Genomic and transcriptomic analyses of aortic stenosis enhance therapeutic target discovery and disease prediction

Aeron M Small; Ta-Yu Yang; Shinsuke Itoh; Sébastien Thériault; Line Dufresne; Ryo Kurosawa; Issei Komuro; Koichi Matsuda; Ha My T Vy; Eric H Farber-Eger; Lauren Lee Shaffer; Kristin M Boulier; Kristin M Corey; Megan E Ramaker; Fabien Laporte; Jean-Jacques Schott; Solena Le Scouarnec; Sasha A Singh; Abhijeet R Sonawane; Harry A Smith; Nicholas Rafaels; Jonas Ghouse; Anna A Raja; Sisse R Ostrowski; Erik Sørensen; Christina Mikkelsen; Ole B Pedersen; Christian Erikstrup; Henrik Ullum; Gardar Sveinbjornsson; Daniel F Gudbjartsson; Erik Abner; Jiwoo Lee; Andrea Ganna; Ulrike Nowak-Göttl; Sarah Finer; Johannes Schumacher; Carlo Maj; Baravan Al-Kassou; Georg Nickenig; Teresa Trenkwalder; Martina Dreβen; Markus Krane; Markus M Nöthen; Marta R Moksnes; Ben M Brumpton; Stacey Knight; Kirk U Knowlton; Lincoln Nadauld; Henning Bundgaard; Colorado Center for Personalized Medicine; Erik Sørensen; Christina Mikkelsen; DBDS Genomic Consortium

doi:10.1038/s41588-025-02417-6

Genomic and transcriptomic analyses of aortic stenosis enhance therapeutic target discovery and disease prediction

Aeron M Small, Ta-Yu Yang, Shinsuke Itoh, Sébastien Thériault, Line Dufresne, Ryo Kurosawa, Issei Komuro, Koichi Matsuda, Ha My T Vy, Eric H Farber-Eger, Lauren Lee Shaffer, Kristin M Boulier, Kristin M Corey, Megan E Ramaker, Fabien Laporte, Jean-Jacques Schott, Solena Le Scouarnec, Sasha A Singh, Abhijeet R Sonawane, Harry A SmithNicholas Rafaels, Jonas Ghouse, Anna A Raja, Sisse R Ostrowski, Erik Sørensen, Christina Mikkelsen, Ole B Pedersen, Christian Erikstrup, Henrik Ullum (Member of author group), Gardar Sveinbjornsson, Daniel F Gudbjartsson, Erik Abner, Jiwoo Lee, Andrea Ganna, Ulrike Nowak-Göttl, Sarah Finer, Johannes Schumacher, Carlo Maj, Baravan Al-Kassou, Georg Nickenig, Teresa Trenkwalder, Martina Dreβen, Markus Krane, Markus M Nöthen, Marta R Moksnes, Ben M Brumpton, Stacey Knight, Kirk U Knowlton, Lincoln Nadauld, Henning Bundgaard, Colorado Center for Personalized Medicine, Erik Sørensen (Member of author group), Christina Mikkelsen (Member of author group), DBDS Genomic Consortium

1 Citation (Scopus)

Abstract

Aortic stenosis (AS) is a common valvular heart disease and has no pharmacological therapies. We performed a multi-ancestry genome-wide association meta-analysis of 86,864 AS cases among 2,853,408 individuals, discovering 241 autosomal independent risk loci and 3 X chromosome risk loci. We additionally performed sex-stratified and ancestry-stratified genome-wide association studies (GWASs), identifying an additional 5 sex-specific risk loci, 11 risk loci in European ancestry individuals and 1 risk locus in African ancestry individuals. We also performed a transcriptome-wide association study using expression quantitative trait loci from human aortic valves, discovering 54 new genes for which genetically predicted expression influences the risk of AS. We then generated a new polygenic risk score for AS. Finally, we performed gene silencing experiments targeting biologically relevant genes identified by our GWAS. Silencing of CMKLR1 and LTBP4 in human valvular interstitial cells substantially decreased mineralization, implicating a role for polyunsaturated fatty acids and transforming growth factor β signaling in AS.

Original language	English
Journal	Nature Genetics
Volume	58
Issue number	1
Pages (from-to)	57-66
Number of pages	10
ISSN	1061-4036
DOIs	https://doi.org/10.1038/s41588-025-02417-6
Publication status	Published - Jan 2026

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Small, A. M., Yang, T.-Y., Itoh, S., Thériault, S., Dufresne, L., Kurosawa, R., Komuro, I., Matsuda, K., Vy, H. M. T., Farber-Eger, E. H., Shaffer, L. L., Boulier, K. M., Corey, K. M., Ramaker, M. E., Laporte, F., Schott, J.-J., Le Scouarnec, S., Singh, S. A., Sonawane, A. R., ... DBDS Genomic Consortium (2026). Genomic and transcriptomic analyses of aortic stenosis enhance therapeutic target discovery and disease prediction. Nature Genetics, 58(1), 57-66. https://doi.org/10.1038/s41588-025-02417-6

Small, AM, Yang, T-Y, Itoh, S, Thériault, S, Dufresne, L, Kurosawa, R, Komuro, I, Matsuda, K, Vy, HMT, Farber-Eger, EH, Shaffer, LL, Boulier, KM, Corey, KM, Ramaker, ME, Laporte, F, Schott, J-J, Le Scouarnec, S, Singh, SA, Sonawane, AR, Smith, HA, Rafaels, N, Ghouse, J , Raja, AA , Ostrowski, SR , Sørensen, E , Mikkelsen, C, Pedersen, OB, Erikstrup, C, Ullum, H, Sveinbjornsson, G, Gudbjartsson, DF, Abner, E, Lee, J, Ganna, A, Nowak-Göttl, U, Finer, S, Schumacher, J, Maj, C, Al-Kassou, B, Nickenig, G, Trenkwalder, T, Dreβen, M, Krane, M, Nöthen, MM, Moksnes, MR, Brumpton, BM, Knight, S, Knowlton, KU, Nadauld, L, Bundgaard, H, Colorado Center for Personalized Medicine, Sørensen, E , Mikkelsen, C & DBDS Genomic Consortium 2026, 'Genomic and transcriptomic analyses of aortic stenosis enhance therapeutic target discovery and disease prediction', Nature Genetics, vol. 58, no. 1, pp. 57-66. https://doi.org/10.1038/s41588-025-02417-6

@article{217f13e4578e42edb9b53e418c4080ff,

title = "Genomic and transcriptomic analyses of aortic stenosis enhance therapeutic target discovery and disease prediction",

abstract = "Aortic stenosis (AS) is a common valvular heart disease and has no pharmacological therapies. We performed a multi-ancestry genome-wide association meta-analysis of 86,864 AS cases among 2,853,408 individuals, discovering 241 autosomal independent risk loci and 3 X chromosome risk loci. We additionally performed sex-stratified and ancestry-stratified genome-wide association studies (GWASs), identifying an additional 5 sex-specific risk loci, 11 risk loci in European ancestry individuals and 1 risk locus in African ancestry individuals. We also performed a transcriptome-wide association study using expression quantitative trait loci from human aortic valves, discovering 54 new genes for which genetically predicted expression influences the risk of AS. We then generated a new polygenic risk score for AS. Finally, we performed gene silencing experiments targeting biologically relevant genes identified by our GWAS. Silencing of CMKLR1 and LTBP4 in human valvular interstitial cells substantially decreased mineralization, implicating a role for polyunsaturated fatty acids and transforming growth factor β signaling in AS.",

author = "Small, \{Aeron M\} and Ta-Yu Yang and Shinsuke Itoh and S{\'e}bastien Th{\'e}riault and Line Dufresne and Ryo Kurosawa and Issei Komuro and Koichi Matsuda and Vy, \{Ha My T\} and Farber-Eger, \{Eric H\} and Shaffer, \{Lauren Lee\} and Boulier, \{Kristin M\} and Corey, \{Kristin M\} and Ramaker, \{Megan E\} and Fabien Laporte and Jean-Jacques Schott and \{Le Scouarnec\}, Solena and Singh, \{Sasha A\} and Sonawane, \{Abhijeet R\} and Smith, \{Harry A\} and Nicholas Rafaels and Jonas Ghouse and Raja, \{Anna A\} and Ostrowski, \{Sisse R\} and Erik S{\o}rensen and Christina Mikkelsen and Pedersen, \{Ole B\} and Christian Erikstrup and Henrik Ullum and Gardar Sveinbjornsson and Gudbjartsson, \{Daniel F\} and Erik Abner and Jiwoo Lee and Andrea Ganna and Ulrike Nowak-G{\"o}ttl and Sarah Finer and Johannes Schumacher and Carlo Maj and Baravan Al-Kassou and Georg Nickenig and Teresa Trenkwalder and Martina Dreβen and Markus Krane and N{\"o}then, \{Markus M\} and Moksnes, \{Marta R\} and Brumpton, \{Ben M\} and Stacey Knight and Knowlton, \{Kirk U\} and Lincoln Nadauld and Henning Bundgaard and \{Colorado Center for Personalized Medicine\} and Erik S{\o}rensen and Christina Mikkelsen and \{DBDS Genomic Consortium\}",

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doi = "10.1038/s41588-025-02417-6",

language = "English",

volume = "58",

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T1 - Genomic and transcriptomic analyses of aortic stenosis enhance therapeutic target discovery and disease prediction

AU - Small, Aeron M

AU - Yang, Ta-Yu

AU - Itoh, Shinsuke

AU - Thériault, Sébastien

AU - Dufresne, Line

AU - Kurosawa, Ryo

AU - Komuro, Issei

AU - Matsuda, Koichi

AU - Vy, Ha My T

AU - Farber-Eger, Eric H

AU - Shaffer, Lauren Lee

AU - Boulier, Kristin M

AU - Corey, Kristin M

AU - Ramaker, Megan E

AU - Laporte, Fabien

AU - Schott, Jean-Jacques

AU - Le Scouarnec, Solena

AU - Singh, Sasha A

AU - Sonawane, Abhijeet R

AU - Smith, Harry A

AU - Rafaels, Nicholas

AU - Ghouse, Jonas

AU - Raja, Anna A

AU - Ostrowski, Sisse R

AU - Sørensen, Erik

AU - Mikkelsen, Christina

AU - Pedersen, Ole B

AU - Erikstrup, Christian

AU - Sveinbjornsson, Gardar

AU - Gudbjartsson, Daniel F

AU - Abner, Erik

AU - Lee, Jiwoo

AU - Ganna, Andrea

AU - Nowak-Göttl, Ulrike

AU - Finer, Sarah

AU - Schumacher, Johannes

AU - Maj, Carlo

AU - Al-Kassou, Baravan

AU - Nickenig, Georg

AU - Trenkwalder, Teresa

AU - Dreβen, Martina

AU - Krane, Markus

AU - Nöthen, Markus M

AU - Moksnes, Marta R

AU - Brumpton, Ben M

AU - Knight, Stacey

AU - Knowlton, Kirk U

AU - Nadauld, Lincoln

AU - Bundgaard, Henning

AU - Colorado Center for Personalized Medicine

AU - DBDS Genomic Consortium

A2 - Ullum, Henrik

A2 - Sørensen, Erik

A2 - Mikkelsen, Christina

PY - 2026/1

Y1 - 2026/1

N2 - Aortic stenosis (AS) is a common valvular heart disease and has no pharmacological therapies. We performed a multi-ancestry genome-wide association meta-analysis of 86,864 AS cases among 2,853,408 individuals, discovering 241 autosomal independent risk loci and 3 X chromosome risk loci. We additionally performed sex-stratified and ancestry-stratified genome-wide association studies (GWASs), identifying an additional 5 sex-specific risk loci, 11 risk loci in European ancestry individuals and 1 risk locus in African ancestry individuals. We also performed a transcriptome-wide association study using expression quantitative trait loci from human aortic valves, discovering 54 new genes for which genetically predicted expression influences the risk of AS. We then generated a new polygenic risk score for AS. Finally, we performed gene silencing experiments targeting biologically relevant genes identified by our GWAS. Silencing of CMKLR1 and LTBP4 in human valvular interstitial cells substantially decreased mineralization, implicating a role for polyunsaturated fatty acids and transforming growth factor β signaling in AS.

AB - Aortic stenosis (AS) is a common valvular heart disease and has no pharmacological therapies. We performed a multi-ancestry genome-wide association meta-analysis of 86,864 AS cases among 2,853,408 individuals, discovering 241 autosomal independent risk loci and 3 X chromosome risk loci. We additionally performed sex-stratified and ancestry-stratified genome-wide association studies (GWASs), identifying an additional 5 sex-specific risk loci, 11 risk loci in European ancestry individuals and 1 risk locus in African ancestry individuals. We also performed a transcriptome-wide association study using expression quantitative trait loci from human aortic valves, discovering 54 new genes for which genetically predicted expression influences the risk of AS. We then generated a new polygenic risk score for AS. Finally, we performed gene silencing experiments targeting biologically relevant genes identified by our GWAS. Silencing of CMKLR1 and LTBP4 in human valvular interstitial cells substantially decreased mineralization, implicating a role for polyunsaturated fatty acids and transforming growth factor β signaling in AS.

U2 - 10.1038/s41588-025-02417-6

DO - 10.1038/s41588-025-02417-6

M3 - Journal article

C2 - 41419686

SN - 1061-4036

VL - 58

SP - 57

EP - 66

JO - Nature Genetics

JF - Nature Genetics

IS - 1

ER -

Genomic and transcriptomic analyses of aortic stenosis enhance therapeutic target discovery and disease prediction

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