Article | Published:

Epidemiology

Height and overall cancer risk and mortality: evidence from a Mendelian randomisation study on 310,000 UK Biobank participants

British Journal of Cancervolume 118pages12621267 (2018) | Download Citation

Abstract

Background

Observational studies have shown that being taller is associated with greater cancer risk. However, the interpretation of such studies can be hampered by important issues such as confounding and reporting bias.

Methods

We used the UK Biobank resource to develop genetic predictors of height and applied these in a Mendelian randomisation framework to estimate the causal relationship between height and cancer. Up to 438,870 UK Biobank participants were considered in our analysis. We addressed two primary cancer outcomes, cancer incidence by age ~60 and cancer mortality by age ~60 (where age ~60 is the typical age of UK Biobank participants).

Results

We found that each genetically predicted 9 cm increase in height conferred an odds ratio of 1.10 (95% confidence interval 1.07–1.13) and 1.09 (1.02–1.16) for diagnosis of any cancer and death from any cancer, respectively. For both risk and mortality, the effect was larger in females than in males.

Conclusions

Height increases the risk of being diagnosed with and dying from cancer. These findings from Mendelian randomisation analyses agree with observational studies and provide evidence that they were not likely to have been strongly affected by confounding or reporting bias.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

Note: This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International licence (CC BY 4.0).

Note: This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License.)

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.

    Hunter, D. J. & Willett, W. C. Diet, body build, and breast cancer. Annu Rev. Nutr. 14, 393–418 (1994).

  2. 2.

    Green, J. et al. Height and cancer incidence in the Million Women Study: prospective cohort, and meta-analysis of prospective studies of height and total cancer risk. Lancet Oncol. 12, 785–794 (2011).

  3. 3.

    Gunnell, D. et al Height, leg length, and cancer risk: a systematic review. Epidemiol. Rev. 23, 313–342 (2001).

  4. 4.

    Katan, M. B. Commentary: Mendelian randomization, 18 years on. Int. J. Epidemiol. 33, 10–11 (2004).

  5. 5.

    Macgregor, S., Cornes, B. K., Martin, N. G. & Visscher, P. M. Bias, precision and heritability of self-reported and clinically measured height in Australian twins. Hum. Genet. 120, 571–580 (2006).

  6. 6.

    Gorber, S. C., Connor Gorber, S., Tremblay, M., Moher, D. & Gorber, B. A comparison of direct vs. self-report measures for assessing height, weight and body mass index: a systematic review. Obes. Rev. 8, 307–326 (2007).

  7. 7.

    Khankari, N. K. et al. Association between adult height and risk of colorectal, lung, and prostate cancer: results from meta-analyses of prospective studies and Mendelian randomization analyses. PLoS Med. 13, e1002118 (2016).

  8. 8.

    Thrift, A. P. et al. Mendelian randomization study of height and risk of colorectal cancer. Int. J. Epidemiol. 44, 662–672 (2015).

  9. 9.

    Zhang, B. et al. Height and breast cancer risk: evidence from prospective studies and Mendelian randomization. J. Natl Cancer Inst. 107 (2015). https://doi.org/10.1093/jnci/djv219.

  10. 10.

    UK10K Consortium et al. The UK10K project identifies rare variants in health and disease. Nature 526, 82–90 (2015).

  11. 11.

    Auton, A., Salcedo, T. Assessing Rare Variation in Complex Traits 71–85 (Springer, New York, 2015).

  12. 12.

    McCarthy, S. et al. A reference panel of 64,976 haplotypes for genotype imputation. Nat. Genet. 48, 1279–1283 (2016).

  13. 13.

    Bycroft, C. et al. Genome-wide genetic data on ~500,000 UK Biobank participants. https://doi.org/10.1101/166298 (2017).

  14. 14.

    Chang, C. C. et al. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience 4, 7 (2015).

  15. 15.

    Burgess, S., Butterworth, A. & Thompson, S. G. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet. Epidemiol. 37, 658–665 (2013).

  16. 16.

    Yavorska, O. O. & Burgess, S. Mendelian randomization: an R package for performing Mendelian randomization analyses using summarized data. Int. J. Epidemiol. https://doi.org/10.1093/ije/dyx034 (2017).

  17. 17.

    Hemani, G. et al. MR-base: a platform for systematic causal inference across the phenome using billions of genetic associations. Preprint at https://www.biorxiv.org/content/early/2016/12/16/078972 (2016).

  18. 18.

    Sawada, N. et al. The association between adult attained height and sitting height with mortality in the European Prospective Investigation into Cancer and Nutrition (EPIC). PLoS One 12, e0173117 (2017).

  19. 19.

    Davies, N. M. et al. The effects of height and BMI on prostate cancer incidence and mortality: a Mendelian randomization study in 20,848 cases and 20,214 controls from the PRACTICAL consortium. Cancer Causes Control 26, 1603–1616 (2015).

  20. 20.

    Burgess, S., Davies, N. M. & Thompson, S. G. Bias due to participant overlap in two-sample Mendelian randomization. Genet. Epidemiol. 40, 597–608 (2016).

  21. 21.

    Göring, H. H., Terwilliger, J. D. & Blangero, J. Large upward bias in estimation of locus-specific effects from genomewide scans. Am. J. Hum. Genet. 69, 1357–1369 (2001).

  22. 22.

    Wood, A. R. et al. Defining the role of common variation in the genomic and biological architecture of adult human height. Nat. Genet. 46, 1173–1186 (2014).

  23. 23.

    Bowden, J., Davey Smith, G. & Burgess, S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int. J. Epidemiol. 44, 512–525 (2015).

  24. 24.

    Bowden, J., Davey Smith, G., Haycock, P. C. & Burgess, S. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet. Epidemiol. 40, 304–314 (2016).

Download references

Acknowledgements

This work is supported by a project grant (1123248) from the Australian National Health and Medical Research Council (NHMRC). J.-S.O. received scholarship support from the University of Queensland and QIMR Berghofer Medical Research Institute. S.M. is supported by a fellowship from the Australian Research Council. D.C.W. and R.E.N. are supported by research fellowships from the NHMRC.

Author information

Affiliations

  1. QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia

    • Jue-Sheng Ong
    • , Jiyuan An
    • , Matthew H. Law
    • , David C. Whiteman
    • , Rachel E. Neale
    • , Puya Gharahkhani
    •  & Stuart MacGregor

Authors

  1. Search for Jue-Sheng Ong in:

  2. Search for Jiyuan An in:

  3. Search for Matthew H. Law in:

  4. Search for David C. Whiteman in:

  5. Search for Rachel E. Neale in:

  6. Search for Puya Gharahkhani in:

  7. Search for Stuart MacGregor in:

Contributions

S.M., R.E.N., P.G. and M.H.L. designed the study and obtained funding. J.-S.O., J.A., P.G., M.H.L. and S.M. analysed the data. S.M., J.-S.O. and P.G. wrote the first draft of the paper. All authors contributed to the final version of the paper.

This work was conducted using the UK Biobank Resource (application number 25331). We thank Scott Wood and John Pearson from QIMR Berghofer for IT support.

Competing interests

The authors declare no competing interests.

Ethical approval

The UK Biobank study was approved by the North West Multi-Centre Research Ethics Committee (reference number 06/MRE09/65), and at recruitment all participants gave informed consent to participate in UK Biobank and be followed up, using a signature capture device.

Funding

This work was conducted using the UK Biobank Resource (application number 25331). We thank Scott Wood and John Pearson from QIMR Berghofer for IT support.

Corresponding author

Correspondence to Jue-Sheng Ong.

Electronic supplementary material

About this article

Publication history

Received

Revised

Accepted

Published

Issue Date

DOI

https://doi.org/10.1038/s41416-018-0063-4

Further reading