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 Folkersen, Andreas Martinsson, Mahyar Heydarpour, Siddharth Prakash, Gylfi Oskarsson, Tomas Gudbjartsson, Arnar Geirsson, Isleifur Olafsson, 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, Gonçalo 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 and Kari Stefansson ()
Additional contact information
Anna Helgadottir: deCODE genetics/Amgen Inc.
Gudmar Thorleifsson: deCODE genetics/Amgen Inc.
Solveig Gretarsdottir: deCODE genetics/Amgen Inc.
Olafur A. Stefansson: deCODE genetics/Amgen Inc.
Vinicius Tragante: deCODE genetics/Amgen Inc.
Rosa B. Thorolfsdottir: deCODE genetics/Amgen Inc.
Ingileif Jonsdottir: deCODE genetics/Amgen Inc.
Thorsteinn Bjornsson: deCODE genetics/Amgen Inc.
Valgerdur Steinthorsdottir: deCODE genetics/Amgen Inc.
Niek Verweij: University Medical Center Groningen
Jonas B. Nielsen: University of Michigan
Wei Zhou: University of Michigan
Lasse Folkersen: Karolinska University Hospital Solna, Karolinska Institutet
Andreas Martinsson: Lund University and Skåne University Hospital
Mahyar Heydarpour: Brigham and Women’s Hospital, 75 Francis Street
Siddharth Prakash: University of Texas Health Science Center at Houston
Gylfi Oskarsson: Landspitali National University Hospital of Iceland
Tomas Gudbjartsson: Landspitali National University Hospital
Arnar Geirsson: Yale University School of Medicine
Isleifur Olafsson: Landspitali National University Hospital
Emil L. Sigurdsson: Heilsugaeslan Solvangi
Peter Almgren: Lund University
Olle Melander: Lund University
Anders Franco-Cereceda: Karolinska University Hospital Solna, Karolinska Institutet
Anders Hamsten: Karolinska University Hospital Solna, Karolinska Institutet
Lars Fritsche: Norwegian University of Science and Technology
Maoxuan Lin: University of Michigan
Bo Yang: University of Michigan
Whitney Hornsby: University of Michigan
Dongchuan Guo: University of Texas Health Science Center at Houston
Chad M. Brummett: University of Michigan
Gonçalo Abecasis: University of Michigan
Michael Mathis: University of Michigan
Dianna Milewicz: University of Texas Health Science Center at Houston
Simon C. Body: Brigham and Women’s Hospital, 75 Francis Street
Per Eriksson: Karolinska University Hospital Solna, Karolinska Institutet
Cristen J. Willer: University of Michigan
Kristian Hveem: Norwegian University of Science and Technology
Christopher Newton-Cheh: Broad Institute of MIT and Harvard
J. Gustav Smith: Lund University and Skåne University Hospital
Ragnar Danielsen: University of Iceland
Gudmundur Thorgeirsson: deCODE genetics/Amgen Inc.
Unnur Thorsteinsdottir: deCODE genetics/Amgen Inc.
Daniel F. Gudbjartsson: deCODE genetics/Amgen Inc.
Hilma Holm: deCODE genetics/Amgen Inc.
Kari Stefansson: deCODE genetics/Amgen Inc.

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: 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 × 10−22) and on chromosome 2q22 in TEX41 (rs1830321; OR = 1.15, P = 1.8 × 10−13). Rs7543130 also associates with bicuspid aortic valve (BAV) (OR = 1.28, P = 6.6 × 10−10) and aortic root diameter (P = 1.30 × 10−8), and rs1830321 associates with BAV (OR = 1.12, P = 5.3 × 10−3) and coronary artery disease (OR = 1.05, P = 9.3 × 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.

Date: 2018
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DOI: 10.1038/s41467-018-03252-6

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