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

• Published in: Nature communications Vol. 9; no. 1; pp. 987 - 10
• Main Authors: 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, 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, Gonçalo, 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.03.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 38/77; 45/23; 45/43; 631/208/205/2138; 692/4019/592/2726; 692/4019/592/75/1539; 692/4019/592/75/591; Abnormalities; Aortic valve; Aortic Valve Stenosis - genetics; Arteriosclerosis; Atherosclerosis; Basic Medicine; Cardiology and Cardiovascular Disease; Cardiovascular disease; Cardiovascular diseases; Case-Control Studies; Cholesterol; Chromosome 1; Chromosome 2; Clinical Medicine; Coronary artery; Coronary artery disease; Coronary Artery Disease - genetics; Genome-Wide Association Study; Genomes; Heart; Heart diseases; Humanities and Social Sciences; Humans; Kardiologi och kardiovaskulära sjukdomar; Klinisk medicin; Loci; Low density lipoprotein; Medical and Health Sciences; Medical Genetics and Genomics (including Gene Therapy); Medicin och hälsovetenskap; Medicinsk genetik och genomik (Här ingår: Genterapi); Medicinska och farmaceutiska grundvetenskaper; multidisciplinary; Pathogenesis; Phenotype; Rheumatic heart disease; Risk analysis; Risk Factors; Risk sharing; Science; Science (multidisciplinary); Stenosis
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-03252-6

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. Aortic valve stenosis (AS) is the most common valvular heart disease. Here the authors identify two new AS loci that also associate with bicuspid aortic valve, aortic root diameter and/or coronary artery disease implicating both developmental abnormalities and atherosclerosis-like processes in AS.