Nature Communications (Aug 2023)
Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits
- Andrew A. Brown,
- Juan J. Fernandez-Tajes,
- Mun-gwan Hong,
- Caroline A. Brorsson,
- Robert W. Koivula,
- David Davtian,
- Théo Dupuis,
- Ambra Sartori,
- Theodora-Dafni Michalettou,
- Ian M. Forgie,
- Jonathan Adam,
- Kristine H. Allin,
- Robert Caiazzo,
- Henna Cederberg,
- Federico De Masi,
- Petra J. M. Elders,
- Giuseppe N. Giordano,
- Mark Haid,
- Torben Hansen,
- Tue H. Hansen,
- Andrew T. Hattersley,
- Alison J. Heggie,
- Cédric Howald,
- Angus G. Jones,
- Tarja Kokkola,
- Markku Laakso,
- Anubha Mahajan,
- Andrea Mari,
- Timothy J. McDonald,
- Donna McEvoy,
- Miranda Mourby,
- Petra B. Musholt,
- Birgitte Nilsson,
- Francois Pattou,
- Deborah Penet,
- Violeta Raverdy,
- Martin Ridderstråle,
- Luciana Romano,
- Femke Rutters,
- Sapna Sharma,
- Harriet Teare,
- Leen ‘t Hart,
- Konstantinos D. Tsirigos,
- Jagadish Vangipurapu,
- Henrik Vestergaard,
- Søren Brunak,
- Paul W. Franks,
- Gary Frost,
- Harald Grallert,
- Bernd Jablonka,
- Mark I. McCarthy,
- Imre Pavo,
- Oluf Pedersen,
- Hartmut Ruetten,
- Mark Walker,
- The DIRECT Consortium,
- Jerzy Adamski,
- Jochen M. Schwenk,
- Ewan R. Pearson,
- Emmanouil T. Dermitzakis,
- Ana Viñuela
Affiliations
- Andrew A. Brown
- Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee
- Juan J. Fernandez-Tajes
- Wellcome Trust Centre for Human Genetics, University of Oxford
- Mun-gwan Hong
- Science for Life Laboratory, School of Biotechnology, KTH - Royal Institute of Technology
- Caroline A. Brorsson
- Department of Health Technology, Technical University of Denmark
- Robert W. Koivula
- Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford
- David Davtian
- Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee
- Théo Dupuis
- Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee
- Ambra Sartori
- Department of Genetic Medicine and Development, University of Geneva Medical School
- Theodora-Dafni Michalettou
- Biosciences Institute, Faculty of Medical Sciences, University of Newcastle
- Ian M. Forgie
- Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee
- Jonathan Adam
- German Center for Diabetes Research (DZD)
- Kristine H. Allin
- The Novo Nordisk Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen
- Robert Caiazzo
- University of Lille, Inserm, Lille Pasteur Institute
- Henna Cederberg
- Internal Medicine, Institute of Clinical Medicine, University of Eastern Finland
- Federico De Masi
- Department of Health Technology, Technical University of Denmark
- Petra J. M. Elders
- Department of General Practice, Amsterdam UMC- location Vumc, Amsterdam Public Health research institute
- Giuseppe N. Giordano
- Department of Clinical Science, Genetic and Molecular Epidemiology, Lund University Diabetes Centre
- Mark Haid
- Metabolomics and Proteomics Core, German Research Center for Environmental Health, Helmholtz Zentrum München
- Torben Hansen
- The Novo Nordisk Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen
- Tue H. Hansen
- The Novo Nordisk Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen
- Andrew T. Hattersley
- Department of Clinical and Biomedical Sciences, University of Exeter College of Medicine & Health
- Alison J. Heggie
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University
- Cédric Howald
- Department of Genetic Medicine and Development, University of Geneva Medical School
- Angus G. Jones
- Department of Clinical and Biomedical Sciences, University of Exeter College of Medicine & Health
- Tarja Kokkola
- Internal Medicine, Institute of Clinical Medicine, University of Eastern Finland
- Markku Laakso
- Internal Medicine, Institute of Clinical Medicine, University of Eastern Finland
- Anubha Mahajan
- Wellcome Trust Centre for Human Genetics, University of Oxford
- Andrea Mari
- Institute of Neuroscience, National Research Council
- Timothy J. McDonald
- Blood Sciences, Royal Devon and Exeter NHS Foundation Trust
- Donna McEvoy
- Diabetes Research Network, Royal Victoria Infirmary
- Miranda Mourby
- Nuffield Department of Population Health, Centre for Health, Law and Emerging Technologies (HeLEX), University of Oxford
- Petra B. Musholt
- Global Development, Sanofi-Aventis Deutschland GmbH, Hoechst Industrial Park
- Birgitte Nilsson
- Department of Health Technology, Technical University of Denmark
- Francois Pattou
- University of Lille, Inserm, Lille Pasteur Institute
- Deborah Penet
- Department of Genetic Medicine and Development, University of Geneva Medical School
- Violeta Raverdy
- University of Lille, Inserm, Lille Pasteur Institute
- Martin Ridderstråle
- Department of Clinical Science, Lund University
- Luciana Romano
- Department of Genetic Medicine and Development, University of Geneva Medical School
- Femke Rutters
- Epidemiology and Data Science, VUMC
- Sapna Sharma
- Research Unit of Molecular Epidemiology, Institute of Epidemiology, German Research Center for Environmental Health, Helmholtz Zentrum München
- Harriet Teare
- Centre for Health Law and Emerging Technologies, Department of Population Health, University of Oxford
- Leen ‘t Hart
- Epidemiology and Data Science, VUMC
- Konstantinos D. Tsirigos
- Department of Health Technology, Technical University of Denmark
- Jagadish Vangipurapu
- Internal Medicine, Institute of Clinical Medicine, University of Eastern Finland
- Henrik Vestergaard
- The Novo Nordisk Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen
- Søren Brunak
- Department of Health Technology, Technical University of Denmark
- Paul W. Franks
- Department of Clinical Science, Genetic and Molecular Epidemiology, Lund University Diabetes Centre
- Gary Frost
- Nutrition and Dietetics Research Group, Imperial College London
- Harald Grallert
- German Center for Diabetes Research (DZD)
- Bernd Jablonka
- Sanofi Partnering, Sanofi-Aventis Deutschland GmbH
- Mark I. McCarthy
- Wellcome Trust Centre for Human Genetics, University of Oxford
- Imre Pavo
- Eli Lilly Regional Operations Ges.m.b.H
- Oluf Pedersen
- Center for Clinical Metabolic Research, Herlev and Gentofte University Hospital
- Hartmut Ruetten
- Sanofi Partnering, Sanofi-Aventis Deutschland GmbH
- Mark Walker
- Translational and Clinical Research Institute, Faculty of Medical Sciences, University of Newcastle
- The DIRECT Consortium
- Jerzy Adamski
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore
- Jochen M. Schwenk
- Science for Life Laboratory, School of Biotechnology, KTH - Royal Institute of Technology
- Ewan R. Pearson
- Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee
- Emmanouil T. Dermitzakis
- Department of Genetic Medicine and Development, University of Geneva Medical School
- Ana Viñuela
- Biosciences Institute, Faculty of Medical Sciences, University of Newcastle
- DOI
- https://doi.org/10.1038/s41467-023-40569-3
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 17
Abstract
Abstract We evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic regions. The highest proportion of share genetic regulation is detected between gene expression and proteins (66.6%), with a further median shared genetic associations across 49 different tissues of 78.3% and 62.4% between plasma proteins and gene expression. We represent the genetic and molecular associations in networks including 2828 known GWAS variants, showing that GWAS variants are more often connected to gene expression in trans than other molecular phenotypes in the network. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants using different molecular phenotypes in an accessible tissue.
