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Mendelian randomization while jointly modeling cis genetics identifies causal relationships between gene expression and lipids

Author

Listed:
  • Adriaan Graaf

    (University of Groningen, University Medical Centre Groningen, Department of Genetics)

  • Annique Claringbould

    (University of Groningen, University Medical Centre Groningen, Department of Genetics
    Oncode institute, Office Jaarbeurs Innovation Mile (JIM))

  • Antoine Rimbert

    (University of Groningen, University Medical Centre Groningen, Department of Pediatrics, Section Molecular Genetics
    Université de Nantes, CNRS, INSERM, l’institut du thorax)

  • Harm-Jan Westra

    (University of Groningen, University Medical Centre Groningen, Department of Genetics
    Oncode institute, Office Jaarbeurs Innovation Mile (JIM))

  • Yang Li

    (University of Groningen, University Medical Centre Groningen, Department of Genetics
    Department of Computational Biology for Individualised Infection Medicine, Centre for Individualised Infection Medicine (CiiM) & TWINCORE, joint ventures between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH)
    Radboud University Medical Center)

  • Cisca Wijmenga

    (University of Groningen, University Medical Centre Groningen, Department of Genetics)

  • Serena Sanna

    (University of Groningen, University Medical Centre Groningen, Department of Genetics
    Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche (CNR), Cittadella Universitaria di Monserrato)

Abstract

Inference of causality between gene expression and complex traits using Mendelian randomization (MR) is confounded by pleiotropy and linkage disequilibrium (LD) of gene-expression quantitative trait loci (eQTL). Here, we propose an MR method, MR-link, that accounts for unobserved pleiotropy and LD by leveraging information from individual-level data, even when only one eQTL variant is present. In simulations, MR-link shows false-positive rates close to expectation (median 0.05) and high power (up to 0.89), outperforming all other tested MR methods and coloc. Application of MR-link to low-density lipoprotein cholesterol (LDL-C) measurements in 12,449 individuals with expression and protein QTL summary statistics from blood and liver identifies 25 genes causally linked to LDL-C. These include the known SORT1 and ApoE genes as well as PVRL2, located in the APOE locus, for which a causal role in liver was not known. Our results showcase the strength of MR-link for transcriptome-wide causal inferences.

Suggested Citation

  • Adriaan Graaf & Annique Claringbould & Antoine Rimbert & Harm-Jan Westra & Yang Li & Cisca Wijmenga & Serena Sanna, 2020. "Mendelian randomization while jointly modeling cis genetics identifies causal relationships between gene expression and lipids," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18716-x
    DOI: 10.1038/s41467-020-18716-x
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    Cited by:

    1. M d Mesbah Uddin & Ngoc Quynh H. Nguyen & Bing Yu & Jennifer A. Brody & Akhil Pampana & Tetsushi Nakao & Myriam Fornage & Jan Bressler & Nona Sotoodehnia & Joshua S. Weinstock & Michael C. Honigberg &, 2022. "Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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