IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-45655-8.html
   My bibliography  Save this article

PheWAS-based clustering of Mendelian Randomisation instruments reveals distinct mechanism-specific causal effects between obesity and educational attainment

Author

Listed:
  • Liza Darrous

    (University Center for Primary Care and Public Health
    Swiss Institute of Bioinformatics
    University of Lausanne)

  • Gibran Hemani

    (University of Bristol
    University of Bristol)

  • George Davey Smith

    (University of Bristol
    University of Bristol)

  • Zoltán Kutalik

    (University Center for Primary Care and Public Health
    Swiss Institute of Bioinformatics
    University of Lausanne)

Abstract

Mendelian Randomisation (MR) estimates causal effects between risk factors and complex outcomes using genetic instruments. Pleiotropy, heritable confounders, and heterogeneous causal effects violate MR assumptions and can lead to biases. To alleviate these, we propose an approach employing a Phenome-Wide association Clustering of the MR instruments (PWC-MR) and apply this method to revisit the surprisingly large apparent causal effect of body mass index (BMI) on educational attainment (EDU): $$\widehat{\alpha }$$ α ̂ = −0.19 [−0.22, −0.16]. First, we cluster 324 BMI-associated genetic instruments based on their association with 407 traits in the UK Biobank, which yields six distinct groups. Subsequent cluster-specific MR reveals heterogeneous causal effect estimates on EDU. A cluster enriched for socio-economic indicators yields the largest BMI-on-EDU causal effect estimate ( $$\widehat{\alpha }$$ α ̂ = −0.49 [−0.56, −0.42]) whereas a cluster enriched for body-mass specific traits provides a more likely estimate ( $$\widehat{\alpha }$$ α ̂ = −0.09 [−0.13, −0.05]). Follow-up analyses confirms these findings: within-sibling MR ( $$\widehat{\alpha }$$ α ̂ = −0.05 [−0.09, −0.01]); MR for childhood BMI on EDU ( $$\widehat{\alpha }$$ α ̂ = −0.03 [−0.06, −0.002]); step-wise multivariable MR ( $$\widehat{\alpha }$$ α ̂ = −0.05 [−0.07, −0.02]) where socio-economic indicators are jointly modelled. Here we show how the in-depth examination of the BMI-EDU causal relationship demonstrates the utility of our PWC-MR approach in revealing distinct pleiotropic pathways and confounder mechanisms.

Suggested Citation

  • Liza Darrous & Gibran Hemani & George Davey Smith & Zoltán Kutalik, 2024. "PheWAS-based clustering of Mendelian Randomisation instruments reveals distinct mechanism-specific causal effects between obesity and educational attainment," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45655-8
    DOI: 10.1038/s41467-024-45655-8
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-45655-8
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-45655-8?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. Matthew R. Robinson & Aaron Kleinman & Mariaelisa Graff & Anna A. E. Vinkhuyzen & David Couper & Michael B. Miller & Wouter J. Peyrot & Abdel Abdellaoui & Brendan P. Zietsch & Ilja M. Nolte & Jana V. , 2017. "Genetic evidence of assortative mating in humans," Nature Human Behaviour, Nature, vol. 1(1), pages 1-13, January.
    2. Claudia Giambartolomei & Damjan Vukcevic & Eric E Schadt & Lude Franke & Aroon D Hingorani & Chris Wallace & Vincent Plagnol, 2014. "Bayesian Test for Colocalisation between Pairs of Genetic Association Studies Using Summary Statistics," PLOS Genetics, Public Library of Science, vol. 10(5), pages 1-15, May.
    3. Simon Haworth & Ruth Mitchell & Laura Corbin & Kaitlin H. Wade & Tom Dudding & Ashley Budu-Aggrey & David Carslake & Gibran Hemani & Lavinia Paternoster & George Davey Smith & Neil Davies & Daniel J. , 2019. "Apparent latent structure within the UK Biobank sample has implications for epidemiological analysis," Nature Communications, Nature, vol. 10(1), pages 1-9, December.
    4. Loïc Yengo & Sailaja Vedantam & Eirini Marouli & Julia Sidorenko & Eric Bartell & Saori Sakaue & Marielisa Graff & Anders U. Eliasen & Yunxuan Jiang & Sridharan Raghavan & Jenkai Miao & Joshua D. Aria, 2022. "A saturated map of common genetic variants associated with human height," Nature, Nature, vol. 610(7933), pages 704-712, October.
    5. Ben Brumpton & Eleanor Sanderson & Karl Heilbron & Fernando Pires Hartwig & Sean Harrison & Gunnhild Åberge Vie & Yoonsu Cho & Laura D. Howe & Amanda Hughes & Dorret I. Boomsma & Alexandra Havdahl & J, 2020. "Avoiding dynastic, assortative mating, and population stratification biases in Mendelian randomization through within-family analyses," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    6. Liza Darrous & Ninon Mounier & Zoltán Kutalik, 2021. "Simultaneous estimation of bi-directional causal effects and heritable confounding from GWAS summary statistics," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    7. Gibran Hemani & Kate Tilling & George Davey Smith, 2017. "Orienting the causal relationship between imprecisely measured traits using GWAS summary data," PLOS Genetics, Public Library of Science, vol. 13(11), pages 1-22, November.
    8. Laurence J. Howe & Daniel J. Lawson & Neil M. Davies & Beate St. Pourcain & Sarah J. Lewis & George Davey Smith & Gibran Hemani, 2019. "Genetic evidence for assortative mating on alcohol consumption in the UK Biobank," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    Full references (including those not matched with items on IDEAS)

    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. Jennifer Sjaarda & Zoltán Kutalik, 2023. "Partner choice, confounding and trait convergence all contribute to phenotypic partner similarity," Nature Human Behaviour, Nature, vol. 7(5), pages 776-789, May.
    2. Yuandan Wei & Jianxin Zhen & Liang Hu & Yuqin Gu & Yanhong Liu & Xinxin Guo & Zijing Yang & Hao Zheng & Shiyao Cheng & Fengxiang Wei & Likuan Xiong & Siyang Liu, 2024. "Genome-wide association studies of thyroid-related hormones, dysfunction, and autoimmunity among 85,421 Chinese pregnancies," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Grace Png & Andrei Barysenka & Linda Repetto & Pau Navarro & Xia Shen & Maik Pietzner & Eleanor Wheeler & Nicholas J. Wareham & Claudia Langenberg & Emmanouil Tsafantakis & Maria Karaleftheri & George, 2021. "Mapping the serum proteome to neurological diseases using whole genome sequencing," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    4. Wenhan Chen & Yang Wu & Zhili Zheng & Ting Qi & Peter M. Visscher & Zhihong Zhu & Jian Yang, 2021. "Improved analyses of GWAS summary statistics by reducing data heterogeneity and errors," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    5. Eva-Maria Stauffer & Richard A. I. Bethlehem & Lena Dorfschmidt & Hyejung Won & Varun Warrier & Edward T. Bullmore, 2023. "The genetic relationships between brain structure and schizophrenia," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    6. Mattia Marchi & Anne Alkema & Charley Xia & Chris H. L. Thio & Li-Yu Chen & Winni Schalkwijk & Gian M. Galeazzi & Silvia Ferrari & Luca Pingani & Hyeokmoon Kweon & Sara Evans-Lacko & W. David Hill & M, 2024. "Investigating the impact of poverty on mental illness in the UK Biobank using Mendelian randomization," Nature Human Behaviour, Nature, vol. 8(9), pages 1771-1783, September.
    7. Hazewinkel, Audinga-Dea & Richmond, Rebecca C. & Wade, Kaitlin H. & Dixon, Padraig, 2022. "Mendelian randomization analysis of the causal impact of body mass index and waist-hip ratio on rates of hospital admission," Economics & Human Biology, Elsevier, vol. 44(C).
    8. David Stacey & Lingyan Chen & Paulina J. Stanczyk & Joanna M. M. Howson & Amy M. Mason & Stephen Burgess & Stephen MacDonald & Jonathan Langdown & Harriett McKinney & Kate Downes & Neda Farahi & James, 2022. "Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    9. Molly Went & Laura Duran-Lozano & Gisli H. Halldorsson & Andrea Gunnell & Nerea Ugidos-Damboriena & Philip Law & Ludvig Ekdahl & Amit Sud & Gudmar Thorleifsson & Malte Thodberg & Thorunn Olafsdottir &, 2024. "Deciphering the genetics and mechanisms of predisposition to multiple myeloma," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    10. Danielle Rasooly & Gina M. Peloso & Alexandre C. Pereira & Hesam Dashti & Claudia Giambartolomei & Eleanor Wheeler & Nay Aung & Brian R. Ferolito & Maik Pietzner & Eric H. Farber-Eger & Quinn Stanton , 2023. "Genome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failure," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    11. Abolfazl Doostparast Torshizi & Dongnhu T. Truong & Liping Hou & Bart Smets & Christopher D. Whelan & Shuwei Li, 2024. "Proteogenomic network analysis reveals dysregulated mechanisms and potential mediators in Parkinson’s disease," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    12. Lucas A. Mavromatis & Daniel B. Rosoff & Andrew S. Bell & Jeesun Jung & Josephin Wagner & Falk W. Lohoff, 2023. "Multi-omic underpinnings of epigenetic aging and human longevity," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    13. Fartein Ask Torvik & Espen Moen Eilertsen & Laurie J. Hannigan & Rosa Cheesman & Laurence J. Howe & Per Magnus & Ted Reichborn-Kjennerud & Ole A. Andreassen & Pål R. Njølstad & Alexandra Havdahl & Eiv, 2022. "Modeling assortative mating and genetic similarities between partners, siblings, and in-laws," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    14. Kenichi Yamamoto & Kyuto Sonehara & Shinichi Namba & Takahiro Konuma & Hironori Masuko & Satoru Miyawaki & Yoichiro Kamatani & Nobuyuki Hizawa & Keiichi Ozono & Loic Yengo & Yukinori Okada, 2023. "Genetic footprints of assortative mating in the Japanese population," Nature Human Behaviour, Nature, vol. 7(1), pages 65-73, January.
    15. Stephanie von Hinke & Nicolai Vitt, 2024. "An analysis of the accuracy of retrospective birth location recall using sibling data," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    16. Thomas Battram & Tom R. Gaunt & Caroline L. Relton & Nicholas J. Timpson & Gibran Hemani, 2022. "A comparison of the genes and genesets identified by GWAS and EWAS of fifteen complex traits," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    17. Marie C. Sadler & Chiara Auwerx & Kaido Lepik & Eleonora Porcu & Zoltán Kutalik, 2022. "Quantifying the role of transcript levels in mediating DNA methylation effects on complex traits and diseases," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    18. Molly Went & Amit Sud & Charlie Mills & Abi Hyde & Richard Culliford & Philip Law & Jayaram Vijayakrishnan & Ines Gockel & Carlo Maj & Johannes Schumacher & Claire Palles & Martin Kaiser & Richard Hou, 2024. "Phenome-wide Mendelian randomisation analysis of 378,142 cases reveals risk factors for eight common cancers," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    19. Eeva Sliz & Jaakko S. Tyrmi & Nilufer Rahmioglu & Krina T. Zondervan & Christian M. Becker & Outi Uimari & Johannes Kettunen, 2023. "Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    20. Jacob Joseph & Chang Liu & Qin Hui & Krishna Aragam & Zeyuan Wang & Brian Charest & Jennifer E. Huffman & Jacob M. Keaton & Todd L. Edwards & Serkalem Demissie & Luc Djousse & Juan P. Casas & J. Micha, 2022. "Genetic architecture of heart failure with preserved versus reduced ejection fraction," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

    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:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45655-8. 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: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    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.