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, Kari Stefansson

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Received: 26th September 17

Aortic valve stenosis (AS) is the most common valvular heart disease, characterized by a thickened and calcified valve causing left ventricular outflow obstruction. Severe AS is a significant cause of morbidity and mortality, affecting approximately 5% of those over 70 years of age1,2,3. Little is known about the genetics of AS, although recently a variant at the LPA locus4 and a rare MYH6 missense variant were found to associate with AS5. We report a large genome-wide association study (GWAS) with a follow-up in up to 7,307 AS cases and 801,073 controls. We identified two new AS loci, on chromosome 1p21 near PALMD (rs7543130; 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 (CAD) (OR=1.05, P=9.3×10-5). These results indicate that AS is partly rooted in the same processes as cardiac development and atherosclerosis.

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