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 L, 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
Nat Commun 9 (1) 987 [2018-03-07; online 2018-03-07]
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.