Use of genetic markers and gene-diet interactions for interrogating population-level causal influences of diet on health
Open accessAbstract
Differences in diet appear to contribute substantially to the burden of disease in populations, and therefore changes in diet could lead to major improvements in public health. This is predicated on the reliable identification of causal effects of nutrition on health, and unfortunately nutritional epidemiology has deficiencies in terms of identifying these. This is reflected in the many cases where observational studies have suggested that a nutritional factor is protective against disease, and randomized controlled trials have failed to verify this. The use of genetic variants as proxy measures of nutritional exposure-an application of the Mendelian randomization principle-can contribute to strengthening causal inference in this field. Genetic variants are not subject to bias due to reverse causation (disease processes influencing exposure, rather than vice versa) or recall bias, and if obvious precautions are applied are not influenced by confounding or attenuation by errors. This is illustrated in the case of epidemiological studies of alcohol intake and various health outcomes, through the use of genetic variants related to alcohol metabolism (in ALDH2 and ADH1B). Examples from other areas of nutritional epidemiology and of the informative nature of gene-environment interactions interpreted within the Mendelian randomization framework are presented, and the potential limitations of the approach addressed.
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Using 97 recently reported independent SNPs to index BMI minimized the risk of shared pleiotropy and linkage-disequilibrium-induced confounding pleiotropic effects.
“However, using as many as 97 recently reported independent SNPs to index BMI, we were able to minimize the risk of shared pleiotropy and linkage-disequilibrium-induced confounding pleiotropic effects [32, 33].”
From Causal relationship between obesity and serum testosterone status in men: A bi-directional mendelian randomization analysis (2017) · cites this paper as [32]
The use of two separate independent genetic instruments with similar point estimates of the causal effect of BMI on serum testosterone further reduced the risk of pleiotropy.
“Moreover, the use of two separate independent genetic instruments with similar point estimates of the causal effect of BMI on serum T further reduced the risk of pleiotropy [32, 33].”
From Causal relationship between obesity and serum testosterone status in men: A bi-directional mendelian randomization analysis (2017) · cites this paper as [32]
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Timpson, N. J., Brennan, P., Gaborieau, V., Moore, L. E., Zaridze, D. G., Matveev, V., Szeszenia‐Dabrowska, N., Lissowska, J., Mateș, D., Bencko, V., et al. (2010) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-09-1019 · Cited by 21 · see citing works
Commentary: Alcohol, coronary heart disease and public health: which evidence-based policy
Bovet, P., & Paccaud, F. (2001) · International Journal of Epidemiology · doi:10.1093/ije/30.4.734 · Cited by 21 · see citing works
Genetic Technologies and Achieving Health for Populations
Baird, P. A. (2000) · International Journal of Health Services · doi:10.2190/e3p3-tq8d-ktdr-nf8k · Cited by 17 · see citing works
Ferrari, P., Carroll, R. J., Gustafson, P., et al. (2008) · Statistics in Medicine · doi:10.1002/sim.3444 · Cited by 15 · see citing works
Fibrinogen, social position, and "Mendelian randomisation".
Jousilahti, P., & Salomaa, V. (2004) · PubMed · Cited by 12 · see citing works
The role of nutritional factors in the aetiology of neural tube defects
Bower, C. I., & Stanley, F. (1992) · Journal of Paediatrics and Child Health · doi:10.1111/j.1440-1754.1992.tb02610.x · Cited by 11 · see citing works
Commentary: Alcohol and coronary heart disease—laying the foundation for future work
Rimm, E. B. (2001) · International Journal of Epidemiology · doi:10.1093/ije/30.4.738 · Cited by 11 · see citing works
Commentary: Genes as instruments for evaluation of markers and causes
Glynn, R. J. (2006) · International Journal of Epidemiology · doi:10.1093/ije/dyl107 · Cited by 10 · see citing works
Alcohol and esophageal cancer, is there an exaggerated accusation?
Memik, F. (2004) · PubMed · Cited by 6 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Mendelian randomization: genetic anchors for causal inference in epidemiological studies
Davey Smith, G., & Hemani, G. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu328 · Cited by 4,677 · see citing works
Self-citationUsing multiple genetic variants as instrumental variables for modifiable risk factors
Palmer, T. M., Lawlor, D. A., Harbord, R. M., Sheehan, N. A., Tobias, J. H., Timpson, N. J., Smith, G. D., & Sterne, J. A. (2012) · Statistical Methods in Medical Research · doi:10.1177/0962280210394459 · Cited by 1,289 · see citing works
Mendelian randomization in cardiometabolic disease: challenges in evaluating causality
Holmes, M. V., Ala-Korpela, M., & Smith, G. D. (2017) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2017.78 · Cited by 679 · see citing works
Taylor, A. E., Fluharty, M. E., Bjørngaard, J. H., Gabrielsen, M. E., Skorpen, F., Marioni, R. E., Campbell, A., Engmann, J., Mirza, S. S., Loukola, A., et al. (2014) · BMJ Open · doi:10.1136/bmjopen-2014-006141 · Cited by 187 · see citing works
Richmond, R. C., Davey Smith, G., Ness, A. R., den Hoed, M., McMahon, G., & Timpson, N. J. (2014) · PLoS Medicine · doi:10.1371/journal.pmed.1001618 · Cited by 167 · see citing works
Taylor, A. E., Davies, N. M., Ware, J. J., VanderWeele, T., Smith, G. D., & Munafò, M. R. (2014) · Economics & Human Biology · doi:10.1016/j.ehb.2013.12.002 · Cited by 166 · see citing works
Self-citationG = E: What GWAS Can Tell Us about the Environment
Gage, S. H., Davey Smith, G., Ware, J. J., Flint, J., & Munafò, M. R. (2016) · PLOS Genetics · doi:10.1371/journal.pgen.1005765 · Cited by 132 · see citing works
Davies, N. M., Hill, W. D., Anderson, E. L., Sanderson, E., Deary, I. J., & Davey Smith, G. (2019) · eLife · doi:10.7554/elife.43990 · Cited by 135 · see citing works
Pleiotropy-robust Mendelian randomization.
van Kippersluis, H., & Rietveld, C. A. (2018) · International Journal of Epidemiology · doi:10.1093/ije/dyx002 · Cited by 125 · see citing works
Eriksson, J., Haring, R., Grarup, N., Vandenput, L., Wallaschofski, H., Lorentzen, E., Hansen, T., Mellström, D., Pedersen, O., Nauck, M., et al. (2017) · PLOS ONE · doi:10.1371/journal.pone.0176277 · Cited by 101 · see citing works
Bias in Mendelian randomization due to assortative mating
Hartwig, F. P., Davies, N. M., & Davey Smith, G. (2018) · Genetic Epidemiology · doi:10.1002/gepi.22138 · Cited by 99 · see citing works
Spiller, W., Slichter, D., Bowden, J., & Davey Smith, G. (2018) · International Journal of Epidemiology · doi:10.1093/ije/dyy204 · Cited by 90 · see citing works
Self-citationMinică, C. C., Dolan, C. V., Boomsma, D. I., de Geus, E., & Neale, M. C. (2018) · Behavior Genetics · doi:10.1007/s10519-018-9904-4 · Cited by 80 · see citing works
Davey Smith, G. (2012) · International Journal of Epidemiology · doi:10.1093/ije/dys016 · Cited by 68 · see citing works
Self-citationMcMahon, G., Taylor, A. E., Davey Smith, G., & Munafò, M. R. (2014) · PLoS ONE · doi:10.1371/journal.pone.0103448 · Cited by 49 · see citing works
Self-citationBoffetta, P., Winn, D. M., Ioannidis, J. P., Thomas, D. C., Little, J., Smith, G. D., Cogliano, V. J., Hecht, S. S., Seminara, D., Vineis, P., et al. (2012) · International Journal of Epidemiology · doi:10.1093/ije/dys010 · Cited by 48 · see citing works
Taylor, P. N., Richmond, R., Davies, N., Sayers, A., Stevenson, K., Woltersdorf, W., Taylor, A., Groom, A., Northstone, K., Ring, S., et al. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-3505 · Cited by 48 · see citing works
Using Mendelian randomisation to infer causality in depression and anxiety research
Gage, S. H., Smith, G. D., Zammit, S., Hickman, M., & Munafò, M. R. (2013) · Depression and Anxiety · doi:10.1002/da.22150 · Cited by 32 · see citing works
Minică, C. C., Boomsma, D. I., Dolan, C. V., de Geus, E., & Neale, M. C. (2020) · International Journal of Epidemiology · doi:10.1093/ije/dyaa013 · Cited by 23 · see citing works
- Authors
- Davey Smith, G.
- Venue
- Genes & Nutrition
- Published
- 2010-09-10
- Volume
- 6
- Issue
- 1
- Pages
- 27-43
- ISSN
- 1555-8932 (ISSN-L)
- 1865-3499
- PMC
- PMC3040803
- OpenAlex
- W2058341652
- Cited by
- 134
- References
- 116
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 3 · 2023: 5 · 2022: 4 · 2021: 2 · 2020: 4 · 2019: 8 · 2018: 9 · 2017: 11 · 2016: 9 · 2015: 15 · 2014: 15 · 2013: 11 · 2012: 17
- FWCI
- 6.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Genes & Nutrition (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Bristol Research (University of Bristol) (submittedVersion)
- Explore Bristol Research (submittedVersion)
- Funders
- University of Bristol (G0600705)
- Medical Research Council (G0600705)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Nutrition, Genetics, and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Physical Performance
- Keywords
- Mendelian randomization, gene-diet interaction, reverse causality, confounding, alcohol consumption, alcohol metabolism, ALDH2, ADH1B, nutritional epidemiology, gene-environment interaction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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