Cargando…

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

Cardiometabolic diseases are frequently polygenic in architecture, comprising a large number of risk alleles with small effects spread across the genome(1–3). Polygenic scores (PGS) aggregate these into a metric representing an individual’s genetic predisposition to disease. PGS have shown promise f...

Descripción completa

Detalles Bibliográficos
Autores principales: Ritchie, Scott C., Lambert, Samuel A., Arnold, Matthew, Teo, Shu Mei, Lim, Sol, Scepanovic, Petar, Marten, Jonathan, Zahid, Sohail, Chaffin, Mark, Liu, Yingying, Abraham, Gad, Ouwehand, Willem H., Roberts, David J., Watkins, Nicholas A., Drew, Brian G., Calkin, Anna C., Di Angelantonio, Emanuele, Soranzo, Nicole, Burgess, Stephen, Chapman, Michael, Kathiresan, Sekar, Khera, Amit V., Danesh, John, Butterworth, Adam S., Inouye, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8574944/
https://www.ncbi.nlm.nih.gov/pubmed/34750571
http://dx.doi.org/10.1038/s42255-021-00478-5
_version_ 1784595591742881792
author Ritchie, Scott C.
Lambert, Samuel A.
Arnold, Matthew
Teo, Shu Mei
Lim, Sol
Scepanovic, Petar
Marten, Jonathan
Zahid, Sohail
Chaffin, Mark
Liu, Yingying
Abraham, Gad
Ouwehand, Willem H.
Roberts, David J.
Watkins, Nicholas A.
Drew, Brian G.
Calkin, Anna C.
Di Angelantonio, Emanuele
Soranzo, Nicole
Burgess, Stephen
Chapman, Michael
Kathiresan, Sekar
Khera, Amit V.
Danesh, John
Butterworth, Adam S.
Inouye, Michael
author_facet Ritchie, Scott C.
Lambert, Samuel A.
Arnold, Matthew
Teo, Shu Mei
Lim, Sol
Scepanovic, Petar
Marten, Jonathan
Zahid, Sohail
Chaffin, Mark
Liu, Yingying
Abraham, Gad
Ouwehand, Willem H.
Roberts, David J.
Watkins, Nicholas A.
Drew, Brian G.
Calkin, Anna C.
Di Angelantonio, Emanuele
Soranzo, Nicole
Burgess, Stephen
Chapman, Michael
Kathiresan, Sekar
Khera, Amit V.
Danesh, John
Butterworth, Adam S.
Inouye, Michael
author_sort Ritchie, Scott C.
collection PubMed
description Cardiometabolic diseases are frequently polygenic in architecture, comprising a large number of risk alleles with small effects spread across the genome(1–3). Polygenic scores (PGS) aggregate these into a metric representing an individual’s genetic predisposition to disease. PGS have shown promise for early risk prediction(4–7) and there is an open question as to whether PGS can also be used to understand disease biology(8). 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.
format Online
Article
Text
id pubmed-8574944
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-85749442021-11-09 Integrative analysis of the plasma proteome and polygenic risk of cardiometabolic diseases Ritchie, Scott C. Lambert, Samuel A. Arnold, Matthew Teo, Shu Mei Lim, Sol Scepanovic, Petar Marten, Jonathan Zahid, Sohail Chaffin, Mark Liu, Yingying Abraham, Gad Ouwehand, Willem H. Roberts, David J. Watkins, Nicholas A. Drew, Brian G. Calkin, Anna C. Di Angelantonio, Emanuele Soranzo, Nicole Burgess, Stephen Chapman, Michael Kathiresan, Sekar Khera, Amit V. Danesh, John Butterworth, Adam S. Inouye, Michael Nat Metab Letter Cardiometabolic diseases are frequently polygenic in architecture, comprising a large number of risk alleles with small effects spread across the genome(1–3). Polygenic scores (PGS) aggregate these into a metric representing an individual’s genetic predisposition to disease. PGS have shown promise for early risk prediction(4–7) and there is an open question as to whether PGS can also be used to understand disease biology(8). 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. Nature Publishing Group UK 2021-11-08 2021 /pmc/articles/PMC8574944/ /pubmed/34750571 http://dx.doi.org/10.1038/s42255-021-00478-5 Text en © The Author(s), under exclusive licence to Springer Nature Limited 2021 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
spellingShingle Letter
Ritchie, Scott C.
Lambert, Samuel A.
Arnold, Matthew
Teo, Shu Mei
Lim, Sol
Scepanovic, Petar
Marten, Jonathan
Zahid, Sohail
Chaffin, Mark
Liu, Yingying
Abraham, Gad
Ouwehand, Willem H.
Roberts, David J.
Watkins, Nicholas A.
Drew, Brian G.
Calkin, Anna C.
Di Angelantonio, Emanuele
Soranzo, Nicole
Burgess, Stephen
Chapman, Michael
Kathiresan, Sekar
Khera, Amit V.
Danesh, John
Butterworth, Adam S.
Inouye, Michael
Integrative analysis of the plasma proteome and polygenic risk of cardiometabolic diseases
title Integrative analysis of the plasma proteome and polygenic risk of cardiometabolic diseases
title_full Integrative analysis of the plasma proteome and polygenic risk of cardiometabolic diseases
title_fullStr Integrative analysis of the plasma proteome and polygenic risk of cardiometabolic diseases
title_full_unstemmed Integrative analysis of the plasma proteome and polygenic risk of cardiometabolic diseases
title_short Integrative analysis of the plasma proteome and polygenic risk of cardiometabolic diseases
title_sort integrative analysis of the plasma proteome and polygenic risk of cardiometabolic diseases
topic Letter
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8574944/
https://www.ncbi.nlm.nih.gov/pubmed/34750571
http://dx.doi.org/10.1038/s42255-021-00478-5
work_keys_str_mv AT ritchiescottc integrativeanalysisoftheplasmaproteomeandpolygenicriskofcardiometabolicdiseases
AT lambertsamuela integrativeanalysisoftheplasmaproteomeandpolygenicriskofcardiometabolicdiseases
AT arnoldmatthew integrativeanalysisoftheplasmaproteomeandpolygenicriskofcardiometabolicdiseases
AT teoshumei integrativeanalysisoftheplasmaproteomeandpolygenicriskofcardiometabolicdiseases
AT limsol integrativeanalysisoftheplasmaproteomeandpolygenicriskofcardiometabolicdiseases
AT scepanovicpetar integrativeanalysisoftheplasmaproteomeandpolygenicriskofcardiometabolicdiseases
AT martenjonathan integrativeanalysisoftheplasmaproteomeandpolygenicriskofcardiometabolicdiseases
AT zahidsohail integrativeanalysisoftheplasmaproteomeandpolygenicriskofcardiometabolicdiseases
AT chaffinmark integrativeanalysisoftheplasmaproteomeandpolygenicriskofcardiometabolicdiseases
AT liuyingying integrativeanalysisoftheplasmaproteomeandpolygenicriskofcardiometabolicdiseases
AT abrahamgad integrativeanalysisoftheplasmaproteomeandpolygenicriskofcardiometabolicdiseases
AT ouwehandwillemh integrativeanalysisoftheplasmaproteomeandpolygenicriskofcardiometabolicdiseases
AT robertsdavidj integrativeanalysisoftheplasmaproteomeandpolygenicriskofcardiometabolicdiseases
AT watkinsnicholasa integrativeanalysisoftheplasmaproteomeandpolygenicriskofcardiometabolicdiseases
AT drewbriang integrativeanalysisoftheplasmaproteomeandpolygenicriskofcardiometabolicdiseases
AT calkinannac integrativeanalysisoftheplasmaproteomeandpolygenicriskofcardiometabolicdiseases
AT diangelantonioemanuele integrativeanalysisoftheplasmaproteomeandpolygenicriskofcardiometabolicdiseases
AT soranzonicole integrativeanalysisoftheplasmaproteomeandpolygenicriskofcardiometabolicdiseases
AT burgessstephen integrativeanalysisoftheplasmaproteomeandpolygenicriskofcardiometabolicdiseases
AT chapmanmichael integrativeanalysisoftheplasmaproteomeandpolygenicriskofcardiometabolicdiseases
AT kathiresansekar integrativeanalysisoftheplasmaproteomeandpolygenicriskofcardiometabolicdiseases
AT kheraamitv integrativeanalysisoftheplasmaproteomeandpolygenicriskofcardiometabolicdiseases
AT daneshjohn integrativeanalysisoftheplasmaproteomeandpolygenicriskofcardiometabolicdiseases
AT butterworthadams integrativeanalysisoftheplasmaproteomeandpolygenicriskofcardiometabolicdiseases
AT inouyemichael integrativeanalysisoftheplasmaproteomeandpolygenicriskofcardiometabolicdiseases