away from nearest GWAS-identified cancer risk variants. Of these 52 loci, for each cancer type, at most five CpG-cancer pairs showing the highest possibility of colocalization (PP.H4) are presented, and all the other pairs are available in Supplementary Data 2–8. The Bonferroni-corrected significance threshold was two-sided P-value of 4.93 × 10−7 for breast cancer, 2.53 × 10−7 for colorectal cancer, 3.98 × 10−7 for renal cell cancer, 2.55 × 10−7 for lung cancer, 2.66 × 10−7 for ovarian cancer, 3.28 × 10−7 for prostate cancer, and 4.22 × 10−7 for testicular germ cell cancer.
b Association Z scores, ORs, 95% CIs, and P-values were evaluated by applying GTEx-based tissue DNA methylation prediction models to cancer GWAS data using SPrediXcan.
c Coefficients of correlation between measured and genetically predicted DNA methylation levels.