Genome-wide analysis yields new loci associating with aortic valve stenosis

Anna Helgadottir*, Gudmar Thorleifsson, Solveig Gretarsdottir, Olafur A. Stefansson, Vinicius Tragante, Rosa B. Thorolfsdottir, Ingileif Jonsdottir, Thorsteinn Bjornsson, Valgerdur Steinthorsdottir, Niek Verweij, Jonas B. Nielsen, Wei Zhou, Lasse Westergaard Folkersen, Andreas Martinsson, Mahyar Heydarpour, Siddharth Prakash, Gylfi Oskarsson, Tomas Gudbjartsson, Arnar Geirsson, Isleifur Olafsson & 26 others Emil L. Sigurdsson, Peter Almgren, Olle Melander, Anders Franco-Cereceda, Anders Hamsten, Lars Fritsche, Maoxuan Lin, Bo Yang, Whitney Hornsby, Dongchuan Guo, Chad M. Brummett, Goncalo Abecasis, Michael Mathis, Dianna Milewicz, Simon C. Body, Per Eriksson, Cristen J. Willer, Kristian Hveem, Christopher Newton-Cheh, J. Gustav Smith, Ragnar Danielsen, Gudmundur Thorgeirsson, Unnur Thorsteinsdottir, Daniel F. Gudbjartsson, Hilma Holm, Kari Stefansson

*Corresponding author for this work

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    Abstract

    Aortic valve stenosis (AS) is the most common valvular heart disease, and valve replacement is the only definitive treatment. Here we report a large genome-wide association (GWA) study of 2,457 Icelandic AS cases and 349,342 controls with a follow-up in up to 4,850 cases and 451,731 controls of European ancestry. We identify two new AS loci, on chromosome 1p21 near PALMD (rs7543130; odds ratio (OR) = 1.20, P = 1.2 x 10(-22)) and on chromosome 2q22 in TEX41 (rs1830321; OR = 1.15, P = 1.8 x 10(-13)). Rs7543130 also associates with bicuspid aortic valve (BAV) (OR = 1.28, P = 6.6 x 10(-10)) and aortic root diameter (P = 1.30 x 10(-8)), and rs1830321 associates with BAV (OR = 1.12, P = 5.3 x 10(-3)) and coronary artery disease (OR = 1.05, P = 9.3 x 10(-5)). The results implicate both cardiac developmental abnormalities and atherosclerosis-like processes in the pathogenesis of AS. We show that several pathways are shared by CAD and AS. Causal analysis suggests that the shared risk factors of Lp(a) and non-high-density lipoprotein cholesterol contribute substantially to the frequent co-occurence of these diseases.
    Original languageEnglish
    Article number987
    JournalNature Communications
    Volume9
    Issue number1
    Number of pages10
    ISSN2041-1723
    DOIs
    Publication statusPublished - 2018

    Bibliographical note

    Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright hold. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

    Cite this

    Helgadottir, A., Thorleifsson, G., Gretarsdottir, S., Stefansson, O. A., Tragante, V., Thorolfsdottir, R. B., ... Stefansson, K. (2018). Genome-wide analysis yields new loci associating with aortic valve stenosis. Nature Communications, 9(1), [987]. https://doi.org/10.1038/s41467-018-03252-6
    Helgadottir, Anna ; Thorleifsson, Gudmar ; Gretarsdottir, Solveig ; Stefansson, Olafur A. ; Tragante, Vinicius ; Thorolfsdottir, Rosa B. ; Jonsdottir, Ingileif ; Bjornsson, Thorsteinn ; Steinthorsdottir, Valgerdur ; Verweij, Niek ; Nielsen, Jonas B. ; Zhou, Wei ; Folkersen, Lasse Westergaard ; Martinsson, Andreas ; Heydarpour, Mahyar ; Prakash, Siddharth ; Oskarsson, Gylfi ; Gudbjartsson, Tomas ; Geirsson, Arnar ; Olafsson, Isleifur ; Sigurdsson, Emil L. ; Almgren, Peter ; Melander, Olle ; Franco-Cereceda, Anders ; Hamsten, Anders ; Fritsche, Lars ; Lin, Maoxuan ; Yang, Bo ; Hornsby, Whitney ; Guo, Dongchuan ; Brummett, Chad M. ; Abecasis, Goncalo ; Mathis, Michael ; Milewicz, Dianna ; Body, Simon C. ; Eriksson, Per ; Willer, Cristen J. ; Hveem, Kristian ; Newton-Cheh, Christopher ; Smith, J. Gustav ; Danielsen, Ragnar ; Thorgeirsson, Gudmundur ; Thorsteinsdottir, Unnur ; Gudbjartsson, Daniel F. ; Holm, Hilma ; Stefansson, Kari. / Genome-wide analysis yields new loci associating with aortic valve stenosis. In: Nature Communications. 2018 ; Vol. 9, No. 1.
    @article{0178db4b231140e5a5bc0f28d9232cfb,
    title = "Genome-wide analysis yields new loci associating with aortic valve stenosis",
    abstract = "Aortic valve stenosis (AS) is the most common valvular heart disease, and valve replacement is the only definitive treatment. Here we report a large genome-wide association (GWA) study of 2,457 Icelandic AS cases and 349,342 controls with a follow-up in up to 4,850 cases and 451,731 controls of European ancestry. We identify two new AS loci, on chromosome 1p21 near PALMD (rs7543130; odds ratio (OR) = 1.20, P = 1.2 x 10(-22)) and on chromosome 2q22 in TEX41 (rs1830321; OR = 1.15, P = 1.8 x 10(-13)). Rs7543130 also associates with bicuspid aortic valve (BAV) (OR = 1.28, P = 6.6 x 10(-10)) and aortic root diameter (P = 1.30 x 10(-8)), and rs1830321 associates with BAV (OR = 1.12, P = 5.3 x 10(-3)) and coronary artery disease (OR = 1.05, P = 9.3 x 10(-5)). The results implicate both cardiac developmental abnormalities and atherosclerosis-like processes in the pathogenesis of AS. We show that several pathways are shared by CAD and AS. Causal analysis suggests that the shared risk factors of Lp(a) and non-high-density lipoprotein cholesterol contribute substantially to the frequent co-occurence of these diseases.",
    author = "Anna Helgadottir and Gudmar Thorleifsson and Solveig Gretarsdottir and Stefansson, {Olafur A.} and Vinicius Tragante and Thorolfsdottir, {Rosa B.} and Ingileif Jonsdottir and Thorsteinn Bjornsson and Valgerdur Steinthorsdottir and Niek Verweij and Nielsen, {Jonas B.} and Wei Zhou and Folkersen, {Lasse Westergaard} and Andreas Martinsson and Mahyar Heydarpour and Siddharth Prakash and Gylfi Oskarsson and Tomas Gudbjartsson and Arnar Geirsson and Isleifur Olafsson and Sigurdsson, {Emil L.} and Peter Almgren and Olle Melander and Anders Franco-Cereceda and Anders Hamsten and Lars Fritsche and Maoxuan Lin and Bo Yang and Whitney Hornsby and Dongchuan Guo and Brummett, {Chad M.} and Goncalo Abecasis and Michael Mathis and Dianna Milewicz and Body, {Simon C.} and Per Eriksson and Willer, {Cristen J.} and Kristian Hveem and Christopher Newton-Cheh and Smith, {J. Gustav} and Ragnar Danielsen and Gudmundur Thorgeirsson and Unnur Thorsteinsdottir and Gudbjartsson, {Daniel F.} and Hilma Holm and Kari Stefansson",
    note = "Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright hold. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.",
    year = "2018",
    doi = "10.1038/s41467-018-03252-6",
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    Helgadottir, A, Thorleifsson, G, Gretarsdottir, S, Stefansson, OA, Tragante, V, Thorolfsdottir, RB, Jonsdottir, I, Bjornsson, T, Steinthorsdottir, V, Verweij, N, Nielsen, JB, Zhou, W, Folkersen, LW, Martinsson, A, Heydarpour, M, Prakash, S, Oskarsson, G, Gudbjartsson, T, Geirsson, A, Olafsson, I, Sigurdsson, EL, Almgren, P, Melander, O, Franco-Cereceda, A, Hamsten, A, Fritsche, L, Lin, M, Yang, B, Hornsby, W, Guo, D, Brummett, CM, Abecasis, G, Mathis, M, Milewicz, D, Body, SC, Eriksson, P, Willer, CJ, Hveem, K, Newton-Cheh, C, Smith, JG, Danielsen, R, Thorgeirsson, G, Thorsteinsdottir, U, Gudbjartsson, DF, Holm, H & Stefansson, K 2018, 'Genome-wide analysis yields new loci associating with aortic valve stenosis', Nature Communications, vol. 9, no. 1, 987. https://doi.org/10.1038/s41467-018-03252-6

    Genome-wide analysis yields new loci associating with aortic valve stenosis. / Helgadottir, Anna; Thorleifsson, Gudmar; Gretarsdottir, Solveig; Stefansson, Olafur A.; Tragante, Vinicius; Thorolfsdottir, Rosa B.; Jonsdottir, Ingileif; Bjornsson, Thorsteinn; Steinthorsdottir, Valgerdur; Verweij, Niek; Nielsen, Jonas B.; Zhou, Wei; Folkersen, Lasse Westergaard; Martinsson, Andreas; Heydarpour, Mahyar; Prakash, Siddharth; Oskarsson, Gylfi; Gudbjartsson, Tomas; Geirsson, Arnar; Olafsson, Isleifur; Sigurdsson, Emil L.; Almgren, Peter; Melander, Olle; Franco-Cereceda, Anders; Hamsten, Anders; Fritsche, Lars; Lin, Maoxuan; Yang, Bo; Hornsby, Whitney; Guo, Dongchuan; Brummett, Chad M.; Abecasis, Goncalo; Mathis, Michael; Milewicz, Dianna; Body, Simon C.; Eriksson, Per; Willer, Cristen J.; Hveem, Kristian; Newton-Cheh, Christopher; Smith, J. Gustav; Danielsen, Ragnar; Thorgeirsson, Gudmundur; Thorsteinsdottir, Unnur; Gudbjartsson, Daniel F.; Holm, Hilma; Stefansson, Kari.

    In: Nature Communications, Vol. 9, No. 1, 987, 2018.

    Research output: Contribution to journalJournal articleResearchpeer-review

    TY - JOUR

    T1 - Genome-wide analysis yields new loci associating with aortic valve stenosis

    AU - Helgadottir, Anna

    AU - Thorleifsson, Gudmar

    AU - Gretarsdottir, Solveig

    AU - Stefansson, Olafur A.

    AU - Tragante, Vinicius

    AU - Thorolfsdottir, Rosa B.

    AU - Jonsdottir, Ingileif

    AU - Bjornsson, Thorsteinn

    AU - Steinthorsdottir, Valgerdur

    AU - Verweij, Niek

    AU - Nielsen, Jonas B.

    AU - Zhou, Wei

    AU - Folkersen, Lasse Westergaard

    AU - Martinsson, Andreas

    AU - Heydarpour, Mahyar

    AU - Prakash, Siddharth

    AU - Oskarsson, Gylfi

    AU - Gudbjartsson, Tomas

    AU - Geirsson, Arnar

    AU - Olafsson, Isleifur

    AU - Sigurdsson, Emil L.

    AU - Almgren, Peter

    AU - Melander, Olle

    AU - Franco-Cereceda, Anders

    AU - Hamsten, Anders

    AU - Fritsche, Lars

    AU - Lin, Maoxuan

    AU - Yang, Bo

    AU - Hornsby, Whitney

    AU - Guo, Dongchuan

    AU - Brummett, Chad M.

    AU - Abecasis, Goncalo

    AU - Mathis, Michael

    AU - Milewicz, Dianna

    AU - Body, Simon C.

    AU - Eriksson, Per

    AU - Willer, Cristen J.

    AU - Hveem, Kristian

    AU - Newton-Cheh, Christopher

    AU - Smith, J. Gustav

    AU - Danielsen, Ragnar

    AU - Thorgeirsson, Gudmundur

    AU - Thorsteinsdottir, Unnur

    AU - Gudbjartsson, Daniel F.

    AU - Holm, Hilma

    AU - Stefansson, Kari

    N1 - Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright hold. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

    PY - 2018

    Y1 - 2018

    N2 - Aortic valve stenosis (AS) is the most common valvular heart disease, and valve replacement is the only definitive treatment. Here we report a large genome-wide association (GWA) study of 2,457 Icelandic AS cases and 349,342 controls with a follow-up in up to 4,850 cases and 451,731 controls of European ancestry. We identify two new AS loci, on chromosome 1p21 near PALMD (rs7543130; odds ratio (OR) = 1.20, P = 1.2 x 10(-22)) and on chromosome 2q22 in TEX41 (rs1830321; OR = 1.15, P = 1.8 x 10(-13)). Rs7543130 also associates with bicuspid aortic valve (BAV) (OR = 1.28, P = 6.6 x 10(-10)) and aortic root diameter (P = 1.30 x 10(-8)), and rs1830321 associates with BAV (OR = 1.12, P = 5.3 x 10(-3)) and coronary artery disease (OR = 1.05, P = 9.3 x 10(-5)). The results implicate both cardiac developmental abnormalities and atherosclerosis-like processes in the pathogenesis of AS. We show that several pathways are shared by CAD and AS. Causal analysis suggests that the shared risk factors of Lp(a) and non-high-density lipoprotein cholesterol contribute substantially to the frequent co-occurence of these diseases.

    AB - Aortic valve stenosis (AS) is the most common valvular heart disease, and valve replacement is the only definitive treatment. Here we report a large genome-wide association (GWA) study of 2,457 Icelandic AS cases and 349,342 controls with a follow-up in up to 4,850 cases and 451,731 controls of European ancestry. We identify two new AS loci, on chromosome 1p21 near PALMD (rs7543130; odds ratio (OR) = 1.20, P = 1.2 x 10(-22)) and on chromosome 2q22 in TEX41 (rs1830321; OR = 1.15, P = 1.8 x 10(-13)). Rs7543130 also associates with bicuspid aortic valve (BAV) (OR = 1.28, P = 6.6 x 10(-10)) and aortic root diameter (P = 1.30 x 10(-8)), and rs1830321 associates with BAV (OR = 1.12, P = 5.3 x 10(-3)) and coronary artery disease (OR = 1.05, P = 9.3 x 10(-5)). The results implicate both cardiac developmental abnormalities and atherosclerosis-like processes in the pathogenesis of AS. We show that several pathways are shared by CAD and AS. Causal analysis suggests that the shared risk factors of Lp(a) and non-high-density lipoprotein cholesterol contribute substantially to the frequent co-occurence of these diseases.

    U2 - 10.1038/s41467-018-03252-6

    DO - 10.1038/s41467-018-03252-6

    M3 - Journal article

    VL - 9

    JO - Nature Communications

    JF - Nature Communications

    SN - 2041-1723

    IS - 1

    M1 - 987

    ER -

    Helgadottir A, Thorleifsson G, Gretarsdottir S, Stefansson OA, Tragante V, Thorolfsdottir RB et al. Genome-wide analysis yields new loci associating with aortic valve stenosis. Nature Communications. 2018;9(1). 987. https://doi.org/10.1038/s41467-018-03252-6