Dissecting the polygenic basis of atherosclerosis via disease-associated cell state signatures

Tiit Örd; Tapio Lönnberg; Valtteri Nurminen; Aarthi Ravindran; Henri Niskanen; Miika Kiema; Kadri Õunap; Maleeha Maria; Pierre R. Moreau; Pashupati P. Mishra; Senthil Palani; Jenni Virta; Heidi Liljenbäck; Einari Aavik; Anne Roivainen; Seppo Ylä-Herttuala; Johanna P. Laakkonen; Terho Lehtimäki; Minna U. Kaikkonen

doi:10.1016/j.ajhg.2023.03.013

Dissecting the polygenic basis of atherosclerosis via disease-associated cell state signatures

Tiit Örd^*
, Tapio Lönnberg
, Valtteri Nurminen
, Aarthi Ravindran
, Henri Niskanen
, Miika Kiema
, Kadri Õunap
, Maleeha Maria
, Pierre R. Moreau
, Pashupati P. Mishra
, Senthil Palani
, Jenni Virta
, Heidi Liljenbäck
, Einari Aavik
, Anne Roivainen
, Seppo Ylä-Herttuala
, Johanna P. Laakkonen
, Terho Lehtimäki
, Minna U. Kaikkonen^*

^*Korresponderande författare för detta arbete

Forskningsoutput: Tidskriftsbidrag › Artikel › Vetenskaplig › Peer review

34 Citeringar (Scopus)

175 Nedladdningar (Pure)

Sammanfattning

Coronary artery disease (CAD) is a pandemic disease where up to half of the risk is explained by genetic factors. Advanced insights into the genetic basis of CAD require deeper understanding of the contributions of different cell types, molecular pathways, and genes to disease heritability. Here, we investigate the biological diversity of atherosclerosis-associated cell states and interrogate their contribution to the genetic risk of CAD by using single-cell and bulk RNA sequencing (RNA-seq) of mouse and human lesions. We identified 12 disease-associated cell states that we characterized further by gene set functional profiling, ligand-receptor prediction, and transcription factor inference. Importantly, Vcam1+ smooth muscle cell state genes contributed most to SNP-based heritability of CAD. In line with this, genetic variants near smooth muscle cell state genes and regulatory elements explained the largest fraction of CAD-risk variance between individuals. Using this information for variant prioritization, we derived a hybrid polygenic risk score (PRS) that demonstrated improved performance over a classical PRS. Our results provide insights into the biological mechanisms associated with CAD risk, which could make a promising contribution to precision medicine and tailored therapeutic interventions in the future.

Originalspråk	Engelska
Sidor (från-till)	722-740
Antal sidor	19
Tidskrift	American Journal of Human Genetics
Volym	110
Nummer	5
DOI	https://doi.org/10.1016/j.ajhg.2023.03.013
Status	Publicerad - 4 maj 2023
MoE-publikationstyp	A1 Tidskriftsartikel-refererad

Finansiering

We acknowledge Single Cell Genomics Core, Genome Center and Cell and Tissue Imaging Unit at University of Eastern Finland, Finnish Functional Genomics Centre, and Biocenter Finland for infrastructure support.‬‬ This research has been conducted with the UK Biobank Resource ( https://www.ukbiobank.ac.uk/ ) under application number 58990. We are grateful to Resolve Biosciences for their excellent service in optimizing and performing the Molecular Cartography experiments. This study was funded by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant no. 802825 to M.U.K.), Academy of Finland (grant no. 333021 and 335973 to M.U.K.; 311081 and 314557‬ to T. Lönnberg‬; 349708 to P.P.M.; 314556 and 335975 to A. Roivainen; 321535 and 328835 to J.P.L.), InFLAMES Flagship Programme of the Academy of Finland (337530 to T. Lönnberg), Finnish Foundation for Cardiovascular Research (M.U.K., P.R.M., and J.P.L.), Instrumentarium Science Foundation (P.R.M.), Ida Montinin Foundation (P.R.M.), Sigrid Jusélius Foundation (M.U.K.), GenomMed doctoral program (740264 to A. Ravindran), and Jane and Aatos Erkko Foundation (A. Roivainen).‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬ ‬‬‬‬‬‬‬‬‬‬‬‬‬The Tampere Vascular Study (TVS) was supported with grants from the Competitive Research Funding of the Tampere University Hospital (grants 9M048 and 9N035 to T. Lehtimäki), the Emil Aaltonen Foundation (to T. Lehtimäki), the Pirkanmaa Regional Fund of the Finnish Cultural Foundation , the Research Foundation of Orion Corporation , the Jenny and Antti Wihuri Foundation , and the Academy of Finland (grants 322098 and 104821 ), the Finnish Foundation for Cardiovascular Research , the Yrjö Jahnsson Foundation , European Union 7th Framework Program (grant 201668 for AtheroRemo), EU Horizon 2020 (grant 755320 for TAXINOMISIS and grant 848146 for To Aition), and the Academy of Finland grant 322098 and Tampere University Hospital Supporting Foundation . We acknowledge Single Cell Genomics Core, Genome Center and Cell and Tissue Imaging Unit at University of Eastern Finland, Finnish Functional Genomics Centre, and Biocenter Finland for infrastructure support.‬‬ This research has been conducted with the UK Biobank Resource (https://www.ukbiobank.ac.uk/) under application number 58990. We are grateful to Resolve Biosciences for their excellent service in optimizing and performing the Molecular Cartography experiments. This study was funded by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant no. 802825 to M.U.K.), Academy of Finland (grant no. 333021 and 335973 to M.U.K.; 311081 and 314557‬ to T. Lönnberg‬; 349708 to P.P.M.; 314556 and 335975 to A. Roivainen; 321535 and 328835 to J.P.L.), InFLAMES Flagship Programme of the Academy of Finland (337530 to T. Lönnberg), Finnish Foundation for Cardiovascular Research (M.U.K. P.R.M. and J.P.L.), Instrumentarium Science Foundation (P.R.M.), Ida Montinin Foundation (P.R.M.), Sigrid Jusélius Foundation (M.U.K.), GenomMed doctoral program (740264 to A. Ravindran), and Jane and Aatos Erkko Foundation (A. Roivainen).‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬ ‬‬‬‬‬‬‬‬‬‬‬‬‬The Tampere Vascular Study (TVS) was supported with grants from the Competitive Research Funding of the Tampere University Hospital (grants 9M048 and 9N035 to T. Lehtimäki), the Emil Aaltonen Foundation (to T. Lehtimäki), the Pirkanmaa Regional Fund of the Finnish Cultural Foundation, the Research Foundation of Orion Corporation, the Jenny and Antti Wihuri Foundation, and the Academy of Finland (grants 322098 and 104821), the Finnish Foundation for Cardiovascular Research, the Yrjö Jahnsson Foundation, European Union 7th Framework Program (grant 201668 for AtheroRemo), EU Horizon 2020 (grant 755320 for TAXINOMISIS and grant 848146 for To Aition), and the Academy of Finland grant 322098 and Tampere University Hospital Supporting Foundation. The authors declare no competing interests.

Åtkomst av dokument

10.1016/j.ajhg.2023.03.013

PIIS0002929723000976Slutlig publicerad version, 5,23 MBLicens: CC BY

https://urn.fi/URN:NBN:fi-fe202402136922

Andra filer och länkar

Länk till publikationen i Scopus

Citera det här

Örd, T., Lönnberg, T., Nurminen, V., Ravindran, A., Niskanen, H., Kiema, M., Õunap, K., Maria, M., Moreau, P. R., Mishra, P. P., Palani, S., Virta, J., Liljenbäck, H., Aavik, E., Roivainen, A., Ylä-Herttuala, S., Laakkonen, J. P., Lehtimäki, T., & Kaikkonen, M. U. (2023). Dissecting the polygenic basis of atherosclerosis via disease-associated cell state signatures. American Journal of Human Genetics, 110(5), 722-740. https://doi.org/10.1016/j.ajhg.2023.03.013

@article{1d47216ff4a94ec5833a65f66457a823,

title = "Dissecting the polygenic basis of atherosclerosis via disease-associated cell state signatures",

abstract = "Coronary artery disease (CAD) is a pandemic disease where up to half of the risk is explained by genetic factors. Advanced insights into the genetic basis of CAD require deeper understanding of the contributions of different cell types, molecular pathways, and genes to disease heritability. Here, we investigate the biological diversity of atherosclerosis-associated cell states and interrogate their contribution to the genetic risk of CAD by using single-cell and bulk RNA sequencing (RNA-seq) of mouse and human lesions. We identified 12 disease-associated cell states that we characterized further by gene set functional profiling, ligand-receptor prediction, and transcription factor inference. Importantly, Vcam1+ smooth muscle cell state genes contributed most to SNP-based heritability of CAD. In line with this, genetic variants near smooth muscle cell state genes and regulatory elements explained the largest fraction of CAD-risk variance between individuals. Using this information for variant prioritization, we derived a hybrid polygenic risk score (PRS) that demonstrated improved performance over a classical PRS. Our results provide insights into the biological mechanisms associated with CAD risk, which could make a promising contribution to precision medicine and tailored therapeutic interventions in the future.",

keywords = "atherosclerosis, cell state, coronary artery disease, genetics, genome-wide association study, GWAS, polygenic risk score, scRNA-seq, single cell",

author = "Tiit {\"O}rd and Tapio L{\"o}nnberg and Valtteri Nurminen and Aarthi Ravindran and Henri Niskanen and Miika Kiema and Kadri {\~O}unap and Maleeha Maria and Moreau, \{Pierre R.\} and Mishra, \{Pashupati P.\} and Senthil Palani and Jenni Virta and Heidi Liljenb{\"a}ck and Einari Aavik and Anne Roivainen and Seppo Yl{\"a}-Herttuala and Laakkonen, \{Johanna P.\} and Terho Lehtim{\"a}ki and Kaikkonen, \{Minna U.\}",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = may,

day = "4",

doi = "10.1016/j.ajhg.2023.03.013",

language = "English",

volume = "110",

pages = "722--740",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "5",

}

Örd, T, Lönnberg, T, Nurminen, V, Ravindran, A, Niskanen, H, Kiema, M, Õunap, K, Maria, M, Moreau, PR, Mishra, PP, Palani, S, Virta, J, Liljenbäck, H, Aavik, E, Roivainen, A, Ylä-Herttuala, S, Laakkonen, JP, Lehtimäki, T & Kaikkonen, MU 2023, 'Dissecting the polygenic basis of atherosclerosis via disease-associated cell state signatures', American Journal of Human Genetics, vol. 110, nr. 5, s. 722-740. https://doi.org/10.1016/j.ajhg.2023.03.013

TY - JOUR

T1 - Dissecting the polygenic basis of atherosclerosis via disease-associated cell state signatures

AU - Örd, Tiit

AU - Lönnberg, Tapio

AU - Nurminen, Valtteri

AU - Ravindran, Aarthi

AU - Niskanen, Henri

AU - Kiema, Miika

AU - Õunap, Kadri

AU - Maria, Maleeha

AU - Moreau, Pierre R.

AU - Mishra, Pashupati P.

AU - Palani, Senthil

AU - Virta, Jenni

AU - Liljenbäck, Heidi

AU - Aavik, Einari

AU - Roivainen, Anne

AU - Ylä-Herttuala, Seppo

AU - Laakkonen, Johanna P.

AU - Lehtimäki, Terho

AU - Kaikkonen, Minna U.

PY - 2023/5/4

Y1 - 2023/5/4

N2 - Coronary artery disease (CAD) is a pandemic disease where up to half of the risk is explained by genetic factors. Advanced insights into the genetic basis of CAD require deeper understanding of the contributions of different cell types, molecular pathways, and genes to disease heritability. Here, we investigate the biological diversity of atherosclerosis-associated cell states and interrogate their contribution to the genetic risk of CAD by using single-cell and bulk RNA sequencing (RNA-seq) of mouse and human lesions. We identified 12 disease-associated cell states that we characterized further by gene set functional profiling, ligand-receptor prediction, and transcription factor inference. Importantly, Vcam1+ smooth muscle cell state genes contributed most to SNP-based heritability of CAD. In line with this, genetic variants near smooth muscle cell state genes and regulatory elements explained the largest fraction of CAD-risk variance between individuals. Using this information for variant prioritization, we derived a hybrid polygenic risk score (PRS) that demonstrated improved performance over a classical PRS. Our results provide insights into the biological mechanisms associated with CAD risk, which could make a promising contribution to precision medicine and tailored therapeutic interventions in the future.

AB - Coronary artery disease (CAD) is a pandemic disease where up to half of the risk is explained by genetic factors. Advanced insights into the genetic basis of CAD require deeper understanding of the contributions of different cell types, molecular pathways, and genes to disease heritability. Here, we investigate the biological diversity of atherosclerosis-associated cell states and interrogate their contribution to the genetic risk of CAD by using single-cell and bulk RNA sequencing (RNA-seq) of mouse and human lesions. We identified 12 disease-associated cell states that we characterized further by gene set functional profiling, ligand-receptor prediction, and transcription factor inference. Importantly, Vcam1+ smooth muscle cell state genes contributed most to SNP-based heritability of CAD. In line with this, genetic variants near smooth muscle cell state genes and regulatory elements explained the largest fraction of CAD-risk variance between individuals. Using this information for variant prioritization, we derived a hybrid polygenic risk score (PRS) that demonstrated improved performance over a classical PRS. Our results provide insights into the biological mechanisms associated with CAD risk, which could make a promising contribution to precision medicine and tailored therapeutic interventions in the future.

KW - atherosclerosis

KW - cell state

KW - coronary artery disease

KW - genetics

KW - genome-wide association study

KW - GWAS

KW - polygenic risk score

KW - scRNA-seq

KW - single cell

UR - https://www.scopus.com/pages/publications/85153608064

U2 - 10.1016/j.ajhg.2023.03.013

DO - 10.1016/j.ajhg.2023.03.013

M3 - Article

C2 - 37060905

AN - SCOPUS:85153608064

SN - 0002-9297

VL - 110

SP - 722

EP - 740

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 5

ER -

Dissecting the polygenic basis of atherosclerosis via disease-associated cell state signatures

Sammanfattning

Finansiering

Åtkomst av dokument

Andra filer och länkar

Fingeravtryck

Citera det här