Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals

Lasse Folkersen; Stefan Gustafsson; Qin Wang; Daniel Hvidberg Hansen; Åsa K. Hedman; Andrew Schork; Karen Page; Daria V. Zhernakova; Yang Wu; James Peters; Niclas Eriksson; Sarah E. Bergen; Thibaud S. Boutin; Andrew D. Bretherick; Stefan Enroth; Anette Kalnapenkis; Jesper R. Gådin; Bianca E. Suur; Yan Chen; Ljubica Matic; Jeremy D. Gale; Julie Lee; Weidong Zhang; Amira Quazi; Mika Ala-Korpela; Seung Hoan Choi; Annique Claringbould; John Danesh; George Davey Smith; Federico de Masi; Sölve Elmståhl; Gunnar Engström; Eric Fauman; Celine Fernandez; Lude Franke; Paul W. Franks; Vilmantas Giedraitis; Chris Haley; Anders Hamsten; Andres Ingason; Åsa Johansson; Peter K. Joshi; Lars Lind; Cecilia M. Lindgren; Steven Lubitz; Tom Palmer; Erin Macdonald-Dunlop; Martin Magnusson; Olle Melander; Karl Michaelsson; Andrew P. Morris; Reedik Mägi; Michael W. Nagle; Peter M. Nilsson; Jan Nilsson; Marju Orho-Melander; Ozren Polasek; Bram Prins; Erik Pålsson; Ting Qi; Marketa Sjögren; Johan Sundström; Praveen Surendran; Urmo Võsa; Thomas Werge; Rasmus Wernersson; Harm-Jan Westra; Jian Yang; Alexandra Zhernakova; Johan Ärnlöv; Jingyuan Fu; J. Gustav Smith; Tõnu Esko; Caroline Hayward; Ulf Gyllensten; Mikael Landen; Agneta Siegbahn; James F. Wilson; Lars Wallentin; Adam S. Butterworth; Michael V. Holmes; Erik Ingelsson; Anders Mälarstig

doi:10.1038/s42255-020-00287-2

Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals

Lasse Folkersen, Stefan Gustafsson, Qin Wang, Daniel Hvidberg Hansen, Åsa K. Hedman, Andrew Schork, Karen Page, Daria V. Zhernakova, Yang Wu, James Peters, Niclas Eriksson, Sarah E. Bergen, Thibaud S. Boutin, Andrew D. Bretherick, Stefan Enroth, Anette Kalnapenkis, Jesper R. Gådin, Bianca E. Suur, Yan Chen, Ljubica MaticJeremy D. Gale, Julie Lee, Weidong Zhang, Amira Quazi, Mika Ala-Korpela, Seung Hoan Choi, Annique Claringbould, John Danesh, George Davey Smith, Federico de Masi, Sölve Elmståhl, Gunnar Engström, Eric Fauman, Celine Fernandez, Lude Franke, Paul W. Franks, Vilmantas Giedraitis, Chris Haley, Anders Hamsten, Andres Ingason, Åsa Johansson, Peter K. Joshi, Lars Lind, Cecilia M. Lindgren, Steven Lubitz, Tom Palmer, Erin Macdonald-Dunlop, Martin Magnusson, Olle Melander, Karl Michaelsson, Andrew P. Morris, Reedik Mägi, Michael W. Nagle, Peter M. Nilsson, Jan Nilsson, Marju Orho-Melander, Ozren Polasek, Bram Prins, Erik Pålsson, Ting Qi, Marketa Sjögren, Johan Sundström, Praveen Surendran, Urmo Võsa, Thomas Werge, Rasmus Wernersson, Harm-Jan Westra, Jian Yang, Alexandra Zhernakova, Johan Ärnlöv, Jingyuan Fu, J. Gustav Smith, Tõnu Esko, Caroline Hayward, Ulf Gyllensten, Mikael Landen, Agneta Siegbahn, James F. Wilson, Lars Wallentin, Adam S. Butterworth, Michael V. Holmes, Erik Ingelsson, Anders Mälarstig^*

^*Corresponding author for this work

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Abstract

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.

Original language	English
Pages (from-to)	1135–1148 (2020)
Number of pages	15
Journal	Nature Metabolism
Volume	2
DOIs	https://doi.org/10.1038/s42255-020-00287-2
Publication status	Published - 16 Oct 2020

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SDG 3 Good Health and Well-being

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10.1038/s42255-020-00287-2

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IEU: MRC Integrative Epidemiology Unit Quinquennial renewal
Gaunt, L. F. (Principal Investigator) & Davey Smith, G. (Principal Investigator)
1/04/18 → 31/03/23
Project: Research

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Folkersen, L., Gustafsson, S., Wang, Q., Hansen, D. H., Hedman, Å. K., Schork, A., Page, K., Zhernakova, D. V., Wu, Y., Peters, J., Eriksson, N., Bergen, S. E., Boutin, T. S., Bretherick, A. D., Enroth, S., Kalnapenkis, A., Gådin, J. R., Suur, B. E., Chen, Y., ... Mälarstig, A. (2020). Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals. Nature Metabolism, 2, 1135–1148 (2020). https://doi.org/10.1038/s42255-020-00287-2

@article{606bf60f93384b5bb48b584b5bfbef3b,

title = "Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals",

abstract = "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.",

author = "Lasse Folkersen and Stefan Gustafsson and Qin Wang and Hansen, \{Daniel Hvidberg\} and Hedman, \{{\AA}sa K.\} and Andrew Schork and Karen Page and Zhernakova, \{Daria V.\} and Yang Wu and James Peters and Niclas Eriksson and Bergen, \{Sarah E.\} and Boutin, \{Thibaud S.\} and Bretherick, \{Andrew D.\} and Stefan Enroth and Anette Kalnapenkis and G{\aa}din, \{Jesper R.\} and Suur, \{Bianca E.\} and Yan Chen and Ljubica Matic and Gale, \{Jeremy D.\} and Julie Lee and Weidong Zhang and Amira Quazi and Mika Ala-Korpela and Choi, \{Seung Hoan\} and Annique Claringbould and John Danesh and \{Davey Smith\}, George and \{de Masi\}, Federico and S{\"o}lve Elmst{\aa}hl and Gunnar Engstr{\"o}m and Eric Fauman and Celine Fernandez and Lude Franke and Franks, \{Paul W.\} and Vilmantas Giedraitis and Chris Haley and Anders Hamsten and Andres Ingason and {\AA}sa Johansson and Joshi, \{Peter K.\} and Lars Lind and Lindgren, \{Cecilia M.\} and Steven Lubitz and Tom Palmer and Erin Macdonald-Dunlop and Martin Magnusson and Olle Melander and Karl Michaelsson and Morris, \{Andrew P.\} and Reedik M{\"a}gi and Nagle, \{Michael W.\} and Nilsson, \{Peter M.\} and Jan Nilsson and Marju Orho-Melander and Ozren Polasek and Bram Prins and Erik P{\aa}lsson and Ting Qi and Marketa Sj{\"o}gren and Johan Sundstr{\"o}m and Praveen Surendran and Urmo V{\~o}sa and Thomas Werge and Rasmus Wernersson and Harm-Jan Westra and Jian Yang and Alexandra Zhernakova and Johan {\"A}rnl{\"o}v and Jingyuan Fu and Smith, \{J. Gustav\} and T{\~o}nu Esko and Caroline Hayward and Ulf Gyllensten and Mikael Landen and Agneta Siegbahn and Wilson, \{James F.\} and Lars Wallentin and Butterworth, \{Adam S.\} and Holmes, \{Michael V.\} and Erik Ingelsson and Anders M{\"a}larstig",

year = "2020",

month = oct,

day = "16",

doi = "10.1038/s42255-020-00287-2",

language = "English",

volume = "2",

pages = "1135–1148 (2020)",

journal = "Nature Metabolism",

issn = "2522-5812",

publisher = "Nature Research",

}

Folkersen, L, Gustafsson, S, Wang, Q, Hansen, DH, Hedman, ÅK, Schork, A, Page, K, Zhernakova, DV, Wu, Y, Peters, J, Eriksson, N, Bergen, SE, Boutin, TS, Bretherick, AD, Enroth, S, Kalnapenkis, A, Gådin, JR, Suur, BE, Chen, Y, Matic, L, Gale, JD, Lee, J, Zhang, W, Quazi, A, Ala-Korpela, M, Choi, SH, Claringbould, A, Danesh, J, Davey Smith, G, de Masi, F, Elmståhl, S, Engström, G, Fauman, E, Fernandez, C, Franke, L, Franks, PW, Giedraitis, V, Haley, C, Hamsten, A, Ingason, A, Johansson, Å, Joshi, PK, Lind, L, Lindgren, CM, Lubitz, S, Palmer, T, Macdonald-Dunlop, E, Magnusson, M, Melander, O, Michaelsson, K, Morris, AP, Mägi, R, Nagle, MW, Nilsson, PM, Nilsson, J, Orho-Melander, M, Polasek, O, Prins, B, Pålsson, E, Qi, T, Sjögren, M, Sundström, J, Surendran, P, Võsa, U, Werge, T, Wernersson, R, Westra, H-J, Yang, J, Zhernakova, A, Ärnlöv, J, Fu, J, Smith, JG, Esko, T, Hayward, C, Gyllensten, U, Landen, M, Siegbahn, A, Wilson, JF, Wallentin, L, Butterworth, AS, Holmes, MV, Ingelsson, E & Mälarstig, A 2020, 'Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals', Nature Metabolism, vol. 2, pp. 1135–1148 (2020). https://doi.org/10.1038/s42255-020-00287-2

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 - Joshi, Peter K.

AU - Lind, Lars

AU - Lindgren, Cecilia M.

AU - Lubitz, Steven

AU - Palmer, Tom

AU - Macdonald-Dunlop, Erin

AU - Magnusson, Martin

AU - Melander, Olle

AU - Michaelsson, Karl

AU - Morris, Andrew P.

AU - Mägi, Reedik

AU - Nagle, Michael W.

AU - Nilsson, Peter M.

AU - Nilsson, Jan

AU - Orho-Melander, Marju

AU - Polasek, Ozren

AU - Prins, Bram

AU - Pålsson, Erik

AU - Qi, Ting

AU - Sjögren, Marketa

AU - Sundström, Johan

AU - Surendran, Praveen

AU - Võsa, Urmo

AU - Werge, Thomas

AU - Wernersson, Rasmus

AU - Westra, Harm-Jan

AU - Yang, Jian

AU - Zhernakova, Alexandra

AU - Ärnlöv, Johan

AU - Fu, Jingyuan

AU - Smith, J. Gustav

AU - Esko, Tõnu

AU - Hayward, Caroline

AU - Gyllensten, Ulf

AU - Landen, Mikael

AU - Siegbahn, Agneta

AU - Wilson, James F.

AU - Wallentin, Lars

AU - Butterworth, Adam S.

AU - Holmes, Michael V.

AU - Ingelsson, Erik

AU - Mälarstig, Anders

PY - 2020/10/16

Y1 - 2020/10/16

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 (Academic Journal)

C2 - 33067605

SN - 2522-5812

VL - 2

SP - 1135–1148 (2020)

JO - Nature Metabolism

JF - Nature Metabolism

ER -

Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals

Abstract

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IEU: MRC Integrative Epidemiology Unit Quinquennial renewal

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