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

Nature Communications, vol. 11, pp. 4930

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.

Authors 12

1. Adriaan van der Graaf

   University Medical Center Groningen · University of Groningen

   Affiliation as printed

   University of Groningen, University Medical Centre Groningen, Department of Genetics, Antonius Deusinglaan 1, 9713, Groningen, AV, The Netherlands

   UMCG - University Medical Center Groningen [Groningen] (PO box 30.001 9700 RB Groningen - Netherlands)

   University of Groningen [Groningen] (PO Box 72 , 9700 AB Groningen - Netherlands)

2. Annique Claringbould

   University Medical Center Groningen · University of Groningen · Oncode Institute

   Affiliation as printed

   Oncode institute, Office Jaarbeurs Innovation Mile (JIM), Jaarbeursplein 6, 3521, Utrecht, AL, The Netherlands

   University of Groningen, University Medical Centre Groningen, Department of Genetics, Antonius Deusinglaan 1, 9713, Groningen, AV, The Netherlands

   Oncode Institute [Utrecht]

   UMCG - University Medical Center Groningen [Groningen] (PO box 30.001 9700 RB Groningen - Netherlands)

   University of Groningen [Groningen] (PO Box 72 , 9700 AB Groningen - Netherlands)

3. Antoine Rimbert

   Centre National de la Recherche Scientifique · University Medical Center Groningen · Inserm · University of Groningen · Institut du Thorax · Université de Nantes · Nantes Université

   Affiliation as printed

   University of Groningen, University Medical Centre Groningen, Department of Pediatrics, Section Molecular Genetics, Antonius Deusinglaan 1, 9713, Groningen, AV, The Netherlands

   Université de Nantes, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France

   ITX - ITX - unité de recherche de l'institut du thorax (8 quai Moncousu - BP 70721 - 44007 Nantes Cedex 1 - France)

   UMCG - University Medical Center Groningen [Groningen] (PO box 30.001 9700 RB Groningen - Netherlands)

   University of Groningen [Groningen] (PO Box 72 , 9700 AB Groningen - Netherlands)

4. Bastiaan T. Heijmans Aachen Molecular Epidemiology Department of Biomedical Data Sciences

   Leiden University Medical Center

   Affiliation as printed

   Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, The Netherlands

5. Peter A.C. ’t Hoen Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, The Netherlands

6. Joyce B. J. van Meurs

   Erasmus MC

   Affiliation as printed

   Department of Internal Medicine, Erasmus MC, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands

7. Rick Jansen

   Amsterdam Neuroscience · Amsterdam UMC Location Vrije Universiteit Amsterdam

   Affiliation as printed

   Department of Psychiatry, VU University Medical Center, Neuroscience Campus Amsterdam, De Boelelaan 1118, 1081 HV, Amsterdam, The Netherlands

8. Lude Franke

   University Medical Center Groningen · University of Groningen · Oncode Institute

   Affiliation as printed

   Oncode institute, Office Jaarbeurs Innovation Mile (JIM), Jaarbeursplein 6, 3521, Utrecht, AL, The Netherlands

   University of Groningen, University Medical Centre Groningen, Department of Genetics, Antonius Deusinglaan 1, 9713, Groningen, AV, The Netherlands

9. Harm-Jan Westra

   University Medical Center Groningen · University of Groningen · Oncode Institute

   Affiliation as printed

   Oncode institute, Office Jaarbeurs Innovation Mile (JIM), Jaarbeursplein 6, 3521, Utrecht, AL, The Netherlands

   University of Groningen, University Medical Centre Groningen, Department of Genetics, Antonius Deusinglaan 1, 9713, Groningen, AV, The Netherlands

   Oncode Institute [Utrecht]

   UMCG - University Medical Center Groningen [Groningen] (PO box 30.001 9700 RB Groningen - Netherlands)

   University of Groningen [Groningen] (PO Box 72 , 9700 AB Groningen - Netherlands)

10. Yang Li

    University Medical Center Groningen · Radboud University Nijmegen · University of Groningen · Radboud University Medical Center · Medizinische Hochschule Hannover · Helmholtz Centre for Infection Research · Centre for Individualised Infection Medicine · Center for Experimental and Clinical Infection Research

    Affiliation as printed

    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), 30625, Hannover, Germany

    Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525, Nijmegen, HP, The Netherlands

    University of Groningen, University Medical Centre Groningen, Department of Genetics, Antonius Deusinglaan 1, 9713, Groningen, AV, The Netherlands

    HZI - Helmholtz Centre for Infection Research (Inhoffenstraße 7, 38124 Braunschweig - Germany)

    MHH - Medizinische Hochschule Hannover = Hannover Medical School (Carl-Neuberg-Straße 1, 30625 Hannover, - Germany)

    Radboud University Medical Center [Nijmegen] (6500 HB Nijmegen - Netherlands)

    UMCG - University Medical Center Groningen [Groningen] (PO box 30.001 9700 RB Groningen - Netherlands)

    University of Groningen [Groningen] (PO Box 72 , 9700 AB Groningen - Netherlands)

11. Cisca Wijmenga

    University Medical Center Groningen · University of Groningen

    Affiliation as printed

    University of Groningen, University Medical Centre Groningen, Department of Genetics, Antonius Deusinglaan 1, 9713, Groningen, AV, The Netherlands

    UMCG - University Medical Center Groningen [Groningen] (PO box 30.001 9700 RB Groningen - Netherlands)

    University of Groningen [Groningen] (PO Box 72 , 9700 AB Groningen - Netherlands)

12. Serena Sanna corresponding

    University Medical Center Groningen · University of Groningen · Institute of Genetic and Biomedical Research · National Research Council

    Affiliation as printed

    Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche (CNR), Cittadella Universitaria di Monserrato, 09042, Monserrato, Italy. serena.sanna@irgb.cnr.it

    University of Groningen, University Medical Centre Groningen, Department of Genetics, Antonius Deusinglaan 1, 9713, Groningen, AV, The Netherlands. serena.sanna@irgb.cnr.it

    IRGB - Istituto di Ricerca Genetica e Biomedica (Cittadella Universitaria di Cagliari - SS 554 Km 4,500, 09042 Monserrato Cagliari, Italie - Italy)

    UMCG - University Medical Center Groningen [Groningen] (PO box 30.001 9700 RB Groningen - Netherlands)

    University of Groningen [Groningen] (PO Box 72 , 9700 AB Groningen - Netherlands)