Genetic predisposition to uterine leiomyoma is determined by loci for genitourinary development and genome stability
- University of Helsinki, Finland
- University of Helsinki and Helsinki University Hospital, Finland
- Faculty of Medicine, University of Oulu, Finland
- Oulu University Hospital, University of Oulu, Finland
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Sweden
Figures
Figure 1
Outline of the study stages and genotyping cohorts.
GRS, genomic risk score. NFBC, Northern Finland Birth Cohort.
Figure 2
Overview of the uterine leiomyoma risk loci and the effect of increased number of MED12-mutated lesions per rs5937008 risk allele.
(A), Manhattan plot of the UK Biobank GWAS on 15,453 UL cases and 392,628 controls. On Y-axis, logarithm transformed association values, and on X-axis, autosomes and the X chromosome. The blue …
Figure 3
Meta-analysis of UL risk revealed rs117245733 at a gene poor region of 13q14.11.
(A) meta-analysis P-values and the genomic context at the locus. Gene symbols and ENCODE tracks (details in Supplementary Methods) are shown for reference; coordinates follow hg19. (B) Hi-C, TADs …
Figure 4
The genomic risk score is elevated in patients with MED12-mutated lesions and in respect to the UL phenotype in the six follow-up cohorts.
On top, GRS association to MED12 mutation status. The rest show GRS association to the UL phenotype in six independent replication cohorts. Associations (P) and test statistics (W) are from Wilcoxon …
Figure 5
Methylation and expression differences in WNT4.
(A), Hi-C, TADs and CpG methylation around the locus with an 1 Mb flank. The needle plot shows the meQTL associations (dashed lines at 10% FDR; green lines denote the two SNPs, rs2235529 and …
Appendix 1—figure 1
Structure of UL predisposition loci.
The lead SNPs from stage one and their genomic context. The LD estimates (r2) were taken from UK10k ALSPAC. Associations are based on the UKBB cohort. Gene symbols and ENCODE tracks (details in …
Appendix 1—figure 2
Clinical background information for the Helsinki cohort patients.
(A,) the number of ULs per patient (n = 457). (B), patient’s age at hysterectomy (n = 392). (C), parity (n = 367). (D), body mass index (BMI; n = 366). (E), menopause status (n = 367).
Appendix 1—figure 3
MED12 mutation status distributions for the Helsinki cohort patients.
On left, mutation-positive tumors per patient (n = 457), and on right, mutation-negative tumors per patient (n = 457).
Appendix 1—figure 4
Genetic separation between the self-reported ancestries in UK Biobank.
Principal components (PC) analysis of ancestry informative markers. In total 1396 autosomal, ancestry informative SNPs were used and the resulting first two PCs are shown: top-left plot shows all …
Appendix 1—figure 5
Association between GRS and phenotype.
One somatic phenotype (MED12 mutation status) and six independent case-control replication cohorts. On left, density plots (bandwidth = 0.2) for each phenotype. X-axis gives GRS values scaled to …
Appendix 1—figure 6
Genomic risk scores in gnomAD populations.
Population-specific genomic risk scores (GRS) as seen based on gnomAD allele frequencies. Y-axis shows the cumulative effect of each of the 57 GRS SNPs; the X-axis is ordered by risk allele …
Appendix 1—figure 7
Association between GRS and number of ULs per patient.
The numbers are based on the Helsinki cohort data of 457 patients with all distinct tumors of ≥1 cm diameter harvested at hysterectomy; details on sample collection are given in Supplementary …
Appendix 1—figure 8
Association between GRS and MED12 mutations.
The numbers are based on the Helsinki cohort data (457 patients). (A) summary of the negative binomial model for MED12-mutation-positive tumor counts. (B) diagnostic plots for the negative binomial …
Appendix 1—figure 9
meQTLs at TERT region.
Hi-C, TADs and CpG methylation around rs2736100 with an 1Mbp flank. The needle plot shows the meQTL associations (dashed lines at 10% FDR; green line denotes the two SNPs; gray ticks denote all CpGs …
Appendix 1—figure 10
Overview of the CpG methylation around TERT in tumor tissue.
There are several CpGs in TERT whose methylation level is associated with rs2736100 genotype (nominal p<0.05). Some of them are also detected in normal tissue (Appendix 1—Table 9). Hypomethylation …
Appendix 1—figure 11
MED12 expression.
Linear model. Here, A is the risk allele. Beta 0.247 ± 0.177.
Appendix 1—figure 12
Telomere lengths in tumors and normals.
Here A denotes the risk allele (see Appendix 1—Table 1 for the allele information). In tumors, shorter telomere length is significantly associated with the risk allele at 5p15.33 (rs2736100) …
Appendix 1—figure 13
The association between risk allele count and telomere length On X-axis, total number of risk alleles at TERT (rs72709458, rs2736100, rs2853676), TERC (rs10936600) and OBFC1 (rs1265164).
On Y-axis, estimated telomere length. Linear regression model p=0.055; 95% CI −408.511 – 4.704 per one risk allele.
Tables
Table 1
Predisposition loci for uterine leiomyoma.
https://doi.org/10.7554/eLife.37110.005| Chr | Position | rs-code | A | B | B freq | OR | P | Likely disease gene |
|---|---|---|---|---|---|---|---|---|
| 6 | 152,562,271 | rs58415480 | C | G | 0.155 | 1.18 | 6.0E-29 | ESR1 |
| X | 131,312,089 | rs5930554 | T | C | 0.311 | 1.14 | 4.3E-25 | ? |
| 17 | 7,571,752 | rs78378222 # | T | G | 0.013 | 1.53 | 9.7E-25 | TP53 |
| 11 | 32,370,380 | rs10835889 | G | A | 0.159 | 1.14 | 5.5E-19 | WT1 |
| 11 | 108,149,207 | rs141379009 | T | G | 0.027 | 1.32 | 2.0E-18 | ATM |
| 9 | 802,228 | rs7027685 | A | T | 0.402 | 1.11 | 3.8E-18 | DMRT1 |
| 1 | 22,450,487 | rs2235529 # | C | T | 0.157 | 1.14 | 1.1E-17 | WNT4/CDC42 |
| X | 70,093,038 | rs5937008 | C | T | 0.520 | 0.91 | 5.6E-16 | MED12 |
| 5 | 1,283,755 | rs72709458 # | C | T | 0.206 | 1.12 | 6.9E-16 | TERT |
| 11 | 225,196 | rs507139 * | G | A | 0.074 | 0.84 | 3.2E-13 | ? |
| 4 | 54,546,192 | rs62323680 | G | A | 0.067 | 1.16 | 8.3E-13 | ? |
| 3 | 169,514,585 | rs10936600 # | A | T | 0.244 | 0.91 | 6.4E-12 | TERC |
| 13 | 41,179,798 | rs7986407 | A | G | 0.310 | 1.09 | 1.2E-11 | FOXO1 |
| 3 | 197,623,337 | rs143835293 | A | G | 0.002 | 1.75 | 1.8E-11 | ? |
| 12 | 46,831,129 | rs12832777 | T | C | 0.701 | 1.09 | 2.3E-11 | ? |
| 22 | 40,669,648 | rs733381 * | A | G | 0.213 | 1.10 | 5.7E-11 | ? |
| 16 | 51,481,596 | rs66998222 | G | A | 0.201 | 0.91 | 8.9E-11 | SALL1 |
| 4 | 70,634,441 | rs2202282 | C | T | 0.497 | 1.07 | 8.7E-10 | ? |
| 2 | 11,702,661 | rs10929757 | A | C | 0.579 | 1.08 | 1.2E-09 | GREB1 |
| 11 | 35,085,453 | rs2553772 | T | G | 0.538 | 1.07 | 4.4E-09 | CD44 |
| 5 | 176,450,837 | rs2456181 | C | G | 0.484 | 1.07 | 6.3E-09 | ? |
| 10 | 105,674,854 | rs1265164 | A | G | 0.869 | 0.91 | 1.0E-08 | OBFC1 |
-
The numbers for B allele frequency (B Freq), odds-ratio (OR, where B is the effect allele) and association (P) are based on the UKBB cohort (15,453 UL cases). Gene symbols are shown for reference. The genomic coordinates follow hg19 and dbSNP build 147. All genome-wide significant (p<5 × 10−8) loci and their highest-association SNP are shown.
* Previously implicated predisposition to ULs.
-
# Previous associations to endometriosis, lung adenocarcinoma, glioma or telomere length; see literature in Appendix 1—table 11
Appendix 1—table 1
Summary of the UKBB cohort individuals.
The UKBB cohort was split into six disjoint, self-reported ancestries. For each ancestry, we summarized the background information for the phenotype (number of UL cases and female controls), …
| Age at first assessment visit | Number of live births | BMI | Age at hysterectomy | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Self-reported ancestry | Phenotype | N | Cases (%) | Mean | SD | Mean | SD | Mean | SD | Ever had hyst. (%) | Mean | SD |
| White British | cases | 15453 | 7.0 | 56.9 | 7.5 | 1.7 | 1.2 | 27.7 | 5.2 | 31.9 | 46.1 | 9.0 |
| controls | 205157 | 56.7 | 7.9 | 1.8 | 1.2 | 27.0 | 5.1 | 7.0 | 42.2 | 10.3 | ||
| Black African | cases | 296 | 19.1 | 49.6 | 6.8 | 2.0 | 1.7 | 31.2 | 5.6 | 22.1 | 45.1 | 8.8 |
| controls | 1256 | 51.8 | 8.1 | 2.8 | 1.8 | 31.3 | 5.7 | 6.5 | 36.4 | 15.4 | ||
| Black | cases | 668 | 24.7 | 50.6 | 6.8 | 1.5 | 1.4 | 30.0 | 6.3 | 24.0 | 41.2 | 12.1 |
| Caribbean | controls | 2041 | 53.0 | 8.2 | 2.2 | 1.7 | 29.8 | 5.9 | 9.7 | 37.2 | 14.8 | |
| White Irish | cases | 398 | 6.0 | 56.5 | 7.6 | 1.8 | 1.4 | 27.8 | 5.2 | 32.6 | 46.6 | 7.2 |
| controls | 6208 | 56.4 | 8.1 | 1.9 | 1.4 | 26.9 | 5.0 | 7.5 | 42.9 | 10.8 | ||
| Asian Indian | cases | 203 | 7.3 | 53.8 | 7.9 | 2.0 | 1.1 | 27.6 | 4.2 | 33.5 | 44.1 | 11.9 |
| controls | 2567 | 53.7 | 8.0 | 2.0 | 1.2 | 27.1 | 4.8 | 6.6 | 39.8 | 13.9 | ||
| Other white | cases | 647 | 6.7 | 54.8 | 7.9 | 1.3 | 1.2 | 26.7 | 5.3 | 23.6 | 46.5 | 8.6 |
| background | controls | 8982 | 54.6 | 8.3 | 1.6 | 1.2 | 26.4 | 5.2 | 5.4 | 42.1 | 11.0 | |
Appendix 1—table 2
Discovery stage GWAS for the UKBB cohort.
The information for B allele frequency (B Freq), odds-ratio (OR) and association (Beta; standard error of Beta; χ2 and P) were collected from the UKBB cohort. All genome-wide significant, …
| rs-code | Chr | Position | A | B | r2 (reference SNP) | B freq | OR | Beta | SE | χ2 | P |
|---|---|---|---|---|---|---|---|---|---|---|---|
| rs2235529 | 1 | 22450487 | C | T | NA | 0.157 | 1.14 | −0.005 | 5.81E-04 | 73.373 | 1.1E-17 |
| rs2092315 | 1 | 22507684 | C | T | 0.14 (rs2235529) | 0.248 | 1.07 | −0.003 | 4.90E-04 | 30.465 | 3.4E-08 |
| rs10929757 | 2 | 11702661 | A | C | NA | 0.579 | 1.08 | −0.003 | 4.32E-04 | 36.947 | 1.2E-09 |
| rs11674184 | 2 | 11721535 | T | G | 0.30 (rs10929757) | 0.386 | 0.94 | 0.002 | 4.36E-04 | 30.082 | 4.1E-08 |
| rs10936600 | 3 | 169514585 | A | T | NA | 0.244 | 0.91 | 0.003 | 4.91E-04 | 47.191 | 6.4E-12 |
| rs143835293 | 3 | 197623337 | A | G | NA | 0.002 | 1.75 | −0.043 | 6.33E-03 | 45.143 | 1.8E-11 |
| rs62323680 | 4 | 54546192 | G | A | NA | 0.067 | 1.16 | −0.006 | 8.49E-04 | 51.212 | 8.3E-13 |
| rs2202282 | 4 | 70634441 | C | T | NA | 0.497 | 1.07 | −0.003 | 4.22E-04 | 37.593 | 8.7E-10 |
| rs72709458 | 5 | 1283755 | C | T | NA | 0.206 | 1.12 | −0.004 | 5.28E-04 | 65.165 | 6.9E-16 |
| rs2736100 | 5 | 1286516 | C | A | 0.23 (rs72709458) | 0.498 | 0.91 | 0.003 | 4.23E-04 | 60.879 | 6.1E-15 |
| rs2853676 | 5 | 1288547 | T | C | 0.23 (rs2736100) | 0.731 | 0.91 | 0.003 | 4.77E-04 | 49.761 | 1.7E-12 |
| rs2456181 | 5 | 176450837 | C | G | NA | 0.484 | 1.07 | −0.002 | 4.24E-04 | 33.743 | 6.3E-09 |
| rs4870084 | 6 | 152543949 | C | T | 0.29 (rs6904757) | 0.189 | 0.92 | 0.003 | 5.44E-04 | 32.941 | 9.5E-09 |
| rs6928363 | 6 | 152546094 | G | A | 0.17 (rs58415480) | 0.485 | 0.92 | 0.003 | 4.24E-04 | 46.849 | 7.7E-12 |
| rs58415480 | 6 | 152562271 | C | G | NA | 0.155 | 1.18 | −0.007 | 5.89E-04 | 124.672 | 6.0E-29 |
| rs75510204 | 6 | 152592680 | T | G | 0.07 (rs58415480) | 0.012 | 1.29 | −0.012 | 2.07E-03 | 32.664 | 1.1E-08 |
| rs6904757 | 6 | 152593102 | A | G | 0.08 (rs6928363) | 0.363 | 0.93 | 0.003 | 4.42E-04 | 41.035 | 1.5E-10 |
| rs144444583 | 6 | 152684585 | T | C | 0.30 (rs58415480) | 0.128 | 1.12 | −0.004 | 6.37E-04 | 45.286 | 1.7E-11 |
| rs138821078 | 9 | 674217 | C | G | 0.13 (rs10975820) | 0.021 | 1.23 | −0.008 | 1.50E-03 | 31.819 | 1.7E-08 |
| rs10975820 | 9 | 684160 | G | A | 0.00 (rs7027685) | 0.142 | 1.12 | −0.004 | 6.08E-04 | 48.602 | 3.1E-12 |
| rs7027685 | 9 | 802228 | A | T | NA | 0.402 | 1.11 | −0.004 | 4.33E-04 | 75.424 | 3.8E-18 |
| rs114680331 | 9 | 815682 | T | C | 0.12 (rs7027685) | 0.100 | 1.11 | −0.004 | 7.21E-04 | 35.577 | 2.5E-09 |
| rs4742448 | 9 | 826585 | C | G | 0.28 (rs7027685) | 0.458 | 1.07 | −0.003 | 4.33E-04 | 33.714 | 6.4E-09 |
| rs2277163 | 9 | 827224 | A | G | 0.07 (rs7027685) | 0.947 | 0.87 | 0.005 | 9.51E-04 | 33.211 | 8.3E-09 |
| rs1265164 | 10 | 105674854 | A | G | NA | 0.869 | 0.91 | 0.004 | 6.27E-04 | 32.772 | 1.0E-08 |
| rs11246003 | 11 | 213723 | T | G | 0.00 (rs507139) | 0.044 | 0.85 | 0.006 | 1.03E-03 | 32.337 | 1.3E-08 |
| rs507139 | 11 | 225196 | G | A | NA | 0.074 | 0.84 | 0.006 | 8.11E-04 | 53.082 | 3.2E-13 |
| rs2207548 | 11 | 32368744 | C | A | 0.24 (rs10835889) | 0.423 | 1.09 | −0.003 | 4.30E-04 | 62.360 | 2.9E-15 |
| rs10835889 | 11 | 32370380 | G | A | NA | 0.159 | 1.14 | −0.005 | 5.81E-04 | 79.234 | 5.5E-19 |
| rs7120483 | 11 | 32406983 | G | C | 0.30 (rs10835889) | 0.120 | 1.12 | −0.004 | 6.51E-04 | 44.481 | 2.6E-11 |
| rs11031783 | 11 | 32459923 | C | A | 0.28 (rs10835889) | 0.204 | 1.09 | −0.003 | 5.25E-04 | 36.687 | 1.4E-09 |
| rs2553772 | 11 | 35085453 | T | G | NA | 0.538 | 1.07 | −0.002 | 4.24E-04 | 34.458 | 4.4E-09 |
| rs59021565 | 11 | 107999907 | C | G | 0.27 (rs141379009) | 0.091 | 1.11 | −0.004 | 7.38E-04 | 30.882 | 2.7E-08 |
| rs141379009 | 11 | 108149207 | T | G | NA | 0.027 | 1.32 | −0.011 | 1.30E-03 | 76.719 | 2.0E-18 |
| rs4988023 | 11 | 108168995 | A | C | 0.00 (rs141379009) | 0.144 | 0.89 | 0.004 | 6.01E-04 | 43.699 | 3.8E-11 |
| rs12223381 | 11 | 108354102 | C | T | 0.12 (rs59021565) | 0.406 | 1.07 | −0.002 | 4.31E-04 | 30.234 | 3.8E-08 |
| rs9669403 | 12 | 46798900 | G | A | 0.28 (rs12832777) | 0.402 | 1.07 | −0.003 | 4.35E-04 | 36.998 | 1.2E-09 |
| rs12832777 | 12 | 46831129 | T | C | NA | 0.701 | 1.09 | −0.003 | 4.61E-04 | 44.734 | 2.3E-11 |
| rs117245733 | 13 | 40723944 | G | A | 0.00 (rs7986407) | 0.016 | 1.26 | −0.010 | 1.74E-03 | 34.519 | 4.2E-09 |
| rs7986407 | 13 | 41179798 | A | G | NA | 0.310 | 1.09 | −0.003 | 4.56E-04 | 45.943 | 1.2E-11 |
| rs66998222 | 16 | 51481596 | G | A | NA | 0.201 | 0.91 | 0.003 | 5.28E-04 | 42.053 | 8.9E-11 |
| rs78378222 | 17 | 7571752 | T | G | NA | 0.013 | 1.53 | −0.020 | 1.93E-03 | 105.457 | 9.7E-25 |
| rs733381 | 22 | 40669648 | A | G | NA | 0.213 | 1.10 | −0.003 | 5.16E-04 | 42.919 | 5.7E-11 |
| rs5936989 | X | 70022420 | T | A | 0.27 (rs5937008) | 0.782 | 0.92 | 0.005 | 9.30E-04 | 32.606 | 1.1E-08 |
| rs5937008 | X | 70093038 | C | T | NA | 0.520 | 0.91 | 0.006 | 7.68E-04 | 65.570 | 5.6E-16 |
| rs7059898 | X | 70149078 | C | A | 0.27 (rs5937008) | 0.359 | 1.07 | −0.005 | 8.11E-04 | 31.756 | 1.7E-08 |
| rs7888560 | X | 131171122 | A | G | 0.19 (rs5930554) | 0.228 | 1.08 | −0.005 | 9.16E-04 | 31.830 | 1.7E-08 |
| rs5930554 | X | 131312089 | T | C | NA | 0.311 | 1.14 | −0.009 | 8.29E-04 | 107.076 | 4.3E-25 |
| rs5933158 | X | 131578034 | A | G | 0.21 (rs5930554) | 0.586 | 1.08 | −0.005 | 7.98E-04 | 38.833 | 4.6E-10 |
| rs5975338 | X | 131626317 | A | G | 0.28 (rs5930554) | 0.129 | 1.10 | −0.006 | 1.14E-03 | 32.201 | 1.4E-08 |
Appendix 1—table 3
Meta-analysis of the UKBB and Helsinki cohorts.
All the genome-wide significant, LD-independent (r2 ≤0.3) associations from the meta-analysis stage. Seven SNPs were LD-independent when compared to the discovery stage SNPs, and rs117245733 is …
| UKBB cohort | Helsinki cohort | Meta-analysis (fixed eff.) | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| rs-code | Chr | Position | A | B | r2 (reference SNP) | Beta | SE | P | Beta | SE | P | Beta | SE | P |
| rs17631680 | 2 | 67090367 | T | C | NA | 0.004 | 0.0007 | 2.1E-07 | 0.005 | 0.0029 | 6.2E-02 | 0.004 | 0.0007 | 4.29E-08 |
| rs1735537 | 3 | 128122820 | T | C | NA | −0.003 | 0.0005 | 1.2E-07 | −0.004 | 0.0021 | 8.7E-02 | −0.003 | 0.0005 | 3.01E-08 |
| rs67751869 | 4 | 54568834 | T | C | 0.14 (rs62323680) | −0.005 | 0.0009 | 9.9E-08 | −0.011 | 0.0039 | 3.7E-03 | −0.005 | 0.0009 | 5.05E-09 |
| rs6901631 | 6 | 152567047 | T | C | 0.26 (rs6904757) | 0.003 | 0.0006 | 5.4E-08 | 0.005 | 0.0031 | 1.2E-01 | 0.003 | 0.0006 | 1.76E-08 |
| rs11790408 | 9 | 876418 | G | T | 0.10 (rs4742448) | 0.002 | 0.0004 | 6.5E-08 | 0.002 | 0.0019 | 3.9E-01 | 0.002 | 0.0004 | 4.89E-08 |
| rs117245733 | 13 | 40723944 | G | A | 0.00 (rs7986407) | −0.010 | 0.0017 | 4.2E-09 | −0.024 | 0.0053 | 8.1E-06 | −0.012 | 0.0017 | 3.18E-12 |
| rs10415391 | 19 | 22652436 | C | T | NA | −0.004 | 0.0007 | 2.8E-07 | −0.006 | 0.0028 | 2.0E-02 | −0.004 | 0.0007 | 2.87E-08 |
| rs62132801 | 19 | 49267882 | A | T | NA | 0.004 | 0.0007 | 3.3E-07 | 0.006 | 0.0029 | 2.8E-02 | 0.004 | 0.0007 | 4.20E-08 |
Appendix 1—table 4
Genomic risk score.
Summary of the GRS and its weights based on the discovery and meta-analysis stages. Dosage-based odds-ratios (OR) and log-odds were collected from the UKBB summary statistics. The A and B alleles …
| rs-code | Chr | Position | A | B | OR | Log-odds | Stage * |
|---|---|---|---|---|---|---|---|
| rs2235529 | 1 | 22450487 | C | T | 1.14 | 0.132 | Stage 1 |
| rs2092315 | 1 | 22507684 | C | T | 1.07 | 0.072 | Stage 1 |
| rs10929757 | 2 | 11702661 | A | C | 1.08 | 0.073 | Stage 1 |
| rs11674184 | 2 | 11721535 | T | G | 0.94 | −0.067 | Stage 1 |
| rs10936600 | 3 | 169514585 | A | T | 0.91 | −0.095 | Stage 1 |
| rs143835293 | 3 | 197623337 | A | G | 1.75 | 0.558 | Stage 1 |
| rs62323680 | 4 | 54546192 | G | A | 1.16 | 0.153 | Stage 1 |
| rs2202282 | 4 | 70634441 | C | T | 1.07 | 0.071 | Stage 1 |
| rs72709458 | 5 | 1283755 | C | T | 1.12 | 0.111 | Stage 1 |
| rs2736100 | 5 | 1286516 | C | A | 0.91 | −0.090 | Stage 1 |
| rs2853676 | 5 | 1288547 | T | C | 0.91 | −0.089 | Stage 1 |
| rs2456181 | 5 | 176450837 | C | G | 1.07 | 0.066 | Stage 1 |
| rs4870084 | 6 | 152543949 | C | T | 0.92 | −0.087 | Stage 1 |
| rs6928363 | 6 | 152546094 | G | A | 0.92 | −0.078 | Stage 1 |
| rs58415480 | 6 | 152562271 | C | G | 1.18 | 0.167 | Stage 1 |
| rs75510204 | 6 | 152592680 | T | G | 1.29 | 0.257 | Stage 1 |
| rs6904757 | 6 | 152593102 | A | G | 0.93 | −0.078 | Stage 1 |
| rs144444583 | 6 | 152684585 | T | C | 1.12 | 0.111 | Stage 1 |
| rs138821078 | 9 | 674217 | C | G | 1.23 | 0.205 | Stage 1 |
| rs10975820 | 9 | 684160 | G | A | 1.12 | 0.112 | Stage 1 |
| rs7027685 | 9 | 802228 | A | T | 1.11 | 0.103 | Stage 1 |
| rs114680331 | 9 | 815682 | T | C | 1.11 | 0.108 | Stage 1 |
| rs4742448 | 9 | 826585 | C | G | 1.07 | 0.066 | Stage 1 |
| rs2277163 | 9 | 827224 | A | G | 0.87 | −0.140 | Stage 1 |
| rs1265164 | 10 | 105674854 | A | G | 0.91 | −0.097 | Stage 1 |
| rs11246003 | 11 | 213723 | T | G | 0.85 | −0.167 | Stage 1 |
| rs507139 | 11 | 225196 | G | A | 0.84 | −0.171 | Stage 1 |
| rs2207548 | 11 | 32368744 | C | A | 1.09 | 0.091 | Stage 1 |
| rs10835889 | 11 | 32370380 | G | A | 1.14 | 0.133 | Stage 1 |
| rs7120483 | 11 | 32406983 | G | C | 1.12 | 0.112 | Stage 1 |
| rs11031783 | 11 | 32459923 | C | A | 1.09 | 0.084 | Stage 1 |
| rs2553772 | 11 | 35085453 | T | G | 1.07 | 0.069 | Stage 1 |
| rs59021565 | 11 | 107999907 | C | G | 1.11 | 0.109 | Stage 1 |
| rs141379009 | 11 | 108149207 | T | G | 1.32 | 0.281 | Stage 1 |
| rs4988023 | 11 | 108168995 | A | C | 0.89 | −0.113 | Stage 1 |
| rs12223381 | 11 | 108354102 | C | T | 1.07 | 0.064 | Stage 1 |
| rs9669403 | 12 | 46798900 | G | A | 1.07 | 0.071 | Stage 1 |
| rs12832777 | 12 | 46831129 | T | C | 1.09 | 0.086 | Stage 1 |
| rs117245733 | 13 | 40723944 | G | A | 1.26 | 0.231 | Stage 1 |
| rs7986407 | 13 | 41179798 | A | G | 1.09 | 0.084 | Stage 1 |
| rs66998222 | 16 | 51481596 | G | A | 0.91 | −0.098 | Stage 1 |
| rs78378222 | 17 | 7571752 | T | G | 1.53 | 0.427 | Stage 1 |
| rs733381 | 22 | 40669648 | A | G | 1.10 | 0.091 | Stage 1 |
| rs5936989 | X | 70022420 | T | A | 0.92 | −0.081 | Stage 1 |
| rs5937008 | X | 70093038 | C | T | 0.91 | −0.094 | Stage 1 |
| rs7059898 | X | 70149078 | C | A | 1.07 | 0.068 | Stage 1 |
| rs7888560 | X | 131171122 | A | G | 1.08 | 0.077 | Stage 1 |
| rs5930554 | X | 131312089 | T | C | 1.14 | 0.129 | Stage 1 |
| rs5933158 | X | 131578034 | A | G | 1.08 | 0.074 | Stage 1 |
| rs5975338 | X | 131626317 | A | G | 1.10 | 0.094 | Stage 1 |
| rs17631680 | 2 | 67090367 | T | C | 0.90 | −0.102 | Stage 2 |
| rs1735537 | 3 | 128122820 | T | C | 1.07 | 0.071 | Stage 2 |
| rs67751869 | 4 | 54568834 | T | C | 1.13 | 0.121 | Stage 2 |
| rs6901631 | 6 | 152567047 | T | C | 0.91 | −0.097 | Stage 2 |
| rs11790408 | 9 | 876418 | G | T | 0.94 | −0.063 | Stage 2 |
| rs10415391 | 19 | 22652436 | C | T | 1.10 | 0.098 | Stage 2 |
| rs62132801 | 19 | 49267882 | A | T | 0.90 | −0.105 | Stage 2 |
-
* Discovered in stage 1 (UKBB GWAS) or in stage 2 (meta-analysis of UKBB and Helsinki)
Appendix 1—table 5
Summary of association tests for SNPs.
Each of the 57 GRS SNPs was tested for an additive effect to age at hysterectomy, degree of somatic allelic imbalance (AI) and tumor counts. Somatic allele imbalance was defined as the mean of the …
| Predictor | Response | Model | Beta | SE | Statistic | P | Q |
|---|---|---|---|---|---|---|---|
| 12:46798900:G:A | MED12mut + count | NB | −0.22 | 0.08 | −2.88 | 0.004 | 0.51 |
| 9:674217:C:G | MED12mut + count | NB | −0.69 | 0.26 | −2.63 | 0.008 | 0.51 |
| X:70093038:C:T | MED12mut + count | NB | 0.21 | 0.08 | 2.62 | 0.009 | 0.51 |
| X:70022420:T:A | MED12mut + count | NB | 0.20 | 0.08 | 2.56 | 0.011 | 0.51 |
| 11:32459923:C:A | MED12mut + count | NB | 0.23 | 0.09 | 2.54 | 0.011 | 0.51 |
| 4:54568834:T:C | log(somatic AI basepairs) | Linear | −0.25 | 0.10 | −2.48 | 0.013 | 0.51 |
| 17:7571752:T:G | MED12mut- count | NB | −0.92 | 0.41 | −2.24 | 0.025 | 0.56 |
| 6:152546094:G:A | MED12mut- count | NB | −0.19 | 0.08 | −2.24 | 0.025 | 0.56 |
| 11:107999907:C:G | Age at hysterectomy | Linear | 3.00 | 1.34 | 2.24 | 0.026 | 0.56 |
| 13:40723944:G:A | MED12mut + count | NB | 0.36 | 0.17 | 2.17 | 0.030 | 0.56 |
| 22:40669648:A:G | MED12mut + count | NB | 0.19 | 0.09 | 2.15 | 0.031 | 0.56 |
| 5:1286516:C:A | MED12mut + count | NB | 0.17 | 0.08 | 2.15 | 0.031 | 0.56 |
| 22:40669648:A:G | Age at hysterectomy | Linear | 1.36 | 0.63 | 2.16 | 0.032 | 0.56 |
| 1:22450487:C:T | Age at hysterectomy | Linear | −1.48 | 0.72 | −2.05 | 0.041 | 0.65 |
| 16:51481596:G:A | log(somatic AI basepairs) | Linear | 0.17 | 0.08 | 2.02 | 0.044 | 0.65 |
| 5:1288547:T:C | Age at hysterectomy | Linear | 1.32 | 0.66 | 2.00 | 0.046 | 0.65 |
Appendix 1—table 6
Summary of all the association tests for GRS.
All GRS related tests from the main text. The notation of MED12mut + and MED12mut- refer to the numbers of MED12-mutation-positive and -negative tumors, respectively. The tests include Wilcoxon …
| GRS * | Cohort | Variable | Test | N cases | N controls | Rate ratio | P | Q |
|---|---|---|---|---|---|---|---|---|
| Stage 1 | Helsinki | UL phenotype | Rank-sum (one-tailed) | 457 | 8899 | - | 8.3e-10 | 1.1e-08 |
| Stage 2 | NFBC | UL phenotype | Rank-sum (one-tailed) | 459 | 2351 | - | 1.1e-05 | 1.1e-04 |
| Stage 2 | Helsinki | Total number of ULs | NB | 457 | - | 1.25 | 0.00105 | 0.0032 |
| Stage 2 | Helsinki | Age at hysterectomy | Linear | 392 | - | 0.50 | 0.48 | 0.48 |
| Stage 2 | Helsinki | Number of MED12mut+ | NB | 457 | - | 1.43 | 3.2e-04 | 0.002 |
| Stage 2 | Helsinki | Number of MED12mut- | NB | 457 | - | 0.79 | 0.0266 | 0.053 |
| Stage 2 | Helsinki | One-or-more MED12mut+ | Rank-sum | 334 | 123 | - | 5.3e-04 | 0.0026 |
| Stage 2 | Helsinki | All MED12mut+ | Rank-sum | 221 | 123 | - | 7.9e-04 | 0.0032 |
| Stage 2 | African # | UL phenotype | Rank-sum (one-tailed) | 296 | 1256 | - | 1.3e-05 | 1.2e-04 |
| Stage 2 | Caribbean# | UL phenotype | Rank-sum (one-tailed) | 668 | 2041 | - | 6.7e-05 | 5.4e-04 |
| Stage 2 | Irish # | UL phenotype | Rank-sum (one-tailed) | 398 | 6208 | - | 8.3e-06 | 9.1e-05 |
| Stage 2 | Indian # | UL phenotype | Rank-sum (one-tailed) | 203 | 2567 | - | 2.9e-04 | 0.0020 |
| Stage 2 | Other white # | UL phenotype | Rank-sum (one-tailed) | 647 | 8982 | - | 6.9e-09 | 8.3e-08 |
-
*Based either on stage 1 (UKBB GWAS) or stage 2 (meta-analysis of UKBB and Helsinki)
# An independent subset of UKBB data (stratified based on self-reported UKBB annotation).
Appendix 1—table 7
Population specific estimates for GRS.
Allele frequencies were collected from gnomAD (version 2.0.1). GRS weights were taken from UKBB summary statistics. The estimate for population specific GRS follows from weighting the allele …
| rs-code | Chr | Pos | A | B | AF_AFR | AF_AMR | AF_ASJ | AF_EAS | AF_FIN | AF_NFE | AF_OTH |
|---|---|---|---|---|---|---|---|---|---|---|---|
| rs58415480 | 6 | 152562271 | C | G | 0.228 | 0.066 | 0.090 | 0.000 | 0.237 | 0.161 | 0.158 |
| rs78378222 | 17 | 7571752 | T | G | 0.002 | 0.004 | 0.000 | 0.000 | 0.020 | 0.018 | 0.015 |
| rs10835889 | 11 | 32370380 | G | A | 0.384 | 0.091 | 0.202 | 0.052 | 0.069 | 0.150 | 0.124 |
| rs141379009 | 11 | 108149207 | T | G | 0.005 | 0.014 | 0.023 | 0.000 | 0.007 | 0.022 | 0.015 |
| rs7027685 | 9 | 802228 | A | T | 0.535 | 0.602 | 0.357 | 0.738 | 0.556 | 0.413 | 0.462 |
| rs2235529 | 1 | 22450487 | C | T | 0.029 | 0.313 | 0.046 | 0.484 | 0.164 | 0.158 | 0.171 |
| rs72709458 | 5 | 1283755 | C | T | 0.139 | 0.137 | 0.183 | 0.134 | 0.221 | 0.188 | 0.180 |
| rs2207548 | 11 | 32368744 | C | A | 0.553 | 0.228 | 0.393 | 0.179 | 0.321 | 0.411 | 0.378 |
| rs2736100 | 5 | 1286516 | C | A | 0.550 | 0.597 | 0.477 | 0.606 | 0.507 | 0.504 | 0.539 |
| rs507139 | 11 | 225196 | G | A | 0.028 | 0.058 | 0.079 | 0.007 | 0.094 | 0.072 | 0.084 |
| rs62323680 | 4 | 54546192 | G | A | 0.020 | 0.032 | 0.099 | 0.002 | 0.045 | 0.070 | 0.060 |
| rs2853676 | 5 | 1288547 | T | C | 0.765 | 0.801 | 0.613 | 0.856 | 0.783 | 0.739 | 0.763 |
| rs10975820 | 9 | 684160 | G | A | 0.669 | 0.397 | 0.212 | 0.586 | 0.257 | 0.171 | 0.255 |
| rs10936600 | 3 | 169514585 | A | T | 0.094 | 0.406 | 0.195 | 0.539 | 0.274 | 0.249 | 0.267 |
| rs6928363 | 6 | 152546094 | G | A | 0.692 | 0.693 | 0.541 | 0.851 | 0.575 | 0.508 | 0.568 |
| rs7986407 | 13 | 41179798 | A | G | 0.446 | 0.459 | 0.277 | 0.739 | 0.384 | 0.311 | 0.367 |
| rs144444583 | 6 | 152684585 | T | C | 0.050 | 0.045 | 0.044 | 0.006 | 0.230 | 0.139 | 0.155 |
| rs143835293 | 3 | 197623337 | A | G | 0.000 | 0.004 | 0.003 | 0.000 | 0.015 | 0.002 | 0.006 |
| rs12832777 | 12 | 46831129 | T | C | 0.918 | 0.740 | 0.762 | 0.902 | 0.651 | 0.675 | 0.669 |
| rs7120483 | 11 | 32406983 | G | C | 0.242 | 0.087 | 0.152 | 0.025 | 0.074 | 0.112 | 0.098 |
| rs4988023 | 11 | 108168995 | A | C | 0.022 | 0.044 | 0.142 | 0.006 | 0.236 | 0.146 | 0.149 |
| rs733381 | 22 | 40669648 | A | G | 0.095 | 0.471 | 0.169 | 0.247 | 0.258 | 0.216 | 0.239 |
| rs66998222 | 16 | 51481596 | G | A | 0.033 | 0.138 | 0.265 | 0.001 | 0.166 | 0.213 | 0.167 |
| rs6904757 | 6 | 152593102 | A | G | 0.443 | 0.579 | 0.401 | 0.625 | 0.379 | 0.392 | 0.401 |
| rs2202282 | 4 | 70634441 | C | T | 0.230 | 0.549 | 0.420 | 0.726 | 0.437 | 0.491 | 0.466 |
| rs10929757 | 2 | 11702661 | A | C | 0.116 | 0.505 | 0.556 | 0.517 | 0.674 | 0.591 | 0.556 |
| rs9669403 | 12 | 46798900 | G | A | 0.615 | 0.476 | 0.406 | 0.266 | 0.396 | 0.382 | 0.369 |
| rs11031783 | 11 | 32459923 | C | A | 0.262 | 0.364 | 0.288 | 0.748 | 0.197 | 0.204 | 0.241 |
| rs114680331 | 9 | 815682 | T | C | 0.065 | 0.178 | 0.067 | 0.128 | 0.190 | 0.115 | 0.133 |
| rs117245733 | 13 | 40723944 | G | A | 0.001 | 0.004 | 0.003 | 0.000 | 0.030 | 0.024 | 0.027 |
| rs2553772 | 11 | 35085453 | T | G | 0.342 | 0.656 | 0.600 | 0.769 | 0.524 | 0.544 | 0.569 |
| rs2456181 | 5 | 176450837 | C | G | 0.796 | 0.355 | 0.533 | 0.481 | 0.500 | 0.511 | 0.505 |
| rs4742448 | 9 | 826585 | C | G | 0.838 | 0.629 | 0.473 | 0.785 | 0.548 | 0.471 | 0.503 |
| rs2277163 | 9 | 827224 | A | G | 0.959 | 0.858 | 0.964 | 0.825 | 0.966 | 0.948 | 0.954 |
| rs4870084 | 6 | 152543949 | C | T | 0.100 | 0.421 | 0.175 | 0.188 | 0.234 | 0.211 | 0.238 |
| rs1265164 | 10 | 105674854 | A | G | 0.469 | 0.891 | 0.825 | 0.985 | 0.890 | 0.863 | 0.873 |
| rs75510204 | 6 | 152592680 | T | G | 0.002 | 0.002 | 0.000 | 0.000 | 0.015 | 0.011 | 0.011 |
| rs11246003 | 11 | 213723 | T | G | 0.060 | 0.047 | 0.033 | 0.149 | 0.022 | 0.035 | 0.038 |
| rs138821078 | 9 | 674217 | C | G | 0.002 | 0.004 | 0.000 | 0.000 | 0.017 | 0.025 | 0.014 |
| rs59021565 | 11 | 107999907 | C | G | 0.038 | 0.112 | 0.119 | 0.049 | 0.050 | 0.086 | 0.054 |
| rs2092315 | 1 | 22507684 | C | T | 0.132 | 0.323 | 0.242 | 0.504 | 0.200 | 0.243 | 0.210 |
| rs12223381 | 11 | 108354102 | C | T | 0.413 | 0.606 | 0.477 | 0.444 | 0.390 | 0.414 | 0.457 |
| rs11674184 | 2 | 11721535 | T | G | 0.259 | 0.476 | 0.334 | 0.414 | 0.403 | 0.384 | 0.389 |
| rs5930554 | X | 131312089 | T | C | 0.752 | 0.174 | 0.296 | 0.104 | 0.320 | 0.319 | 0.311 |
| rs5937008 | X | 70093038 | C | T | 0.145 | 0.383 | 0.414 | 0.563 | 0.486 | 0.520 | 0.485 |
| rs5933158 | X | 131578034 | A | G | 0.710 | 0.588 | 0.500 | 0.686 | 0.650 | 0.605 | 0.741 |
| rs5936989 | X | 70022420 | T | A | 0.742 | 0.888 | 0.767 | 0.994 | 0.677 | 0.778 | 0.810 |
| rs5975338 | X | 131626317 | A | G | 0.409 | 0.103 | 0.099 | 0.091 | 0.161 | 0.145 | 0.151 |
| rs7059898 | X | 70149078 | C | A | 0.143 | 0.167 | 0.355 | 0.001 | 0.340 | 0.342 | 0.276 |
| rs7888560 | X | 131171122 | A | G | 0.142 | 0.090 | 0.199 | 0.000 | 0.244 | 0.217 | 0.201 |
| rs67751869 | 4 | 54568834 | T | C | 0.085 | 0.030 | 0.099 | 0.022 | 0.053 | 0.062 | 0.067 |
| rs6901631 | 6 | 152567047 | T | C | 0.256 | 0.249 | 0.182 | 0.122 | 0.102 | 0.120 | 0.127 |
| rs10415391 | 19 | 22652436 | C | T | 0.202 | 0.074 | 0.110 | 0.225 | 0.130 | 0.107 | 0.144 |
| rs1735537 | 3 | 128122820 | T | C | 0.523 | 0.385 | 0.262 | 0.425 | 0.249 | 0.251 | 0.288 |
| rs62132801 | 19 | 49267882 | A | T | 0.013 | 0.070 | 0.053 | 0.009 | 0.112 | 0.103 | 0.092 |
| rs17631680 | 2 | 67090367 | T | C | 0.018 | 0.061 | 0.050 | 0.001 | 0.100 | 0.102 | 0.082 |
| rs11790408 | 9 | 876418 | G | T | 0.110 | 0.307 | 0.387 | 0.246 | 0.355 | 0.380 | 0.353 |
| AFR | AMR | ASJ | EAS | FIN | NFE | OTH | |||||
| GRS | 4.718 | 4.059 | 4.068 | 4.196 | 4.168 | 4.091 | 4.116 | ||||
Appendix 1—table 8
eQTLs in tumor and normal tissue.
Here, B is the effect allele. All local permutation p<0.05 are shown. Full table of eQTLs is given in Supplementary file 4.
| Tissue | Gene | ID | N | Best SNP | Distance | Nominal P | Permutation P | FDR |
|---|---|---|---|---|---|---|---|---|
| T | RP11- 816J6.3 | ENSG00000269889.1 | 82 | rs67795055 | 42457 | 9.10E-05 | 4.03E-04 | 0.224 |
| T | RUFY3 | ENSG00000018189.8 | 8 | rs7660770 | −972945 | 7.84E-04 | 6.68E-04 | 0.370 |
| T | TRIP13 | ENSG00000071539.9 | 22 | rs2736099 | 394581 | 1.63E-04 | 2.27E-03 | 1 |
| N | RN7SL832P | ENSG00000243819.3 | 28 | rs7570979 | 886958 | 4.06E-04 | 2.75E-03 | 1 |
| N | LNX1 | ENSG00000072201.9 | 25 | rs62323674 | 212300 | 7.12E-04 | 3.22E-03 | 1 |
| N | RP11- 849F2.8 | ENSG00000269928.1 | 5 | rs143094271 | −665038 | 2.43E-03 | 4.00E-03 | 1 |
| T | MIR5006 | ENSG00000264190.1 | 158 | rs9549254 | −907660 | 6.10E-04 | 4.42E-03 | 1 |
| N | RP11- 423H2.3 | ENSG00000249684.1 | 50 | rs183686 | −883235 | 3.36E-03 | 5.55E-03 | 1 |
| N | SLC7A3 | ENSG00000165349.7 | 148 | rs4360450 | 965 | 6.75E-04 | 7.38E-03 | 1 |
| T | ALPL | ENSG00000162551.9 | 52 | . | 521370 | 8.48E-04 | 7.59E-03 | 1 |
| N | PRRG4 | ENSG00000135378.3 | 167 | rs11031737 | −478718 | 3.99E-04 | 8.59E-03 | 1 |
| N | RP11- 791G15.2 | ENSG00000272275.1 | 28 | rs6432220 | 802714 | 1.24E-03 | 8.81E-03 | 1 |
| T | ZDHHC11B | ENSG00000206077.6 | 22 | rs2736099 | 576864 | 9.74E-04 | 1.02E-02 | 1 |
| T | ACAP1 | ENSG00000072818.7 | 5 | rs78378222 | 331903 | 4.83E-03 | 1.04E-02 | 1 |
| N | HNRNPA1P48 | ENSG00000224578.3 | 20 | rs55881068 | −212266 | 4.97E-03 | 1.12E-02 | 1 |
| T | WNT4 | ENSG00000162552.10 | 52 | rs12042083 | 28933 | 1.30E-03 | 1.16E-02 | 1 |
| T | LRRIQ4 | ENSG00000188306.6 | 82 | rs13074500 | 25860 | 2.96E-03 | 1.20E-02 | 1 |
| T | TEX11 | ENSG00000120498.9 | 148 | rs11795627 | 208650 | 1.30E-03 | 1.23E-02 | 1 |
| T | AC011994.1 | ENSG00000265583.1 | 28 | rs11685032 | −73236 | 1.84E-03 | 1.32E-02 | 1 |
| T | FRMD7 | ENSG00000165694.5 | 215 | rs5933158 | 367012 | 8.40E-04 | 1.33E-02 | 1 |
| N | TRAPPC1 | ENSG00000170043.7 | 5 | rs138420351 | −133601 | 7.23E-03 | 1.44E-02 | 1 |
| T | RP11- 423H2.1 | ENSG00000170089.11 | 72 | rs353496 | −806511 | 9.37E-03 | 1.51E-02 | 1 |
| N | SDHAP3 | ENSG00000185986.10 | 22 | rs11742908 | −297655 | 1.42E-03 | 1.58E-02 | 1 |
| T | CDC42-IT1 | ENSG00000230068.2 | 52 | rs10917167 | 118400 | 2.10E-03 | 1.80E-02 | 1 |
| N | RP11- 362K14.6 | ENSG00000270096.1 | 82 | rs12638862 | −35245 | 4.49E-03 | 1.96E-02 | 1 |
| T | TNRC6B | ENSG00000100354.16 | 32 | rs12484951 | 262253 | 8.29E-03 | 1.97E-02 | 1 |
| N | DNAH2 | ENSG00000183914.10 | 5 | rs143094271 | −157571 | 9.73E-03 | 1.98E-02 | 1 |
| N | SALL1 | ENSG00000103449.7 | 20 | rs12933686 | 308913 | 9.53E-03 | 2.13E-02 | 1 |
| T | XXyac- YRM2039.2 | ENSG00000181404.13 | 71 | rs138821078 | 659705 | 1.69E-03 | 2.22E-02 | 1 |
| N | ITPRIP | ENSG00000148841.11 | 8 | rs9419958 | −395949 | 1.43E-02 | 2.39E-02 | 1 |
| T | RNASEK- C17orf49 | ENSG00000161939.14 | 5 | . | 501685 | 1.19E-02 | 2.43E-02 | 1 |
| T | UQCRFS1P1 | ENSG00000226085.2 | 32 | rs1807579 | 256926 | 1.06E-02 | 2.44E-02 | 1 |
| T | FOXO1 | ENSG00000150907.6 | 166 | rs9549260 | 124299 | 2.94E-03 | 2.61E-02 | 1 |
| T | NDUFS6 | ENSG00000145494.7 | 22 | rs7734992 | −521387 | 2.81E-03 | 2.82E-02 | 1 |
| T | RP11- 259O2.3 | ENSG00000249731.1 | 22 | rs7710703 | −680704 | 2.89E-03 | 2.84E-02 | 1 |
| T | CDC42 | ENSG00000070831.11 | 52 | rs41307810 | −25076 | 3.35E-03 | 2.91E-02 | 1 |
| T | RP3- 363L9.1 | ENSG00000227064.1 | 215 | rs3764771 | −830073 | 2.03E-03 | 2.97E-02 | 1 |
| T | RP11- 362K14.7 | ENSG00000270135.1 | 82 | rs67795055 | 18611 | 7.45E-03 | 3.07E-02 | 1 |
| N | AMIGO2 | ENSG00000139211.5 | 155 | rs9706162 | −606808 | 6.28E-03 | 3.08E-02 | 1 |
| T | LPIN1 | ENSG00000134324.7 | 28 | rs11685032 | −143427 | 5.06E-03 | 3.33E-02 | 1 |
| T | MBNL3 | ENSG00000076770.10 | 215 | rs1263155 | 190718 | 2.55E-03 | 3.37E-02 | 1 |
| N | TOX3 | ENSG00000103460.12 | 5 | rs12325192 | −983789 | 3.24E-02 | 3.38E-02 | 1 |
| N | DANCR | ENSG00000226950.2 | 23 | rs62325482 | 885823 | 8.24E-03 | 3.54E-02 | 1 |
| T | DMRT1 | ENSG00000137090.7 | 71 | rs12004436 | −158261 | 3.09E-03 | 3.64E-02 | 1 |
| N | NT5C2 | ENSG00000076685.14 | 8 | rs1265164 | 828913 | 2.05E-02 | 3.75E-02 | 1 |
| T | TMEM256- PLSCR3 | ENSG00000187838.12 | 5 | rs138420351 | 407016 | 1.77E-02 | 3.81E-02 | 1 |
| T | RP11- 401P9.4 | ENSG00000261685.2 | 20 | rs12933686 | 799079 | 1.64E-02 | 3.84E-02 | 1 |
| N | CTC1 | ENSG00000178971.9 | 5 | rs143094271 | −667090 | 1.89E-02 | 4.03E-02 | 1 |
| N | SULT1B1 | ENSG00000173597.4 | 19 | rs13133166 | 13318 | 1.49E-02 | 4.04E-02 | 1 |
| N | TNK1 | ENSG00000174292.8 | 5 | rs143094271 | 179248 | 2.24E-02 | 4.21E-02 | 1 |
| T | SOX15 | ENSG00000129194.3 | 5 | rs138420351 | 208566 | 2.02E-02 | 4.30E-02 | 1 |
| T | UGT2A1 | ENSG00000173610.7 | 19 | rs1587766 | 112959 | 2.06E-02 | 4.31E-02 | 1 |
| T | RP4- 607I7.1 | ENSG00000255521.1 | 34 | rs2553783 | −82085 | 2.66E-02 | 4.41E-02 | 1 |
| N | SENP3 | ENSG00000161956.8 | 5 | rs78378222 | 106559 | 2.19E-02 | 4.45E-02 | 1 |
| N | KDM6B | ENSG00000132510.6 | 5 | rs143094271 | −280121 | 2.16E-02 | 4.54E-02 | 1 |
| T | SKIL | ENSG00000136603.9 | 82 | rs34194057 | −525916 | 1.13E-02 | 4.63E-02 | 1 |
| T | EPHB2 | ENSG00000133216.12 | 52 | . | −680104 | 6.04E-03 | 4.97E-02 | 1 |
Appendix 1—table 9
cis-meQTLs in candidate genes where FDR < 0.1.
The statistics were calculated with an additive linear model. Here B is used as the effect allele. Full Table of cis-meQTLs with nominal significance (p-value<0.05) is given in Supplementary file 5.
| Tissue | SNP | CpG* | Beta | t-stat | p-value | FDR | Gene | CpG island | Promoter | AA | AB | BB |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| N | 13_ 41179798 | 13_ 41189143 | −0.413 | −19.837 | 6.57E-20 | 4.88E-15 | FOXO1 | no | no | 15 | 16 | 4 |
| T | 13_ 41179798 | 13_ 41189143 | −0.333 | −8.296 | 3.29E-11 | 7.74E-07 | FOXO1 | no | no | 28 | 23 | 5 |
| T | 5_1283755 | 5_ 1285974 | −0.427 | −7.167 | 2.21E-09 | 3.46E-05 | TERT | no | no | 36 | 17 | 3 |
| N | 5_ 1283755 | 5_ 1285974 | −0.461 | −7.46 | 1.42E-08 | 1.11E-04 | TERT | no | no | 18 | 14 | 3 |
| T | 5_ 1286516 | 5_ 1277576 | −0.289 | −6.358 | 4.53E-08 | 3.99E-04 | TERT | yes | no | 7 | 29 | 20 |
| T | 1_ 22450487 | 1_ 22456326 | −0.123 | −5.507 | 1.04E-06 | 6.36E-03 | WNT4 | no | no | 40 | 15 | 1 |
| N | 5_ 1286516 | 5_ 1285974 | 0.426 | 5.477 | 4.51E-06 | 1.76E-02 | TERT | no | no | 6 | 22 | 7 |
| T | 5_ 1286516 | 5_ 1285974 | 0.299 | 4.739 | 1.61E-05 | 4.82E-02 | TERT | no | no | 7 | 29 | 20 |
| N | 13_ 41179798 | 13_ 41223110 | −0.174 | −4.957 | 2.10E-05 | 5.36E-02 | FOXO1 | no | no | 15 | 16 | 4 |
| N | 5_ 1283755 | 5_ 1282413 | −0.17 | −4.816 | 3.16E-05 | 7.12E-02 | TERT | no | no | 18 | 14 | 3 |
| T | 11_ 225196 | 11_ 195431 | 0.222 | 4.452 | 4.31E-05 | 9.21E-02 | BET1L | no | ODF3 | 48 | 8 | 0 |
-
* Minimum CpG coverage of ≥2 required in ≥90% of samples. CpG in 1 Mb flank from the SNP.
Appendix 1—table 10
Replication of previously suggested UL predisposition loci.
For study details, see the literature references in the main text. The population, locus, gene and risk allele (RA) information were collected from the original studies. The associations, P (UKBB) …
| Study | Population | Locus | Suggested gene | SNP | RA | Method | P (UKBB) |
|---|---|---|---|---|---|---|---|
| Cha et al. | Japanese | 22q13.1 | TNRC6B | rs12484776 | G | GWAS | 1.0E-10 |
| Edwards et al. | European Americans | 22q13.1 | TNRC6B | rs12484776 | G | GWAS | 1.0E-10 |
| Cha et al. | Japanese | 11p15.5 | BET1L | rs2280543 | G | GWAS | 2.2E-08 |
| Edwards et al. | European Americans | 11p15.5 | BET1L | rs2280543 | G | GWAS | 2.2E-08 |
| Zhang et al. | African Americans | 1q42.2 | PCNXL2 | rs7546784 | - | Admixture | 3.6E-02 |
| Zhang et al. | African Americans | 2q32.2 | PMS1 | rs256552 | - | Admixture | 1.8E-01 |
| Cha et al. | Japanese | 10q24.33 | SLK | rs7913069 | A | GWAS | 3.4E-01 |
| Hellwege et al. | African American | 22q13.1 | CYTH4 | rs5995416 | C | GWAS | 5.3E-01 |
| Hellwege et al. | African American | 22q13.1 | CYTH4 | rs739187 | C | GWAS | 6.2E-01 |
| Hellwege et al. | African American | 22q13.1 | CYTH4 | rs713939 | C | GWAS | 8.0E-01 |
| Hellwege et al. | African American | 22q13.1 | CYTH4 | rs4821628 | G | GWAS | 8.1E-01 |
| Eggert et al. | Multiple | 17q25.3 | FASN | rs4247357 | A | Linkage and GWAS | 8.1E-01 |
Appendix 1—table 11
GWAS catalog and references to earlier literature on GRS SNPs.
The GRS SNPs rs10936600, rs11674184, rs2235529, rs2736100, rs2853676, rs72709458 and rs78378222 were found in the GWAS catalog (version 1.0.1; www.ebi.ac.uk/gwas). The numbers for allele frequency …
| Pubmed | Date | Journal | Gene symbol | Risk allele | AF | OR | P | |
|---|---|---|---|---|---|---|---|---|
| 18835860 | 2008-10-01 | J Med Genet | Idiopathic pulmonary fibrosis | TERT | rs2736100-A | 0.41 | 2.11 | 3.00E-08 |
| 19578367 | 2009-07-05 | Nat Genet | Glioma | TERT | rs2736100-G | 0.49 | 1.27 | 2.00E-17 |
| 19578367 | 2009-07-05 | Nat Genet | Glioma | TERT | rs2853676-A | 0.73 | 1.26 | 4.00E-14 |
| 19836008 | 2009-10-15 | Am J Hum Genet | Lung adenocarcinoma | TERT | rs2736100-G | 0.5 | 1.12 | 2.00E-10 |
| 20139978 | 2010-02-07 | Nat Genet | Red blood cell count | TERT | rs2736100-G | 0.4 | 0.07 | 3.00E-08 |
| 20543847 | 2010-06-13 | Nat Genet | Testicular germ cell cancer | TERT | rs2736100-T | 0.49 | 1.33 | 8.00E-15 |
| 20700438 | 2010-08-05 | PLoS Genet | Lung adenocarcinoma | TERT | rs2736100-G | 0.39 | 1.46 | 2.00E-22 |
| 20871597 | 2010-09-26 | Nat Genet | Lung adenocarcinoma | TERT | rs2736100-C | 0.39 | 1.27 | 3.00E-11 |
| 21531791 | 2011-04-29 | Hum Mol Genet | Glioma | TERT | rs2736100-? | - | 1.25 | 1.00E-14 |
| 21725308 | 2011-07-03 | Nat Genet | Lung cancer | TERT | rs2736100-C | 0.41 | 1.27 | 1.00E-27 |
| 21827660 | 2011-08-09 | BMC Med Genomics | Glioma | TERT | rs2736100-? | - | - | 7.00E-09 |
| 21946351 | 2011-09-25 | Nat Genet | Basal cell carcinoma | TP53 | rs78378222-C | - | 2.16 | 2.00E-20 |
| 22886559 | 2012-08-11 | Hum Genet | Glioma | TERT | rs2736100-G | 0.494 | 1.30 | 4.00E-09 |
| 23143601 | 2012-11-11 | Nat Genet | Lung cancer | TERT | rs2736100-G | 0.4 | 1.38 | 4.00E-27 |
| 23472165 | 2013-03-05 | PLoS One | Endometriosis | WNT4 | rs2235529-T | 0.152 | 1.28 | 7.00E-09 |
| 23472165 | 2013-03-05 | PLoS One | Endometriosis | WNT4 | rs2235529-C | 0.709 | 1.19 | 6.00E-06 |
| 23472165 | 2013-03-05 | PLoS One | Endometriosis | WNT4 | rs2235529-T | 0.134 | 1.25 | 8.00E-07 |
| 23472165 | 2013-03-05 | PLoS One | Endometriosis | WNT4 | rs2235529-A | 0.153 | 1.30 | 3.00E-09 |
| 23583980 | 2013-04-14 | Nat Genet | Interstitial lung disease | TERT | rs2736100-A | 0.49 | 1.37 | 2.00E-19 |
| 24403052 | 2014-01-08 | Hum Mol Genet | Basal cell carcinoma | TP53 | rs78378222-G | - | 2.24 | 4.00E-22 |
| 24465473 | 2014-01-21 | PLoS One | Telomere length | TERT | rs2736100-C | 0.08 | 4.00E-06 | |
| 24908248 | 2014-06-08 | Nat Genet | Glioma (high-grade) | TERT | rs2736100-C | 0.51 | 1.39 | 1.00E-15 |
| 24945404 | 2014-06-19 | PLoS Genet | Bone mineral density (paediatric, upper limb) | WNT4 | rs2235529-C | 0.85 | 0.12 | 1.00E-08 |
| 24945404 | 2014-06-19 | PLoS Genet | Bone mineral density (paediatric, upper limb) | WNT4 | rs2235529-C | - | 0.12 | 3.00E-07 |
| 25855136 | 2015-04-09 | Nat Commun | Basal cell carcinoma | TP53 | rs78378222-G | 0.018 | 2.07 | 1.00E-20 |
| 26424050 | 2015-10-01 | Nat Commun | Glioblastoma | - | rs72709458-T | - | 1.68 | 6.00E-24 |
| 27363682 | 2016-07-01 | Nat Commun | Multiple myeloma | - | rs10936600-A | - | 1.20 | 6.00E-15 |
| 27501781 | 2016-08-09 | Nat Commun | EGFR mutation-positive lung adenocarcinoma | TERT | rs2736100-G | 0.387 | 1.42 | 2.00E-31 |
| 27539887 | 2016-08-19 | Nat Commun | Basal cell carcinoma | TP53 | rs78378222-G | 0.01 | 1.41 | 2.00E-10 |
| 27863252 | 2016-11-17 | Cell | Mean corpuscular hemoglobin | TP53 | rs78378222-G | 0.0121 | 0.10 | 6.00E-09 |
| 27863252 | 2016-11-17 | Cell | Mean corpuscular hemoglobin | TERT | rs2736100-A | 0.4982 | 0.04 | 5.00E-34 |
| 27863252 | 2016-11-17 | Cell | Platelet count | TERT | rs2736100-A | 0.4984 | 0.03 | 3.00E-20 |
| 28017375 | 2016-12-22 | Am J Hum Genet | Mean corpuscular volume | TERT | rs2736100-A | - | 0.00 | 3.00E-06 |
| 28017375 | 2016-12-22 | Am J Hum Genet | Mean corpuscular volume | TERT | rs2736100-? | - | - | 2.00E-11 |
| 28017375 | 2016-12-22 | Am J Hum Genet | Mean corpuscular hemoglobin | TERT | rs2736100-? | - | - | 1.00E-08 |
| 28135244 | 2017-01-30 | Nat Genet | Pulse pressure | TP53 | rs78378222-T | 0.99 | 0.90 | 2.00E-10 |
| 28346443 | 2017-03-27 | Nat Genet | Glioma | TP53 | rs78378222-G | 0.013 | 2.53 | 9.00E-38 |
| 28346443 | 2017-03-27 | Nat Genet | Glioblastoma | TP53 | rs78378222-G | 0.013 | 2.63 | 5.00E-29 |
| 28346443 | 2017-03-27 | Nat Genet | Non-glioblastoma glioma | TP53 | rs78378222-G | 0.013 | 2.73 | 5.00E-27 |
| 28537267 | 2017-05-24 | Nat Commun | Endometriosis | GREB1 | rs11674184-T | 0.61 | 1.13 | 3.00E-17 |
| 28537267 | 2017-05-24 | Nat Commun | Endometriosis | GREB1 | rs11674184-T | 0.61 | 1.12 | 3.00E-14 |
| 28604728 | 2017-06-12 | Nat Genet | Testicular germ cell tumor | TERT | rs2736100-A | 0.51 | 1.28 | 9.00E-25 |
| 28604732 | 2017-06-12 | Nat Genet | Testicular germ cell tumor | TERT | rs2736100-A | 0.5 | 1.29 | 8.00E-20 |
Additional files
-
Supplementary file 1
Summary statistics for the UKBB and Helsinki cohorts.
For each of the 57 GRS SNPs, we report the allele frequency, association effect size and P-value, together with the heterogeneity estimates Cochrane's Q-value and I2 index.
- https://doi.org/10.7554/eLife.37110.009
-
Supplementary file 2
Summary statistics for UKBB, Helsinki and NFBC.
For each of the 57 GRS SNPs, we report the allele frequency, association effect size and P-value, together with the heterogeneity estimates Cochrane's Q-value and I2 index.
- https://doi.org/10.7554/eLife.37110.010
-
Supplementary file 3
Summary statistics for the five UKBB follow-up cohorts.
For each of the 57 GRS SNPs, we report the allele frequency, association effect size and P-value, together with the heterogeneity estimates Cochrane's Q-value and I2 index.
- https://doi.org/10.7554/eLife.37110.011
-
Supplementary file 4
All the cis-eQTL summary statistics.
Tumors (T) and myometrium normal tissues (N) were analyzed separately. For each SNP, we report the local permutation test results from FastQTL (details in the Methods section).
- https://doi.org/10.7554/eLife.37110.012
-
Supplementary file 5
All the cis-meQTL summary statistics and annotation for their genomic context.
Tumors and myometrium normal tissues were analyzed separately. The association statistics are based on MatrixEQTL (details in the Methods section).
- https://doi.org/10.7554/eLife.37110.013
-
Supplementary file 6
Pathway-based analysis of the genome-wide significant SNPs.
Includes target gene prioritization, pathway enrichment and tissue-specific expression profiling results from the DEPICT framework (details in the Methods section).
- https://doi.org/10.7554/eLife.37110.014
-
Transparent reporting form
- https://doi.org/10.7554/eLife.37110.015
