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Quantifying the role of transcript levels in mediating DNA methylation effects on complex traits and diseases

Author

Listed:
  • Marie C. Sadler

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

  • Chiara Auwerx

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

  • Kaido Lepik

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

  • Eleonora Porcu

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

  • Zoltán Kutalik

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

Abstract

High-dimensional omics datasets provide valuable resources to determine the causal role of molecular traits in mediating the path from genotype to phenotype. Making use of molecular quantitative trait loci (QTL) and genome-wide association study (GWAS) summary statistics, we propose a multivariable Mendelian randomization (MVMR) framework to quantify the proportion of the impact of the DNA methylome (DNAm) on complex traits that is propagated through the assayed transcriptome. Evaluating 50 complex traits, we find that on average at least 28.3% (95% CI: [26.9%–29.8%]) of DNAm-to-trait effects are mediated through (typically multiple) transcripts in the cis-region. Several regulatory mechanisms are hypothesized, including methylation of the promoter probe cg10385390 (chr1:8’022’505) increasing the risk for inflammatory bowel disease by reducing PARK7 expression. The proposed integrative framework can be extended to other omics layers to identify causal molecular chains, providing a powerful tool to map and interpret GWAS signals.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35196-3
    DOI: 10.1038/s41467-022-35196-3
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    1. Clare Bycroft & Colin Freeman & Desislava Petkova & Gavin Band & Lloyd T. Elliott & Kevin Sharp & Allan Motyer & Damjan Vukcevic & Olivier Delaneau & Jared O’Connell & Adrian Cortes & Samantha Welsh &, 2018. "The UK Biobank resource with deep phenotyping and genomic data," Nature, Nature, vol. 562(7726), pages 203-209, October.
    2. Verena Zuber & Johanna Maria Colijn & Caroline Klaver & Stephen Burgess, 2020. "Selecting likely causal risk factors from high-throughput experiments using multivariable Mendelian randomization," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    3. Christian Gieger & Aparna Radhakrishnan & Ana Cvejic & Weihong Tang & Eleonora Porcu & Giorgio Pistis & Jovana Serbanovic-Canic & Ulrich Elling & Alison H. Goodall & Yann Labrune & Lorna M. Lopez & Re, 2011. "New gene functions in megakaryopoiesis and platelet formation," Nature, Nature, vol. 480(7376), pages 201-208, December.
    4. 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.
    5. 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.
    6. Eleonora Porcu & Sina Rüeger & Kaido Lepik & Federico A. Santoni & Alexandre Reymond & Zoltán Kutalik, 2019. "Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    7. Benjamin B. Sun & Joseph C. Maranville & James E. Peters & David Stacey & James R. Staley & James Blackshaw & Stephen Burgess & Tao Jiang & Ellie Paige & Praveen Surendran & Clare Oliver-Williams & Mi, 2018. "Genomic atlas of the human plasma proteome," Nature, Nature, vol. 558(7708), pages 73-79, June.
    8. Zhihong Zhu & Zhili Zheng & Futao Zhang & Yang Wu & Maciej Trzaskowski & Robert Maier & Matthew R. Robinson & John J. McGrath & Peter M. Visscher & Naomi R. Wray & Jian Yang, 2018. "Causal associations between risk factors and common diseases inferred from GWAS summary data," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    9. Eleonora Porcu & Marie C. Sadler & Kaido Lepik & Chiara Auwerx & Andrew R. Wood & Antoine Weihs & Maroun S. Bou Sleiman & Diogo M. Ribeiro & Stefania Bandinelli & Toshiko Tanaka & Matthias Nauck & Uwe, 2021. "Differentially expressed genes reflect disease-induced rather than disease-causing changes in the transcriptome," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    10. Yang Wu & Jian Zeng & Futao Zhang & Zhihong Zhu & Ting Qi & Zhili Zheng & Luke R. Lloyd-Jones & Riccardo E. Marioni & Nicholas G. Martin & Grant W. Montgomery & Ian J. Deary & Naomi R. Wray & Peter M., 2018. "Integrative analysis of omics summary data reveals putative mechanisms underlying complex traits," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    11. Diego Garrido-Martín & Beatrice Borsari & Miquel Calvo & Ferran Reverter & Roderic Guigó, 2021. "Identification and analysis of splicing quantitative trait loci across multiple tissues in the human genome," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
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