TY - JOUR
T1 - Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals
AU - Folkersen, Lasse
AU - Gustafsson, Stefan
AU - Wang, Qin
AU - Hansen, Daniel Hvidberg
AU - Hedman, Åsa K
AU - Schork, Andrew
AU - Page, Karen
AU - Zhernakova, Daria V
AU - Wu, Yang
AU - Peters, James
AU - Eriksson, Niclas
AU - Bergen, Sarah E
AU - Boutin, Thibaud S
AU - Bretherick, Andrew D
AU - Enroth, Stefan
AU - Kalnapenkis, Anette
AU - Gådin, Jesper R
AU - Suur, Bianca E
AU - Chen, Yan
AU - Matic, Ljubica
AU - Gale, Jeremy D
AU - Lee, Julie
AU - Zhang, Weidong
AU - Quazi, Amira
AU - Ala-Korpela, Mika
AU - Choi, Seung Hoan
AU - Claringbould, Annique
AU - Danesh, John
AU - Davey Smith, George
AU - de Masi, Federico
AU - Elmståhl, Sölve
AU - Engström, Gunnar
AU - Fauman, Eric
AU - Fernandez, Celine
AU - Franke, Lude
AU - Franks, Paul W
AU - Giedraitis, Vilmantas
AU - Haley, Chris
AU - Hamsten, Anders
AU - Ingason, Andres
AU - Johansson, Åsa
AU - Lindgren, Cecilia M
AU - Magnusson, Martin
AU - Melander, Olle
AU - Nilsson, Peter M
AU - Nilsson, Jan
AU - Orho-Melander, Marju
AU - Sjögren, Marketa
AU - Smith, Gustav
AU - Yang, Jian
AU - Wallentin, Lars
AU - SCALLOP Consortium
N1 - These authors contributed equally: Lasse Folkersen, Stefan Gustafsson, Qin Wang, Michael V. Holmes, Erik Ingelsson, Anders Mälarstig
PY - 2020/10
Y1 - 2020/10
N2 - Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
AB - Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
U2 - 10.1038/s42255-020-00287-2
DO - 10.1038/s42255-020-00287-2
M3 - Article
C2 - 33067605
SN - 2522-5812
VL - 2
SP - 1135
EP - 1148
JO - Nature Metabolism
JF - Nature Metabolism
IS - 10
ER -
