Phenome-wide analyses establish a specific association between aortic valve PALMD expression and calcific aortic valve stenosis

Zhonglin Li,Patrick Mathieu,Sébastien Thériault,Yohan Bossé,Nathalie Gaudreault,Benoit J Arsenault

doi:10.1038/s42003-020-01210-x

Abstract

Calcific aortic valve stenosis (CAVS) is a frequent heart disease with significant morbidity and mortality. Recent genomic studies have identified a locus near the gene PALMD (palmdelphin) strongly associated with CAVS. Here, we show that genetically-determined expression of PALMD in the aortic valve is inversely associated with CAVS, with a stronger effect in women, in a meta-analysis of two large cohorts totaling 2359 cases and 350,060 controls. We further demonstrate the specificity of this relationship by showing the absence of other significant association between the genetically-determined expression of PALMD in 9 tissues and 852 phenotypes. Using genome-wide association studies meta-analyses of cardiovascular traits, we identify a significant colocalized positive association between genetically-determined expression of PALMD in four non-cardiac tissues (brain anterior cingulate cortex, esophagus muscularis, tibial nerve and subcutaneous adipose tissue) and atrial fibrillation. The present work further establishes PALMD as a promising molecular target for CAVS.

Highlights

Calcific aortic valve stenosis (CAVS) is a frequent heart disease with significant morbidity and mortality
Using an expression quantitative trait loci dataset in human aortic valves, we showed that a decrease of PALMD expression in the valve is associated with CAVS risk and that this relationship is likely causal[9]
We show that the association with CAVS is specific to the aortic valve and that PALMD expression in other tissues could be associated with atrial fibrillation

Summary

Introduction

Calcific aortic valve stenosis (CAVS) is a frequent heart disease with significant morbidity and mortality. The availability of comprehensive phenotypic data from electronic health records, such as in the UK Biobank[12], has made possible the use of phenome-wide association studies (pheWAS) to examine the impact of one or many genetic variants across a broad range of human phenotypes[13,14] These can include vital signs, physical traits, health conditions (using a standardized disease classification), surgical procedures, imaging and laboratory test results. Recent advances in the field of transcriptomic analyses have made possible the prediction of gene expression in different tissues from genotypes[16,17,18] This allows to go one step further in target prioritization and evaluate the association of the level of gene expression in a specific tissue with a wide range of health conditions. We show that the association with CAVS is specific to the aortic valve and that PALMD expression in other tissues could be associated with atrial fibrillation

Methods

Results

Conclusion