Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-08-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-40569-3 |
| _version_ | 1827710012266381312 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Andrew A. Brown |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T17:31:14Z |
| format | Article |
| id | doaj.art-03b888dddec54ecd93647492ab5dd5aa |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:31:14Z |
| publishDate | 2023-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-03b888dddec54ecd93647492ab5dd5aa2023-11-20T09:59:41ZengNature PortfolioNature Communications2041-17232023-08-0114111710.1038/s41467-023-40569-3Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traitsAndrew A. Brown0Juan J. Fernandez-Tajes1Mun-gwan Hong2Caroline A. Brorsson3Robert W. Koivula4David Davtian5Théo Dupuis6Ambra Sartori7Theodora-Dafni Michalettou8Ian M. Forgie9Jonathan Adam10Kristine H. Allin11Robert Caiazzo12Henna Cederberg13Federico De Masi14Petra J. M. Elders15Giuseppe N. Giordano16Mark Haid17Torben Hansen18Tue H. Hansen19Andrew T. Hattersley20Alison J. Heggie21Cédric Howald22Angus G. Jones23Tarja Kokkola24Markku Laakso25Anubha Mahajan26Andrea Mari27Timothy J. McDonald28Donna McEvoy29Miranda Mourby30Petra B. Musholt31Birgitte Nilsson32Francois Pattou33Deborah Penet34Violeta Raverdy35Martin Ridderstråle36Luciana Romano37Femke Rutters38Sapna Sharma39Harriet Teare40Leen ‘t Hart41Konstantinos D. Tsirigos42Jagadish Vangipurapu43Henrik Vestergaard44Søren Brunak45Paul W. Franks46Gary Frost47Harald Grallert48Bernd Jablonka49Mark I. McCarthy50Imre Pavo51Oluf Pedersen52Hartmut Ruetten53Mark Walker54The DIRECT ConsortiumJerzy Adamski55Jochen M. Schwenk56Ewan R. Pearson57Emmanouil T. Dermitzakis58Ana Viñuela59Population Health and Genomics, Ninewells Hospital and Medical School, University of DundeeWellcome Trust Centre for Human Genetics, University of OxfordScience for Life Laboratory, School of Biotechnology, KTH - Royal Institute of TechnologyDepartment of Health Technology, Technical University of DenmarkOxford Centre for Diabetes Endocrinology and Metabolism, University of OxfordPopulation Health and Genomics, Ninewells Hospital and Medical School, University of DundeePopulation Health and Genomics, Ninewells Hospital and Medical School, University of DundeeDepartment of Genetic Medicine and Development, University of Geneva Medical SchoolBiosciences Institute, Faculty of Medical Sciences, University of NewcastlePopulation Health and Genomics, Ninewells Hospital and Medical School, University of DundeeGerman Center for Diabetes Research (DZD)The Novo Nordisk Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of CopenhagenUniversity of Lille, Inserm, Lille Pasteur InstituteInternal Medicine, Institute of Clinical Medicine, University of Eastern FinlandDepartment of Health Technology, Technical University of DenmarkDepartment of General Practice, Amsterdam UMC- location Vumc, Amsterdam Public Health research instituteDepartment of Clinical Science, Genetic and Molecular Epidemiology, Lund University Diabetes CentreMetabolomics and Proteomics Core, German Research Center for Environmental Health, Helmholtz Zentrum MünchenThe Novo Nordisk Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of CopenhagenThe Novo Nordisk Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of CopenhagenDepartment of Clinical and Biomedical Sciences, University of Exeter College of Medicine & HealthInstitute of Cellular Medicine, Faculty of Medical Sciences, Newcastle UniversityDepartment of Genetic Medicine and Development, University of Geneva Medical SchoolDepartment of Clinical and Biomedical Sciences, University of Exeter College of Medicine & HealthInternal Medicine, Institute of Clinical Medicine, University of Eastern FinlandInternal Medicine, Institute of Clinical Medicine, University of Eastern FinlandWellcome Trust Centre for Human Genetics, University of OxfordInstitute of Neuroscience, National Research CouncilBlood Sciences, Royal Devon and Exeter NHS Foundation TrustDiabetes Research Network, Royal Victoria InfirmaryNuffield Department of Population Health, Centre for Health, Law and Emerging Technologies (HeLEX), University of OxfordGlobal Development, Sanofi-Aventis Deutschland GmbH, Hoechst Industrial ParkDepartment of Health Technology, Technical University of DenmarkUniversity of Lille, Inserm, Lille Pasteur InstituteDepartment of Genetic Medicine and Development, University of Geneva Medical SchoolUniversity of Lille, Inserm, Lille Pasteur InstituteDepartment of Clinical Science, Lund UniversityDepartment of Genetic Medicine and Development, University of Geneva Medical SchoolEpidemiology and Data Science, VUMCResearch Unit of Molecular Epidemiology, Institute of Epidemiology, German Research Center for Environmental Health, Helmholtz Zentrum MünchenCentre for Health Law and Emerging Technologies, Department of Population Health, University of OxfordEpidemiology and Data Science, VUMCDepartment of Health Technology, Technical University of DenmarkInternal Medicine, Institute of Clinical Medicine, University of Eastern FinlandThe Novo Nordisk Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of CopenhagenDepartment of Health Technology, Technical University of DenmarkDepartment of Clinical Science, Genetic and Molecular Epidemiology, Lund University Diabetes CentreNutrition and Dietetics Research Group, Imperial College LondonGerman Center for Diabetes Research (DZD)Sanofi Partnering, Sanofi-Aventis Deutschland GmbHWellcome Trust Centre for Human Genetics, University of OxfordEli Lilly Regional Operations Ges.m.b.HCenter for Clinical Metabolic Research, Herlev and Gentofte University HospitalSanofi Partnering, Sanofi-Aventis Deutschland GmbHTranslational and Clinical Research Institute, Faculty of Medical Sciences, University of NewcastleDepartment of Biochemistry, Yong Loo Lin School of Medicine, National University of SingaporeScience for Life Laboratory, School of Biotechnology, KTH - Royal Institute of TechnologyPopulation Health and Genomics, Ninewells Hospital and Medical School, University of DundeeDepartment of Genetic Medicine and Development, University of Geneva Medical SchoolBiosciences Institute, Faculty of Medical Sciences, University of NewcastleAbstract 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.https://doi.org/10.1038/s41467-023-40569-3 |
| spellingShingle | 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 Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits Nature Communications |
| title | Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits |
| title_full | Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits |
| title_fullStr | Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits |
| title_full_unstemmed | Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits |
| title_short | Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits |
| title_sort | genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits |
| url | https://doi.org/10.1038/s41467-023-40569-3 |
| work_keys_str_mv | AT andrewabrown geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT juanjfernandeztajes geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT mungwanhong geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT carolineabrorsson geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT robertwkoivula geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT daviddavtian geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT theodupuis geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT ambrasartori geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT theodoradafnimichalettou geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT ianmforgie geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT jonathanadam geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT kristinehallin geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT robertcaiazzo geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT hennacederberg geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT federicodemasi geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT petrajmelders geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT giuseppengiordano geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT markhaid geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT torbenhansen geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT tuehhansen geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT andrewthattersley geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT alisonjheggie geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT cedrichowald geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT angusgjones geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT tarjakokkola geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT markkulaakso geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT anubhamahajan geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT andreamari geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT timothyjmcdonald geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT donnamcevoy geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT mirandamourby geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT petrabmusholt geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT birgittenilsson geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT francoispattou geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT deborahpenet geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT violetaraverdy geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT martinridderstrale geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT lucianaromano geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT femkerutters geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT sapnasharma geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT harrietteare geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT leenthart geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT konstantinosdtsirigos geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT jagadishvangipurapu geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT henrikvestergaard geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT sørenbrunak geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT paulwfranks geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT garyfrost geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT haraldgrallert geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT berndjablonka geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT markimccarthy geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT imrepavo geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT olufpedersen geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT hartmutruetten geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT markwalker geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT thedirectconsortium geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT jerzyadamski geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT jochenmschwenk geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT ewanrpearson geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT emmanouiltdermitzakis geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits AT anavinuela geneticanalysisofbloodmolecularphenotypesrevealscommonpropertiesintheregulatorynetworksaffectingcomplextraits |