IDEAS home Printed from https://ideas.repec.org/a/plo/pgen00/1007951.html
   My bibliography  Save this article

Searching for the causal effects of body mass index in over 300 000 participants in UK Biobank, using Mendelian randomization

Author

Listed:
  • Louise A C Millard
  • Neil M Davies
  • Kate Tilling
  • Tom R Gaunt
  • George Davey Smith

Abstract

Mendelian randomization (MR) has been used to estimate the causal effect of body mass index (BMI) on particular traits thought to be affected by BMI. However, BMI may also be a modifiable, causal risk factor for outcomes where there is no prior reason to suggest that a causal effect exists. We performed a MR phenome-wide association study (MR-pheWAS) to search for the causal effects of BMI in UK Biobank (n = 334 968), using the PHESANT open-source phenome scan tool. A subset of identified associations were followed up with a formal two-stage instrumental variable analysis in UK Biobank, to estimate the causal effect of BMI on these phenotypes. Of the 22 922 tests performed, our MR-pheWAS identified 587 associations below a stringent P value threshold corresponding to a 5% estimated false discovery rate. These included many previously identified causal effects, for instance, an adverse effect of higher BMI on risk of diabetes and hypertension. We also identified several novel effects, including protective effects of higher BMI on a set of psychosocial traits, identified initially in our preliminary MR-pheWAS in circa 115,000 UK Biobank participants and replicated in a different subset of circa 223,000 UK Biobank participants. Our comprehensive MR-pheWAS identified potential causal effects of BMI on a large and diverse set of phenotypes. This included both previously identified causal effects, and novel effects such as a protective effect of higher BMI on feelings of nervousness.Author summary: Mendelian randomization uses genetic variants associated with an exposure to investigate causality. For example, there are several genetic variants that have been robustly associated with body mass index, and these can be used to test whether body mass index causally affects other traits. Usually, Mendelian randomization studies focus on particular outcomes, for instance, estimating the causal effect of body mass index on blood pressure. However, a trait (such as body mass index) may be a modifiable, causal risk factor for outcomes where there is no prior reason to suggest that a causal effect exists. We recently published a novel tool called PHESANT, that allows comprehensive phenome scans to be performed, allowing researchers to search for the causal effects of a trait of interest across over 22,000 traits in UK Biobank. In this work we used PHESANT to search for the causal effects of body mass index. We identified previously established effects, for example, adverse effects of higher body mass index on risk of diabetes and hypertension. We also identified novel effects, such as a protective effect of higher body mass index on feelings of nervousness, and these need replicating in an independent sample and using other study designs.

Suggested Citation

  • Louise A C Millard & Neil M Davies & Kate Tilling & Tom R Gaunt & George Davey Smith, 2019. "Searching for the causal effects of body mass index in over 300 000 participants in UK Biobank, using Mendelian randomization," PLOS Genetics, Public Library of Science, vol. 15(2), pages 1-20, February.
  • Handle: RePEc:plo:pgen00:1007951
    DOI: 10.1371/journal.pgen.1007951
    as

    Download full text from publisher

    File URL: https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1007951
    Download Restriction: no

    File URL: https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1007951&type=printable
    Download Restriction: no

    File URL: https://libkey.io/10.1371/journal.pgen.1007951?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Børge G Nordestgaard & Tom M Palmer & Marianne Benn & Jeppe Zacho & Anne Tybjærg-Hansen & George Davey Smith & Nicholas J Timpson, 2012. "The Effect of Elevated Body Mass Index on Ischemic Heart Disease Risk: Causal Estimates from a Mendelian Randomisation Approach," PLOS Medicine, Public Library of Science, vol. 9(5), pages 1-13, May.
    2. Rebecca C Richmond & George Davey Smith & Andy R Ness & Marcel den Hoed & George McMahon & Nicholas J Timpson, 2014. "Assessing Causality in the Association between Child Adiposity and Physical Activity Levels: A Mendelian Randomization Analysis," PLOS Medicine, Public Library of Science, vol. 11(3), pages 1-16, March.
    3. Alastair J Noyce & Demis A Kia & Gibran Hemani & Aude Nicolas & T Ryan Price & Eduardo De Pablo-Fernandez & Philip C Haycock & Patrick A Lewis & Thomas Foltynie & George Davey Smith & International Pa, 2017. "Estimating the causal influence of body mass index on risk of Parkinson disease: A Mendelian randomisation study," PLOS Medicine, Public Library of Science, vol. 14(6), pages 1-19, June.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Massaro, Alessandro & Giardinelli, Vito O. M. & Cosoli, Gabriele & Magaletti, Nicola & Leogrande, Angelo, 2022. "The Prediction of Hypertension Risk," MPRA Paper 113242, University Library of Munich, Germany.
    2. Jie Huang & Jennifer E. Huffman & Yunfeng Huang & Ítalo Valle & Themistocles L. Assimes & Sridharan Raghavan & Benjamin F. Voight & Chang Liu & Albert-László Barabási & Rose D. L. Huang & Qin Hui & Xu, 2022. "Genomics and phenomics of body mass index reveals a complex disease network," Nature Communications, Nature, vol. 13(1), pages 1-10, December.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Artur Nagapetyan & Alexander Drozd & Dmitry Subbotovsky, 2023. "How to Determine the Optimal Number of Cardiologists in a Region?," Mathematics, MDPI, vol. 11(21), pages 1-23, October.
    2. Emyr Reisha Isaura & Yang-Ching Chen & Shwu-Huey Yang, 2018. "Pathways from Food Consumption Score to Cardiovascular Disease: A Seven-Year Follow-Up Study of Indonesian Adults," IJERPH, MDPI, vol. 15(8), pages 1-15, July.
    3. Emyr Reisha Isaura & Yang-Ching Chen & Shwu-Huey Yang, 2018. "The Association of Food Consumption Scores, Body Shape Index, and Hypertension in a Seven-Year Follow-Up among Indonesian Adults: A Longitudinal Study," IJERPH, MDPI, vol. 15(1), pages 1-12, January.
    4. Rikstje Wiersma & Esther Hartman & Hendrika Marike Boezen & Eva Corpeleijn, 2020. "Adiposity and High Blood Pressure during Childhood: A Prospective Analysis of the Role of Physical Activity Intensity and Sedentary Time in the GECKO Drenthe Cohort," IJERPH, MDPI, vol. 17(24), pages 1-14, December.
    5. Ditte Nørbo Sørensen & Torben Martinussen & Eric Tchetgen Tchetgen, 2019. "A causal proportional hazards estimator under homogeneous or heterogeneous selection in an IV setting," Lifetime Data Analysis: An International Journal Devoted to Statistical Methods and Applications for Time-to-Event Data, Springer, vol. 25(4), pages 639-659, October.
    6. Chibo Liu & Sihua Mou & Chunqin Pan, 2013. "The FTO Gene rs9939609 Polymorphism Predicts Risk of Cardiovascular Disease: A Systematic Review and Meta-Analysis," PLOS ONE, Public Library of Science, vol. 8(8), pages 1-7, August.
    7. Sarah L. Taylor & Robert J. Noonan & Zoe R. Knowles & Michael B. Owen & Bronagh McGrane & Whitney B. Curry & Stuart J. Fairclough, 2018. "Evaluation of a Pilot School-Based Physical Activity Clustered Randomised Controlled Trial—Active Schools: Skelmersdale," IJERPH, MDPI, vol. 15(5), pages 1-18, May.
    8. Lisa Stolzenberg & Stewart J. D’Alessio & Jamie L. Flexon, 2019. "The Impact of Violent Crime on Obesity," Social Sciences, MDPI, vol. 8(12), pages 1-12, December.
    9. David M Evans & Marie Jo A Brion & Lavinia Paternoster & John P Kemp & George McMahon & Marcus Munafò & John B Whitfield & Sarah E Medland & Grant W Montgomery & The GIANT consortium & The CRP consort, 2013. "Mining the Human Phenome Using Allelic Scores That Index Biological Intermediates," PLOS Genetics, Public Library of Science, vol. 9(10), pages 1-15, October.
    10. Haoran Xue & Wei Pan, 2020. "Inferring causal direction between two traits in the presence of horizontal pleiotropy with GWAS summary data," PLOS Genetics, Public Library of Science, vol. 16(11), pages 1-30, November.
    11. Taylor, Amy E. & Davies, Neil M. & Ware, Jennifer J. & VanderWeele, Tyler & Smith, George Davey & Munafò, Marcus R., 2014. "Mendelian randomization in health research: Using appropriate genetic variants and avoiding biased estimates," Economics & Human Biology, Elsevier, vol. 13(C), pages 99-106.
    12. Karen Schellong & Sandra Schulz & Thomas Harder & Andreas Plagemann, 2012. "Birth Weight and Long-Term Overweight Risk: Systematic Review and a Meta-Analysis Including 643,902 Persons from 66 Studies and 26 Countries Globally," PLOS ONE, Public Library of Science, vol. 7(10), pages 1-1, October.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:plo:pgen00:1007951. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: plosgenetics (email available below). General contact details of provider: https://journals.plos.org/plosgenetics/ .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.