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Systematic discovery of gene-environment interactions underlying the human plasma proteome in UK Biobank

Author

Listed:
  • Robert F. Hillary

    (Optima Partners
    University of Edinburgh
    Biogen Inc.)

  • Danni A. Gadd

    (Optima Partners
    University of Edinburgh
    Biogen Inc.)

  • Zhana Kuncheva

    (Optima Partners
    Biogen Inc.
    The University of Edinburgh)

  • Tasos Mangelis

    (Optima Partners
    Biogen Inc.
    The University of Edinburgh)

  • Tinchi Lin

    (Biogen Inc.)

  • Kyle Ferber

    (Biogen Inc.)

  • Helen McLaughlin

    (Biogen Inc.)

  • Heiko Runz

    (Biogen Inc.)

  • Riccardo E. Marioni

    (Optima Partners
    University of Edinburgh
    Biogen Inc.)

  • Christopher N. Foley

    (Optima Partners
    Biogen Inc.
    The University of Edinburgh)

  • Benjamin B. Sun

    (Biogen Inc.
    University of Cambridge)

Abstract

Understanding how gene-environment interactions (GEIs) influence the circulating proteome could aid in biomarker discovery and validation. The presence of GEIs can be inferred from single nucleotide polymorphisms that associate with phenotypic variability - termed variance quantitative trait loci (vQTLs). Here, vQTL association studies are performed on plasma levels of 1463 proteins in 52,363 UK Biobank participants. A set of 677 independent vQTLs are identified across 568 proteins. They include 67 variants that lack conventional additive main effects on protein levels. Over 1100 GEIs are identified between 101 proteins and 153 environmental exposures. GEI analyses uncover possible mechanisms that explain why 13/67 vQTL-only sites lack corresponding main effects. Additional analyses also highlight how age, sex, epistatic interactions and statistical artefacts may underscore associations between genetic variation and variance heterogeneity. This study establishes the most comprehensive database yet of vQTLs and GEIs for the human proteome.

Suggested Citation

  • Robert F. Hillary & Danni A. Gadd & Zhana Kuncheva & Tasos Mangelis & Tinchi Lin & Kyle Ferber & Helen McLaughlin & Heiko Runz & Riccardo E. Marioni & Christopher N. Foley & Benjamin B. Sun, 2024. "Systematic discovery of gene-environment interactions underlying the human plasma proteome in UK Biobank," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51744-5
    DOI: 10.1038/s41467-024-51744-5
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    1. Chen Yao & George Chen & Ci Song & Joshua Keefe & Michael Mendelson & Tianxiao Huan & Benjamin B. Sun & Annika Laser & Joseph C. Maranville & Hongsheng Wu & Jennifer E. Ho & Paul Courchesne & Asya Lya, 2018. "Author Correction: Genome‐wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease," Nature Communications, Nature, vol. 9(1), pages 1-1, December.
    2. Karsten Suhre & Matthias Arnold & Aditya Mukund Bhagwat & Richard J. Cotton & Rudolf Engelke & Johannes Raffler & Hina Sarwath & Gaurav Thareja & Annika Wahl & Robert Kirk DeLisle & Larry Gold & Marij, 2017. "Connecting genetic risk to disease end points through the human blood plasma proteome," Nature Communications, Nature, vol. 8(1), pages 1-14, April.
    3. 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.
    4. Guillaume Paré & Nancy R Cook & Paul M Ridker & Daniel I Chasman, 2010. "On the Use of Variance per Genotype as a Tool to Identify Quantitative Trait Interaction Effects: A Report from the Women's Genome Health Study," PLOS Genetics, Public Library of Science, vol. 6(6), pages 1-10, June.
    5. 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.
    6. Jian Yang & Ruth J. F. Loos & Joseph E. Powell & Sarah E. Medland & Elizabeth K. Speliotes & Daniel I. Chasman & Lynda M. Rose & Gudmar Thorleifsson & Valgerdur Steinthorsdottir & Reedik Mägi & Lindsa, 2012. "FTO genotype is associated with phenotypic variability of body mass index," Nature, Nature, vol. 490(7419), pages 267-272, October.
    7. Chen Yao & George Chen & Ci Song & Joshua Keefe & Michael Mendelson & Tianxiao Huan & Benjamin B. Sun & Annika Laser & Joseph C. Maranville & Hongsheng Wu & Jennifer E. Ho & Paul Courchesne & Asya Lya, 2018. "Genome‐wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    8. Kenneth E. Westerman & Timothy D. Majarian & Franco Giulianini & Dong-Keun Jang & Jenkai Miao & Jose C. Florez & Han Chen & Daniel I. Chasman & Miriam S. Udler & Alisa K. Manning & Joanne B. Cole, 2022. "Variance-quantitative trait loci enable systematic discovery of gene-environment interactions for cardiometabolic serum biomarkers," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    9. Benjamin B. Sun & Joshua Chiou & Matthew Traylor & Christian Benner & Yi-Hsiang Hsu & Tom G. Richardson & Praveen Surendran & Anubha Mahajan & Chloe Robins & Steven G. Vasquez-Grinnell & Liping Hou & , 2023. "Plasma proteomic associations with genetics and health in the UK Biobank," Nature, Nature, vol. 622(7982), pages 329-338, October.
    10. Karsten Suhre & Matthias Arnold & Aditya Mukund Bhagwat & Richard J. Cotton & Rudolf Engelke & Johannes Raffler & Hina Sarwath & Gaurav Thareja & Annika Wahl & Robert Kirk DeLisle & Larry Gold & Marij, 2017. "Erratum: Connecting genetic risk to disease end points through the human blood plasma proteome," Nature Communications, Nature, vol. 8(1), pages 1-1, April.
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