Genetic association analyses highlight IL6, ALPL, and NAV1 as three new susceptibility genes underlying calcific aortic valve stenosis
By
Sébastien Thériault,
Christian Dina,
David Messika-Zeitoun,
Solena Le Scouarnec,
Romain Capoulade,
Nathalie Gaudreault,
Sidwell Rigade,
Zhonglin Li,
Floriane Simonet,
Maxime Lamontagne,
Marie-Annick Clavel,
Benoit J. Arsenault,
Anne-Sophie Boureau,
Simon Lecointe,
Estelle Baron,
Stéphanie Bonnaud,
Matilde Karakachoff,
Eric Charpentier,
Imen Fellah,
Jean-Christian Roussel,
Jean Philippe Verhoye,
Christophe Baufreton,
Vincent Probst,
Ronan Roussel,
the D.E.S.I.R. Study Group,
Richard Redon,
François Dagenais,
Philippe Pibarot,
Patrick Mathieu,
Thierry Le Tourneau,
Yohan Bossé,
Jean-Jacques Schott
Posted 11 Jan 2019
bioRxiv DOI: 10.1101/515494
To date, only two replicated loci, LPA and PALMD, have been identified as causal genes for calcific aortic valve stenosis (CAVS) using genome-wide and transcriptome-wide association study (TWAS). To identify additional susceptibility genes for CAVS, we performed a GWAS meta-analysis totaling 5,115 cases and 354,072 controls of European descent. Four loci achieved genome-wide significance, including two new loci: IL6 (interleukin 6) on 7p15.3 and ALPL (alkaline phosphatase) on 1p36.12. A TWAS integrating an eQTL study of 233 human aortic valves identified NAV1 (neuron navigator 1) on 1q32.1 as a new candidate causal gene. The CAVS risk alleles were associated with higher mRNA expression of NAV1 in valve tissues. Association results at the genome-wide scale showed genetic correlation with coronary artery disease and cardiovascular risk factors. Our study highlights three new loci implicating inflammation, mineralization and blood vessel integrity in CAVS pathogenesis and supports shared genetic etiology with cardiovascular traits.
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