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

Figures

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  Fig. 1. PALMD genetically-determined expression in the aortic valve and CAVS risk in women and men. Forest plot showing the association between PALMD genetically-determined expression in the aortic valve and CAVS according to sex in UK Biobank and QUEBEC-CAVS. OR: Odds ratios for CAVS per SD increase in genetically-determined expression of PALMD in the aortic valve.

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  Fig. 2. Aortic valve PALMD eQTL and GWAS association with CAVS. LocusCompare plot30 showing the relationship between aortic valve PALMD eQTL and GWAS association with CAVS for variants located within 1 Mb of PALMD. Colocalization PP4 = 99.7%. GWAS association was obtained from a meta-analysis of QUEBEC-CAVS and UK Biobank. The lead GWAS variant is annotated.

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  Fig. 3. PALMD expression in 233 human aortic valves. Boxplot representing PALMD expression according to sex and rs6702619 genotype in aortic valve tissue from 117 women and 116 men with CAVS. W: Women, M: Men. “G” is the CAVS risk allele at rs6702619. Whiskers represent the most extreme data points, which are no more than 1.5 times the interquartile range. The empty circle represents an outlier data point. Box boundaries represent the first and third quartiles. The center mark represents the median. Phet = 0.36 for the effect of rs6702619 on expression between sex (Woolf’s test for heterogeneity).

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  Fig. 4. PheWAS of PALMD genetically-determined expression in the aortic valve. Each triangle represents a different phenotype in the UK Biobank (n = 852). Triangles pointing up and down are positive and negative associations with PALMD genetically-determined expression in the aortic valve, respectively. The pink horizontal line represents the threshold for significance after correcting for multiple testing (P = 0.05/852 = 5.9 × 10−5). The blue horizontal line represents the threshold for nominal significance (P = 0.05).

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  Fig. 5. PALMD genetically-determined expression in 9 tissues and 21 cardiovascular phenotypes. Analyses were performed using S-PrediXcan16 and summary statistics from available GWAS meta-analyses (Supplementary Table 2). HDL high-density lipoprotein, LDL low-density lipoprotein, CKD chronic kidney disease, eGFR estimated glomerular filtration rate, BMI body-mass index. *PFDR < 0.05.

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  Fig. 6. PALMD eQTL in selected tissues and GWAS association with atrial fibrillation and stroke. LocusCompare plots30 showing the relationship between PALMD eQTL and GWAS association with atrial fibrillation and stroke for variants located within 1 Mb of PALMD. a Esophagus muscularis and atrial fibrillation, colocalization PP4 = 97.0%. b Subcutaneous adipose tissue and cardio-embolic stroke, colocalization PP4 = 5.4%. c Aortic valve and all ischemic stroke, colocalization PP4 = 15.7%. GWAS associations were obtained from Nielsen et al.31 and the MEGASTROKE Consortium32. The lead GWAS variant is annotated.