1. Genetics and Genomics
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Genetic predisposition to uterine leiomyoma is determined by loci for genitourinary development and genome stability

  1. Niko Välimäki
  2. Heli Kuisma
  3. Annukka Pasanen
  4. Oskari Heikinheimo
  5. Jari Sjöberg
  6. Ralf Bützow
  7. Nanna Sarvilinna
  8. Hanna-Riikka Heinonen
  9. Jaana Tolvanen
  10. Simona Bramante
  11. Tomas Tanskanen
  12. Juha Auvinen
  13. Outi Uimari
  14. Amjad Alkodsi
  15. Rainer Lehtonen
  16. Eevi Kaasinen
  17. Kimmo Palin
  18. Lauri A Aaltonen  Is a corresponding author
  1. University of Helsinki, Finland
  2. University of Helsinki and Helsinki University Hospital, Finland
  3. Faculty of Medicine, University of Oulu, Finland
  4. Oulu University Hospital, University of Oulu, Finland
  5. Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Sweden
Research Article
Cite this article as: eLife 2018;7:e37110 doi: 10.7554/eLife.37110
18 figures, 12 tables, 2 data sets and 7 additional files

Figures

Outline of the study stages and genotyping cohorts.

GRS, genomic risk score. NFBC, Northern Finland Birth Cohort.

https://doi.org/10.7554/eLife.37110.003
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 horizontal line denotes genome-wide significance (p=5 × 10−8). Gene symbols shown for reference. (B), MED12 region in more detail. ENCODE tracks (details in Supplementary Methods) are shown for reference. (C), The risk allele near MED12 (rs5937008) is observed with a significant increase in number of MED12-mutation-positive tumors (p=0.009; negative binomial regression; RR = 1.23 per risk allele; n = 457 Helsinki cohort patients).

https://doi.org/10.7554/eLife.37110.004
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 and CpG methylation around the locus with a 1 Mb flank. The needle plot shows the meQTL associations (dashed lines at 10% FDR; green line denotes the SNP; gray ticks denote all CpGs tested; blue needle for positive coefficient, red for negative coefficient) for tumors (above x-axis; nAA = 53, nAB = 3) and normals (below x-axis; nAA = 33, nAB = 2). (C) UCSC genome browser tracks related to conservation and regulation at the locus.

https://doi.org/10.7554/eLife.37110.006
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 rank-sum tests. Only females were included as the control samples. The X-axes show the GRS distributions for each phenotype.

https://doi.org/10.7554/eLife.37110.007
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 rs2092315; gray ticks denote all CpGs tested; blue needle for positive coefficient, red for negative coefficient) for tumors (above x-axis; nAA = 40, nAB = 15, nBB = 1 for rs2235529 and nAA = 32, nAB = 23 for rs2092315) and normals (below x-axis; nAA = 23, nAB = 12 and nAA = 17, nAB = 17, nBB = 1). (B), Methylation differences in tumors (n = 56) at CpG chr1:22456326 by SNP rs2235529. (C), WNT4 expression differences in tumors (n = 41) stratified by the rs12042083 genotype. B is the risk allele, and the P-value is corrected for local multiple testing (permutation based test).

https://doi.org/10.7554/eLife.37110.008
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 Supplementary Methods) are shown for reference; coordinates follow hg19. See main text Table 1 for more information. In total 22 figures, ordered by genomic position.

https://doi.org/10.7554/eLife.37110.028
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).

https://doi.org/10.7554/eLife.37110.029
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).

https://doi.org/10.7554/eLife.37110.030
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 23,266 samples colored according to their self-reported ancestry. The subsequent plots show the same data divided by the self-reported ancestry. Bottom-left plot displays the variance explained by the first ten PCs. Bottom-right violin plot displays the distribution of the first principal component for cases (n = 2,212) and controls (n = 21,054). The phenotype is more prevalent in individuals with increased African ancestry (p<2.2 × 10−16; Wilcoxon rank sum W = 3 × 107).

https://doi.org/10.7554/eLife.37110.031
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 unit variance with respect to the controls. Dashed lines denote the mean GRS for cases and controls. Associations (P) and test statistics (W) are from Wilcoxon rank-sum tests. C-scores, Nagelkerke’s R2 (pseudo R2) and Receiver operating characteristic (ROC; on right) are from a logistic regression model. Positive predictive values (PPV) were computed from the highest GRS quartile, and odds ratios (OR and 95% CI) from the top and bottom GRS quartiles.

https://doi.org/10.7554/eLife.37110.032
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 frequency. The population names displayed here follow the naming convention of the gnomAD database.

https://doi.org/10.7554/eLife.37110.033
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 Methods. A, summary of the model. B, diagnostic plots for the model.

https://doi.org/10.7554/eLife.37110.034
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 model. (C, D) similar model for the MED12-mutation-negative tumor counts.

https://doi.org/10.7554/eLife.37110.035
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 tested; blue needle for positive coefficient, red for negative coefficient) for tumors (above x-axis; nAA = 8, nAB = 32, nBB = 16) and normals (below x-axis; nAA = 5, nAB = 22, nBB = 7). The only significant meQTLs were seen around TERT.

https://doi.org/10.7554/eLife.37110.036
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 refers to decreased methylation in BB vs. AA genotype and hypermethylation the opposite.

https://doi.org/10.7554/eLife.37110.037
Appendix 1—figure 11
MED12 expression.

Linear model. Here, A is the risk allele. Beta 0.247 ± 0.177.

https://doi.org/10.7554/eLife.37110.038
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) (Kruskal-Wallis test).

https://doi.org/10.7554/eLife.37110.039
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.

https://doi.org/10.7554/eLife.37110.040

Tables

Table 1
Predisposition loci for uterine leiomyoma.
https://doi.org/10.7554/eLife.37110.005
ChrPositionrs-codeABB freqORPLikely disease gene
6152,562,271rs58415480CG0.1551.186.0E-29ESR1
X131,312,089rs5930554TC0.3111.144.3E-25?
177,571,752rs78378222 #TG0.0131.539.7E-25TP53
1132,370,380rs10835889GA0.1591.145.5E-19WT1
11108,149,207rs141379009TG0.0271.322.0E-18ATM
9802,228rs7027685AT0.4021.113.8E-18DMRT1
122,450,487rs2235529 #CT0.1571.141.1E-17WNT4/CDC42
X70,093,038rs5937008CT0.5200.915.6E-16MED12
51,283,755rs72709458 #CT0.2061.126.9E-16TERT
11225,196rs507139 *GA0.0740.843.2E-13?
454,546,192rs62323680GA0.0671.168.3E-13?
3169,514,585rs10936600 #AT0.2440.916.4E-12TERC
1341,179,798rs7986407AG0.3101.091.2E-11FOXO1
3197,623,337rs143835293AG0.0021.751.8E-11?
1246,831,129rs12832777TC0.7011.092.3E-11?
2240,669,648rs733381 *AG0.2131.105.7E-11?
1651,481,596rs66998222GA0.2010.918.9E-11SALL1
470,634,441rs2202282CT0.4971.078.7E-10?
211,702,661rs10929757AC0.5791.081.2E-09GREB1
1135,085,453rs2553772TG0.5381.074.4E-09CD44
5176,450,837rs2456181CG0.4841.076.3E-09?
10105,674,854rs1265164AG0.8690.911.0E-08OBFC1
  1. 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.

  2. # 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), proportion of cases (%), age at first assessment visit (mean and SD), number of live births (mean and SD), body mass index (BMI; mean and SD), proportion of hysterectomy cases (%) and age at hysterectomy (mean and SD).

https://doi.org/10.7554/eLife.37110.017
Age at first assessment visitNumber of live birthsBMIAge at hysterectomy
Self-reported ancestryPhenotypeNCases (%)MeanSDMeanSDMeanSDEver had hyst. (%)MeanSD
White Britishcases154537.056.97.51.71.227.75.231.946.19.0
controls20515756.77.91.81.227.05.17.042.210.3
Black Africancases29619.149.66.82.01.731.25.622.145.18.8
controls125651.88.12.81.831.35.76.536.415.4
Blackcases66824.750.66.81.51.430.06.324.041.212.1
Caribbeancontrols204153.08.22.21.729.85.99.737.214.8
White
Irish
cases3986.056.57.61.81.427.85.232.646.67.2
controls620856.48.11.91.426.95.07.542.910.8
Asian Indiancases2037.353.87.92.01.127.64.233.544.111.9
controls256753.78.02.01.227.14.86.639.813.9
Other whitecases6476.754.87.91.31.226.75.323.646.58.6
 backgroundcontrols898254.68.31.61.226.45.25.442.111.0
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, LD-independent (r2 ≤0.3 pruned in order of UKBB association) SNPs that passed imputation QC are shown. SNPs with r2 = NA are the lead-SNPs of each distinct locus. The A and B alleles are on GRCh37 forward strand. OR was computed from SNP dosages and B as the effect allele. Rows are sorted by genomic position.

https://doi.org/10.7554/eLife.37110.018
rs-codeChrPositionABr2 (reference
SNP)
B freqORBetaSEχ2P
rs2235529122450487CTNA0.1571.14−0.0055.81E-0473.3731.1E-17
rs2092315122507684CT0.14
(rs2235529)
0.2481.07−0.0034.90E-0430.4653.4E-08
rs10929757211702661ACNA0.5791.08−0.0034.32E-0436.9471.2E-09
rs11674184211721535TG0.30
(rs10929757)
0.3860.940.0024.36E-0430.0824.1E-08
rs109366003169514585ATNA0.2440.910.0034.91E-0447.1916.4E-12
rs1438352933197623337AGNA0.0021.75−0.0436.33E-0345.1431.8E-11
rs62323680454546192GANA0.0671.16−0.0068.49E-0451.2128.3E-13
rs2202282470634441CTNA0.4971.07−0.0034.22E-0437.5938.7E-10
rs7270945851283755CTNA0.2061.12−0.0045.28E-0465.1656.9E-16
rs273610051286516CA0.23 (rs72709458)0.4980.910.0034.23E-0460.8796.1E-15
rs285367651288547TC0.23 (rs2736100)0.7310.910.0034.77E-0449.7611.7E-12
rs24561815176450837CGNA0.4841.07−0.0024.24E-0433.7436.3E-09
rs48700846152543949CT0.29 (rs6904757)0.1890.920.0035.44E-0432.9419.5E-09
rs69283636152546094GA0.17 (rs58415480)0.4850.920.0034.24E-0446.8497.7E-12
rs584154806152562271CGNA0.1551.18−0.0075.89E-04124.6726.0E-29
rs755102046152592680TG0.07 (rs58415480)0.0121.29−0.0122.07E-0332.6641.1E-08
rs69047576152593102AG0.08 (rs6928363)0.3630.930.0034.42E-0441.0351.5E-10
rs1444445836152684585TC0.30 (rs58415480)0.1281.12−0.0046.37E-0445.2861.7E-11
rs1388210789674217CG0.13 (rs10975820)0.0211.23−0.0081.50E-0331.8191.7E-08
rs109758209684160GA0.00 (rs7027685)0.1421.12−0.0046.08E-0448.6023.1E-12
rs70276859802228ATNA0.4021.11−0.0044.33E-0475.4243.8E-18
rs1146803319815682TC0.12 (rs7027685)0.1001.11−0.0047.21E-0435.5772.5E-09
rs47424489826585CG0.28 (rs7027685)0.4581.07−0.0034.33E-0433.7146.4E-09
rs22771639827224AG0.07 (rs7027685)0.9470.870.0059.51E-0433.2118.3E-09
rs126516410105674854AGNA0.8690.910.0046.27E-0432.7721.0E-08
rs1124600311213723TG0.00 (rs507139)0.0440.850.0061.03E-0332.3371.3E-08
rs50713911225196GANA0.0740.840.0068.11E-0453.0823.2E-13
rs22075481132368744CA0.24 (rs10835889)0.4231.09−0.0034.30E-0462.3602.9E-15
rs108358891132370380GANA0.1591.14−0.0055.81E-0479.2345.5E-19
rs71204831132406983GC0.30 (rs10835889)0.1201.12−0.0046.51E-0444.4812.6E-11
rs110317831132459923CA0.28 (rs10835889)0.2041.09−0.0035.25E-0436.6871.4E-09
rs25537721135085453TGNA0.5381.07−0.0024.24E-0434.4584.4E-09
rs5902156511107999907CG0.27 (rs141379009)0.0911.11−0.0047.38E-0430.8822.7E-08
rs14137900911108149207TGNA0.0271.32−0.0111.30E-0376.7192.0E-18
rs498802311108168995AC0.00 (rs141379009)0.1440.890.0046.01E-0443.6993.8E-11
rs1222338111108354102CT0.12 (rs59021565)0.4061.07−0.0024.31E-0430.2343.8E-08
rs96694031246798900GA0.28 (rs12832777)0.4021.07−0.0034.35E-0436.9981.2E-09
rs128327771246831129TCNA0.7011.09−0.0034.61E-0444.7342.3E-11
rs1172457331340723944GA0.00 (rs7986407)0.0161.26−0.0101.74E-0334.5194.2E-09
rs79864071341179798AGNA0.3101.09−0.0034.56E-0445.9431.2E-11
rs669982221651481596GANA0.2010.910.0035.28E-0442.0538.9E-11
rs78378222177571752TGNA0.0131.53−0.0201.93E-03105.4579.7E-25
rs7333812240669648AGNA0.2131.10−0.0035.16E-0442.9195.7E-11
rs5936989X70022420TA0.27 (rs5937008)0.7820.920.0059.30E-0432.6061.1E-08
rs5937008X70093038CTNA0.5200.910.0067.68E-0465.5705.6E-16
rs7059898X70149078CA0.27 (rs5937008)0.3591.07−0.0058.11E-0431.7561.7E-08
rs7888560X131171122AG0.19 (rs5930554)0.2281.08−0.0059.16E-0431.8301.7E-08
rs5930554X131312089TCNA0.3111.14−0.0098.29E-04107.0764.3E-25
rs5933158X131578034AG0.21 (rs5930554)0.5861.08−0.0057.98E-0438.8334.6E-10
rs5975338X131626317AG0.28 (rs5930554)0.1291.10−0.0061.14E-0332.2011.4E-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 shown for reference. The numbers for regression coefficients (Beta), standard error of beta (SE) and association (P) were collected from the UKBB and Helsinki summary statistics and their fixed effect model meta-analysis. The bolded SNP was the only one to reach a suggestive association (p<10−5) in both cohorts.

https://doi.org/10.7554/eLife.37110.019
UKBB cohortHelsinki cohortMeta-analysis (fixed eff.)
rs-codeChrPositionABr2 (reference
SNP)
BetaSEPBetaSEPBetaSEP
rs17631680267090367TCNA0.0040.00072.1E-070.0050.00296.2E-020.0040.00074.29E-08
rs17355373128122820TCNA−0.0030.00051.2E-07−0.0040.00218.7E-02−0.0030.00053.01E-08
rs67751869454568834TC0.14 (rs62323680)−0.0050.00099.9E-08−0.0110.00393.7E-03−0.0050.00095.05E-09
rs69016316152567047TC0.26 (rs6904757)0.0030.00065.4E-080.0050.00311.2E-010.0030.00061.76E-08
rs117904089876418GT0.10 (rs4742448)0.0020.00046.5E-080.0020.00193.9E-010.0020.00044.89E-08
rs1172457331340723944GA0.00 (rs7986407)−0.0100.00174.2E-09−0.0240.00538.1E-06−0.0120.00173.18E-12
rs104153911922652436CTNA−0.0040.00072.8E-07−0.0060.00282.0E-02−0.0040.00072.87E-08
rs621328011949267882ATNA0.0040.00073.3E-070.0060.00292.8E-020.0040.00074.20E-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 are on GRCh37 forward strand, and the B allele is the effect allele. In total 50 SNPs from stage 1 and seven SNPs from stage 2.

https://doi.org/10.7554/eLife.37110.020
rs-codeChrPositionABORLog-oddsStage *
rs2235529122450487CT1.140.132Stage 1
rs2092315122507684CT1.070.072Stage 1
rs10929757211702661AC1.080.073Stage 1
rs11674184211721535TG0.94−0.067Stage 1
rs109366003169514585AT0.91−0.095Stage 1
rs1438352933197623337AG1.750.558Stage 1
rs62323680454546192GA1.160.153Stage 1
rs2202282470634441CT1.070.071Stage 1
rs7270945851283755CT1.120.111Stage 1
rs273610051286516CA0.91−0.090Stage 1
rs285367651288547TC0.91−0.089Stage 1
rs24561815176450837CG1.070.066Stage 1
rs48700846152543949CT0.92−0.087Stage 1
rs69283636152546094GA0.92−0.078Stage 1
rs584154806152562271CG1.180.167Stage 1
rs755102046152592680TG1.290.257Stage 1
rs69047576152593102AG0.93−0.078Stage 1
rs1444445836152684585TC1.120.111Stage 1
rs1388210789674217CG1.230.205Stage 1
rs109758209684160GA1.120.112Stage 1
rs70276859802228AT1.110.103Stage 1
rs1146803319815682TC1.110.108Stage 1
rs47424489826585CG1.070.066Stage 1
rs22771639827224AG0.87−0.140Stage 1
rs126516410105674854AG0.91−0.097Stage 1
rs1124600311213723TG0.85−0.167Stage 1
rs50713911225196GA0.84−0.171Stage 1
rs22075481132368744CA1.090.091Stage 1
rs108358891132370380GA1.140.133Stage 1
rs71204831132406983GC1.120.112Stage 1
rs110317831132459923CA1.090.084Stage 1
rs25537721135085453TG1.070.069Stage 1
rs5902156511107999907CG1.110.109Stage 1
rs14137900911108149207TG1.320.281Stage 1
rs498802311108168995AC0.89−0.113Stage 1
rs1222338111108354102CT1.070.064Stage 1
rs96694031246798900GA1.070.071Stage 1
rs128327771246831129TC1.090.086Stage 1
rs1172457331340723944GA1.260.231Stage 1
rs79864071341179798AG1.090.084Stage 1
rs669982221651481596GA0.91−0.098Stage 1
rs78378222177571752TG1.530.427Stage 1
rs7333812240669648AG1.100.091Stage 1
rs5936989X70022420TA0.92−0.081Stage 1
rs5937008X70093038CT0.91−0.094Stage 1
rs7059898X70149078CA1.070.068Stage 1
rs7888560X131171122AG1.080.077Stage 1
rs5930554X131312089TC1.140.129Stage 1
rs5933158X131578034AG1.080.074Stage 1
rs5975338X131626317AG1.100.094Stage 1
rs17631680267090367TC0.90−0.102Stage 2
rs17355373128122820TC1.070.071Stage 2
rs67751869454568834TC1.130.121Stage 2
rs69016316152567047TC0.91−0.097Stage 2
rs117904089876418GT0.94−0.063Stage 2
rs104153911922652436CT1.100.098Stage 2
rs621328011949267882AT0.90−0.105Stage 2
  1. * 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 length of somatic allelic imbalance over all tumors of a patient. Tests of MED12 mutation positive and negative tumors are denoted by MED12mut + and MED12mut-, respectively. The numbers for regression coefficient (Beta), standard error of beta (SE), test statistic (z) and association (P) were taken by fitting either a linear regression or negative binomial (NB) regression model (response ~predictor). The nominal P-values were adjusted for FDR (Q). The risk allele was used as the effect allele for Beta. In total 228 tests, all p<0.05 are shown.

https://doi.org/10.7554/eLife.37110.021
PredictorResponseModelBetaSEStatisticPQ
12:46798900:G:AMED12mut + countNB−0.220.08−2.880.0040.51
9:674217:C:GMED12mut + countNB−0.690.26−2.630.0080.51
X:70093038:C:TMED12mut + countNB0.210.082.620.0090.51
X:70022420:T:AMED12mut + countNB0.200.082.560.0110.51
11:32459923:C:AMED12mut + countNB0.230.092.540.0110.51
4:54568834:T:Clog(somatic AI basepairs)Linear−0.250.10−2.480.0130.51
17:7571752:T:GMED12mut- countNB−0.920.41−2.240.0250.56
6:152546094:G:AMED12mut- countNB−0.190.08−2.240.0250.56
11:107999907:C:GAge at hysterectomyLinear3.001.342.240.0260.56
13:40723944:G:AMED12mut + countNB0.360.172.170.0300.56
22:40669648:A:GMED12mut + countNB0.190.092.150.0310.56
5:1286516:C:AMED12mut + countNB0.170.082.150.0310.56
22:40669648:A:GAge at hysterectomyLinear1.360.632.160.0320.56
1:22450487:C:TAge at hysterectomyLinear−1.480.72−2.050.0410.65
16:51481596:G:Alog(somatic AI basepairs)Linear0.170.082.020.0440.65
5:1288547:T:CAge at hysterectomyLinear1.320.662.000.0460.65
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 rank-sum and models for linear and negative binomial (NB) regression (variable ~GRS). The P values were adjusted for FWER with the Holm-Bonferroni method (Q). Significant associations (Q < 0.05) are shown bolded. Note that population association tests include only the female controls.

https://doi.org/10.7554/eLife.37110.022
GRS *CohortVariableTestN casesN controlsRate ratioPQ
 Stage 1HelsinkiUL phenotypeRank-sum (one-tailed)4578899-8.3e-101.1e-08
 Stage 2NFBCUL phenotypeRank-sum (one-tailed)4592351-1.1e-051.1e-04
 Stage 2HelsinkiTotal number of ULsNB457-1.250.001050.0032
 Stage 2HelsinkiAge at hysterectomyLinear392-0.500.480.48
 Stage 2HelsinkiNumber of MED12mut+NB457-1.433.2e-040.002
 Stage 2HelsinkiNumber of MED12mut-NB457-0.790.02660.053
 Stage 2HelsinkiOne-or-more MED12mut+Rank-sum334123-5.3e-040.0026
 Stage 2HelsinkiAll MED12mut+Rank-sum221123-7.9e-040.0032
 Stage 2African #UL phenotypeRank-sum (one-tailed)2961256-1.3e-051.2e-04
 Stage 2Caribbean#UL phenotypeRank-sum (one-tailed)6682041-6.7e-055.4e-04
 Stage 2Irish #UL phenotypeRank-sum (one-tailed)3986208-8.3e-069.1e-05
 Stage 2Indian #UL phenotypeRank-sum (one-tailed)2032567-2.9e-040.0020
 Stage 2Other white #UL phenotypeRank-sum (one-tailed)6478982-6.9e-098.3e-08
  1. *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 frequencies with log-odds. The final values were scaled with a factor two to make them comparable with SNP dosage-based GRS. See Appendix-figure 6 for an explanation of the population acronyms.

https://doi.org/10.7554/eLife.37110.023
rs-codeChrPosABAF_AFRAF_AMRAF_ASJAF_EASAF_FINAF_NFEAF_OTH
 rs584154806152562271CG0.2280.0660.0900.0000.2370.1610.158
 rs78378222177571752TG0.0020.0040.0000.0000.0200.0180.015
 rs108358891132370380GA0.3840.0910.2020.0520.0690.1500.124
 rs14137900911108149207TG0.0050.0140.0230.0000.0070.0220.015
rs70276859802228AT0.5350.6020.3570.7380.5560.4130.462
rs2235529122450487CT0.0290.3130.0460.4840.1640.1580.171
 rs7270945851283755CT0.1390.1370.1830.1340.2210.1880.180
rs22075481132368744CA0.5530.2280.3930.1790.3210.4110.378
rs273610051286516CA0.5500.5970.4770.6060.5070.5040.539
rs50713911225196GA0.0280.0580.0790.0070.0940.0720.084
 rs62323680454546192GA0.0200.0320.0990.0020.0450.0700.060
rs285367651288547TC0.7650.8010.6130.8560.7830.7390.763
 rs109758209684160GA0.6690.3970.2120.5860.2570.1710.255
 rs109366003169514585AT0.0940.4060.1950.5390.2740.2490.267
rs69283636152546094GA0.6920.6930.5410.8510.5750.5080.568
rs79864071341179798AG0.4460.4590.2770.7390.3840.3110.367
 rs1444445836152684585TC0.0500.0450.0440.0060.2300.1390.155
 rs1438352933197623337AG0.0000.0040.0030.0000.0150.0020.006
 rs128327771246831129TC0.9180.7400.7620.9020.6510.6750.669
rs71204831132406983GC0.2420.0870.1520.0250.0740.1120.098
rs498802311108168995AC0.0220.0440.1420.0060.2360.1460.149
rs7333812240669648AG0.0950.4710.1690.2470.2580.2160.239
 rs669982221651481596GA0.0330.1380.2650.0010.1660.2130.167
rs69047576152593102AG0.4430.5790.4010.6250.3790.3920.401
rs2202282470634441CT0.2300.5490.4200.7260.4370.4910.466
 rs10929757211702661AC0.1160.5050.5560.5170.6740.5910.556
rs96694031246798900GA0.6150.4760.4060.2660.3960.3820.369
 rs110317831132459923CA0.2620.3640.2880.7480.1970.2040.241
 rs1146803319815682TC0.0650.1780.0670.1280.1900.1150.133
 rs1172457331340723944GA0.0010.0040.0030.0000.0300.0240.027
rs25537721135085453TG0.3420.6560.6000.7690.5240.5440.569
rs24561815176450837CG0.7960.3550.5330.4810.5000.5110.505
rs47424489826585CG0.8380.6290.4730.7850.5480.4710.503
rs22771639827224AG0.9590.8580.9640.8250.9660.9480.954
rs48700846152543949CT0.1000.4210.1750.1880.2340.2110.238
rs126516410105674854AG0.4690.8910.8250.9850.8900.8630.873
 rs755102046152592680TG0.0020.0020.0000.0000.0150.0110.011
 rs1124600311213723TG0.0600.0470.0330.1490.0220.0350.038
 rs1388210789674217CG0.0020.0040.0000.0000.0170.0250.014
 rs5902156511107999907CG0.0380.1120.1190.0490.0500.0860.054
rs2092315122507684CT0.1320.3230.2420.5040.2000.2430.210
 rs1222338111108354102CT0.4130.6060.4770.4440.3900.4140.457
 rs11674184211721535TG0.2590.4760.3340.4140.4030.3840.389
rs5930554X131312089TC0.7520.1740.2960.1040.3200.3190.311
rs5937008X70093038CT0.1450.3830.4140.5630.4860.5200.485
rs5933158X131578034AG0.7100.5880.5000.6860.6500.6050.741
rs5936989X70022420TA0.7420.8880.7670.9940.6770.7780.810
rs5975338X131626317AG0.4090.1030.0990.0910.1610.1450.151
rs7059898X70149078CA0.1430.1670.3550.0010.3400.3420.276
rs7888560X131171122AG0.1420.0900.1990.0000.2440.2170.201
 rs67751869454568834TC0.0850.0300.0990.0220.0530.0620.067
rs69016316152567047TC0.2560.2490.1820.1220.1020.1200.127
 rs104153911922652436CT0.2020.0740.1100.2250.1300.1070.144
rs17355373128122820TC0.5230.3850.2620.4250.2490.2510.288
 rs621328011949267882AT0.0130.0700.0530.0090.1120.1030.092
 rs17631680267090367TC0.0180.0610.0500.0010.1000.1020.082
 rs117904089876418GT0.1100.3070.3870.2460.3550.3800.353
AFRAMRASJEASFINNFEOTH
GRS4.7184.0594.0684.1964.1684.0914.116
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.

https://doi.org/10.7554/eLife.37110.024
TissueGeneIDNBest SNPDistanceNominal
P
Permutation
P
FDR
TRP11-
816J6.3
ENSG00000269889.182rs67795055424579.10E-054.03E-040.224
TRUFY3ENSG00000018189.88rs7660770−9729457.84E-046.68E-040.370
TTRIP13ENSG00000071539.922rs27360993945811.63E-042.27E-031
NRN7SL832PENSG00000243819.328rs75709798869584.06E-042.75E-031
NLNX1ENSG00000072201.925rs623236742123007.12E-043.22E-031
NRP11-
849F2.8
ENSG00000269928.15rs143094271−6650382.43E-034.00E-031
TMIR5006ENSG00000264190.1158rs9549254−9076606.10E-044.42E-031
NRP11-
423H2.3
ENSG00000249684.150rs183686−8832353.36E-035.55E-031
NSLC7A3ENSG00000165349.7148rs43604509656.75E-047.38E-031
TALPLENSG00000162551.952.5213708.48E-047.59E-031
NPRRG4ENSG00000135378.3167rs11031737−4787183.99E-048.59E-031
NRP11-
791G15.2
ENSG00000272275.128rs64322208027141.24E-038.81E-031
TZDHHC11BENSG00000206077.622rs27360995768649.74E-041.02E-021
TACAP1ENSG00000072818.75rs783782223319034.83E-031.04E-021
NHNRNPA1P48ENSG00000224578.320rs55881068−2122664.97E-031.12E-021
TWNT4ENSG00000162552.1052rs12042083289331.30E-031.16E-021
TLRRIQ4ENSG00000188306.682rs13074500258602.96E-031.20E-021
TTEX11ENSG00000120498.9148rs117956272086501.30E-031.23E-021
TAC011994.1ENSG00000265583.128rs11685032−732361.84E-031.32E-021
TFRMD7ENSG00000165694.5215rs59331583670128.40E-041.33E-021
NTRAPPC1ENSG00000170043.75rs138420351−1336017.23E-031.44E-021
TRP11-
423H2.1
ENSG00000170089.1172rs353496−8065119.37E-031.51E-021
NSDHAP3ENSG00000185986.1022rs11742908−2976551.42E-031.58E-021
TCDC42-IT1ENSG00000230068.252rs109171671184002.10E-031.80E-021
NRP11-
362K14.6
ENSG00000270096.182rs12638862−352454.49E-031.96E-021
TTNRC6BENSG00000100354.1632rs124849512622538.29E-031.97E-021
NDNAH2ENSG00000183914.105rs143094271−1575719.73E-031.98E-021
NSALL1ENSG00000103449.720rs129336863089139.53E-032.13E-021
TXXyac-
YRM2039.2
ENSG00000181404.1371rs1388210786597051.69E-032.22E-021
NITPRIPENSG00000148841.118rs9419958−3959491.43E-022.39E-021
TRNASEK-
C17orf49
ENSG00000161939.145.5016851.19E-022.43E-021
TUQCRFS1P1ENSG00000226085.232rs18075792569261.06E-022.44E-021
TFOXO1ENSG00000150907.6166rs95492601242992.94E-032.61E-021
TNDUFS6ENSG00000145494.722rs7734992−5213872.81E-032.82E-021
TRP11-
259O2.3
ENSG00000249731.122rs7710703−6807042.89E-032.84E-021
TCDC42ENSG00000070831.1152rs41307810−250763.35E-032.91E-021
TRP3-
363L9.1
ENSG00000227064.1215rs3764771−8300732.03E-032.97E-021
TRP11-
362K14.7
ENSG00000270135.182rs67795055186117.45E-033.07E-021
NAMIGO2ENSG00000139211.5155rs9706162−6068086.28E-033.08E-021
TLPIN1ENSG00000134324.728rs11685032−1434275.06E-033.33E-021
TMBNL3ENSG00000076770.10215rs12631551907182.55E-033.37E-021
NTOX3ENSG00000103460.125rs12325192−9837893.24E-023.38E-021
NDANCRENSG00000226950.223rs623254828858238.24E-033.54E-021
TDMRT1ENSG00000137090.771rs12004436−1582613.09E-033.64E-021
NNT5C2ENSG00000076685.148rs12651648289132.05E-023.75E-021
TTMEM256-
PLSCR3
ENSG00000187838.125rs1384203514070161.77E-023.81E-021
TRP11-
401P9.4
ENSG00000261685.220rs129336867990791.64E-023.84E-021
NCTC1ENSG00000178971.95rs143094271−6670901.89E-024.03E-021
NSULT1B1ENSG00000173597.419rs13133166133181.49E-024.04E-021
NTNK1ENSG00000174292.85rs1430942711792482.24E-024.21E-021
TSOX15ENSG00000129194.35rs1384203512085662.02E-024.30E-021
TUGT2A1ENSG00000173610.719rs15877661129592.06E-024.31E-021
TRP4-
607I7.1
ENSG00000255521.134rs2553783−820852.66E-024.41E-021
NSENP3ENSG00000161956.85rs783782221065592.19E-024.45E-021
NKDM6BENSG00000132510.65rs143094271−2801212.16E-024.54E-021
TSKILENSG00000136603.982rs34194057−5259161.13E-024.63E-021
TEPHB2ENSG00000133216.1252.−6801046.04E-034.97E-021
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.

https://doi.org/10.7554/eLife.37110.025
TissueSNPCpG*Betat-statp-valueFDRGeneCpG islandPromoterAAABBB
N13_
41179798
13_
41189143
−0.413−19.8376.57E-204.88E-15FOXO1nono15164
T13_
41179798
13_
41189143
−0.333−8.2963.29E-117.74E-07FOXO1nono28235
T5_12837555_
1285974
−0.427−7.1672.21E-093.46E-05TERTnono36173
N5_
1283755
5_
1285974
−0.461−7.461.42E-081.11E-04TERTnono18143
T5_
1286516
5_
1277576
−0.289−6.3584.53E-083.99E-04TERTyesno72920
T1_
22450487
1_
22456326
−0.123−5.5071.04E-066.36E-03WNT4nono40151
N5_
1286516
5_
1285974
0.4265.4774.51E-061.76E-02TERTnono6227
T5_
1286516
5_
1285974
0.2994.7391.61E-054.82E-02TERTnono72920
N13_
41179798
13_
41223110
−0.174−4.9572.10E-055.36E-02FOXO1nono15164
N5_
1283755
5_
1282413
−0.17−4.8163.16E-057.12E-02TERTnono18143
T11_
225196
11_
195431
0.2224.4524.31E-059.21E-02BET1LnoODF34880
  1. * 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) column, were taken from the UKBB summary statistics for 15,453 UL cases. The bolded values pass FWER (Bonferroni for seven independent loci; p<0.05/7).

https://doi.org/10.7554/eLife.37110.026
StudyPopulationLocusSuggested geneSNPRAMethodP (UKBB)
Cha et al.Japanese22q13.1TNRC6Brs12484776GGWAS1.0E-10
Edwards et al.European Americans22q13.1TNRC6Brs12484776GGWAS1.0E-10
Cha et al.Japanese11p15.5BET1Lrs2280543GGWAS2.2E-08
Edwards et al.European Americans11p15.5BET1Lrs2280543GGWAS2.2E-08
Zhang et al.African Americans1q42.2PCNXL2rs7546784-Admixture3.6E-02
Zhang et al.African Americans2q32.2PMS1rs256552-Admixture1.8E-01
Cha et al.Japanese10q24.33SLKrs7913069AGWAS3.4E-01
Hellwege et al.African American22q13.1CYTH4rs5995416CGWAS5.3E-01
Hellwege et al.African American22q13.1CYTH4rs739187CGWAS6.2E-01
Hellwege et al.African American22q13.1CYTH4rs713939CGWAS8.0E-01
Hellwege et al.African American22q13.1CYTH4rs4821628GGWAS8.1E-01
Eggert et al.Multiple17q25.3FASNrs4247357ALinkage
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 (AF), odds-ratio (OR) and association (P) follow those reported in the GWAS catalog.

https://doi.org/10.7554/eLife.37110.027
PubmedDateJournalGene symbolRisk alleleAFORP
188358602008-10-01J Med GenetIdiopathic pulmonary fibrosisTERTrs2736100-A0.412.113.00E-08
195783672009-07-05Nat GenetGliomaTERTrs2736100-G0.491.272.00E-17
195783672009-07-05Nat GenetGliomaTERTrs2853676-A0.731.264.00E-14
198360082009-10-15Am J Hum GenetLung adenocarcinomaTERTrs2736100-G0.51.122.00E-10
201399782010-02-07Nat GenetRed blood cell countTERTrs2736100-G0.40.073.00E-08
205438472010-06-13Nat GenetTesticular germ cell cancerTERTrs2736100-T0.491.338.00E-15
207004382010-08-05PLoS GenetLung adenocarcinomaTERTrs2736100-G0.391.462.00E-22
208715972010-09-26Nat GenetLung adenocarcinomaTERTrs2736100-C0.391.273.00E-11
215317912011-04-29Hum Mol GenetGliomaTERTrs2736100-?-1.251.00E-14
217253082011-07-03Nat GenetLung cancerTERTrs2736100-C0.411.271.00E-27
218276602011-08-09BMC Med GenomicsGliomaTERTrs2736100-?--7.00E-09
219463512011-09-25Nat GenetBasal cell carcinomaTP53rs78378222-C-2.162.00E-20
228865592012-08-11Hum GenetGliomaTERTrs2736100-G0.4941.304.00E-09
231436012012-11-11Nat GenetLung cancerTERTrs2736100-G0.41.384.00E-27
234721652013-03-05PLoS OneEndometriosisWNT4rs2235529-T0.1521.287.00E-09
234721652013-03-05PLoS OneEndometriosisWNT4rs2235529-C0.7091.196.00E-06
234721652013-03-05PLoS OneEndometriosisWNT4rs2235529-T0.1341.258.00E-07
234721652013-03-05PLoS OneEndometriosisWNT4rs2235529-A0.1531.303.00E-09
235839802013-04-14Nat GenetInterstitial lung diseaseTERTrs2736100-A0.491.372.00E-19
244030522014-01-08Hum Mol GenetBasal cell carcinomaTP53rs78378222-G-2.244.00E-22
244654732014-01-21PLoS OneTelomere lengthTERTrs2736100-C0.084.00E-06
249082482014-06-08Nat GenetGlioma (high-grade)TERTrs2736100-C0.511.391.00E-15
 249454042014-06-19PLoS GenetBone mineral density (paediatric, upper limb)WNT4rs2235529-C0.850.121.00E-08
 249454042014-06-19PLoS GenetBone mineral density (paediatric, upper limb)WNT4rs2235529-C-0.123.00E-07
 258551362015-04-09Nat CommunBasal cell carcinomaTP53rs78378222-G0.0182.071.00E-20
 264240502015-10-01Nat CommunGlioblastoma-rs72709458-T-1.686.00E-24
273636822016-07-01Nat CommunMultiple myeloma-rs10936600-A-1.206.00E-15
275017812016-08-09Nat CommunEGFR mutation-positive lung adenocarcinomaTERTrs2736100-G0.3871.422.00E-31
275398872016-08-19Nat CommunBasal cell carcinomaTP53rs78378222-G0.011.412.00E-10
278632522016-11-17CellMean corpuscular hemoglobinTP53rs78378222-G0.01210.106.00E-09
278632522016-11-17CellMean corpuscular hemoglobinTERTrs2736100-A0.49820.045.00E-34
278632522016-11-17CellPlatelet countTERTrs2736100-A0.49840.033.00E-20
280173752016-12-22Am J Hum GenetMean corpuscular volumeTERTrs2736100-A-0.003.00E-06
280173752016-12-22Am J Hum GenetMean corpuscular volumeTERTrs2736100-?--2.00E-11
280173752016-12-22Am J Hum GenetMean corpuscular hemoglobinTERTrs2736100-?--1.00E-08
281352442017-01-30Nat GenetPulse pressureTP53rs78378222-T0.990.902.00E-10
283464432017-03-27Nat GenetGliomaTP53rs78378222-G0.0132.539.00E-38
283464432017-03-27Nat GenetGlioblastomaTP53rs78378222-G0.0132.635.00E-29
283464432017-03-27Nat GenetNon-glioblastoma gliomaTP53rs78378222-G0.0132.735.00E-27
285372672017-05-24Nat CommunEndometriosisGREB1rs11674184-T0.611.133.00E-17
285372672017-05-24Nat CommunEndometriosisGREB1rs11674184-T0.611.123.00E-14
286047282017-06-12Nat GenetTesticular germ cell tumorTERTrs2736100-A0.511.289.00E-25
286047322017-06-12Nat GenetTesticular germ cell tumorTERTrs2736100-A0.51.298.00E-20

Data availability

The UKBB data is available through the UK Biobank (http://www.ukbiobank.ac.uk). The NFBC data can be requested from the Northern Finland Birth Cohorts' Project Center at the Medical Faculty, University of Oulu (http://www.oulu.fi/nfbc/). The summary statistics that support the findings presented in this work are included in Supplementary Tables and Supplementary Data.

The following previously published data sets were used
  1. 1
  2. 2

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

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