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Integrative analysis of the plasma proteome and polygenic risk of cardiometabolic diseases.

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cam.issuedOnline2021-11-08
datacite.isderivedfrom.doi10.1101/2019.12.14.876474
dc.contributor.authorRitchie, Scott C
dc.contributor.authorLambert, Samuel A
dc.contributor.authorArnold, Matthew
dc.contributor.authorTeo, Shu Mei
dc.contributor.authorLim, Sol
dc.contributor.authorScepanovic, Petar
dc.contributor.authorMarten, Jonathan
dc.contributor.authorZahid, Sohail
dc.contributor.authorChaffin, Mark
dc.contributor.authorLiu, Yingying
dc.contributor.authorAbraham, Gad
dc.contributor.authorOuwehand, Willem H
dc.contributor.authorRoberts, David J
dc.contributor.authorWatkins, Nicholas A
dc.contributor.authorDrew, Brian G
dc.contributor.authorCalkin, Anna C
dc.contributor.authorDi Angelantonio, Emanuele
dc.contributor.authorSoranzo, Nicole
dc.contributor.authorBurgess, Stephen
dc.contributor.authorChapman, Michael
dc.contributor.authorKathiresan, Sekar
dc.contributor.authorKhera, Amit V
dc.contributor.authorDanesh, John
dc.contributor.authorButterworth, Adam S
dc.contributor.authorInouye, Michael
dc.contributor.orcidRitchie, Scott C [0000-0002-8454-9548]
dc.contributor.orcidLambert, Samuel A [0000-0001-8222-008X]
dc.contributor.orcidArnold, Matthew [0000-0001-6339-1115]
dc.contributor.orcidLim, Sol [0000-0001-7786-3355]
dc.contributor.orcidChaffin, Mark [0000-0002-1234-5562]
dc.contributor.orcidOuwehand, Willem H [0000-0002-7744-1790]
dc.contributor.orcidDrew, Brian G [0000-0002-7839-9467]
dc.contributor.orcidCalkin, Anna C [0000-0002-9861-0602]
dc.contributor.orcidSoranzo, Nicole [0000-0003-1095-3852]
dc.contributor.orcidBurgess, Stephen [0000-0001-5365-8760]
dc.contributor.orcidChapman, Michael [0000-0002-4582-6303]
dc.contributor.orcidKathiresan, Sekar [0000-0002-3711-7101]
dc.contributor.orcidButterworth, Adam S [0000-0002-6915-9015]
dc.contributor.orcidInouye, Michael [0000-0001-9413-6520]
dc.date.accessioned2022-01-07T16:46:58Z
dc.date.available2022-01-07T16:46:58Z
dc.date.issued2021-11
dc.date.updated2022-01-07T16:46:57Z
dc.description.abstractCardiometabolic diseases are frequently polygenic in architecture, comprising a large number of risk alleles with small effects spread across the genome1-3. Polygenic scores (PGS) aggregate these into a metric representing an individual's genetic predisposition to disease. PGS have shown promise for early risk prediction4-7 and there is an open question as to whether PGS can also be used to understand disease biology8. Here, we demonstrate that cardiometabolic disease PGS can be used to elucidate the proteins underlying disease pathogenesis. In 3,087 healthy individuals, we found that PGS for coronary artery disease, type 2 diabetes, chronic kidney disease and ischaemic stroke are associated with the levels of 49 plasma proteins. Associations were polygenic in architecture, largely independent of cis and trans protein quantitative trait loci and present for proteins without quantitative trait loci. Over a follow-up of 7.7 years, 28 of these proteins associated with future myocardial infarction or type 2 diabetes events, 16 of which were mediators between polygenic risk and incident disease. Twelve of these were druggable targets with therapeutic potential. Our results demonstrate the potential for PGS to uncover causal disease biology and targets with therapeutic potential, including those that may be missed by approaches utilizing information at a single locus.
dc.identifier.doi10.17863/CAM.79774
dc.identifier.eissn2522-5812
dc.identifier.issn2522-5812
dc.identifier.otherPMC8574944
dc.identifier.other34750571
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/332328
dc.languageeng
dc.language.isoeng
dc.publisherSpringer Science and Business Media LLC
dc.publisher.urlhttp://dx.doi.org/10.1038/s42255-021-00478-5
dc.sourceessn: 2522-5812
dc.sourcenlmid: 101736592
dc.subjectAdult
dc.subjectBiomarkers
dc.subjectBlood Proteins
dc.subjectDisease Management
dc.subjectDisease Susceptibility
dc.subjectEngland
dc.subjectFemale
dc.subjectGenetic Predisposition to Disease
dc.subjectHeart Diseases
dc.subjectHumans
dc.subjectMale
dc.subjectMetabolic Diseases
dc.subjectMiddle Aged
dc.subjectMultifactorial Inheritance
dc.subjectProteome
dc.subjectPublic Health Surveillance
dc.subjectYoung Adult
dc.titleIntegrative analysis of the plasma proteome and polygenic risk of cardiometabolic diseases.
dc.typeArticle
dcterms.dateAccepted2021-09-14
prism.endingPage1483
prism.issueIdentifier11
prism.publicationNameNat Metab
prism.startingPage1476
prism.volume3
pubs.funder-project-idMedical Research Council (MR/L003120/1)
pubs.funder-project-idBritish Heart Foundation (None)
pubs.funder-project-idBritish Heart Foundation (RG/18/13/33946)
pubs.funder-project-idWellcome Trust (204623/Z/16/Z)
pubs.funder-project-idNational Institute for Health and Care Research (IS-BRC-1215-20014)
pubs.funder-project-idMedical Research Council (MC_UU_00002/7)
pubs.funder-project-idEngineering and Physical Sciences Research Council (EP/P020259/1)
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1038/s42255-021-00478-5

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