We have previously demonstrated that p.Arg721Trp associates strongly with SSS and AF, atrial arrhythmias that are common in the elderly and frequently coexist.31 With larger sample sizes, these associations have become stronger; however, previously reported association with thoracic aortic aneurysm is no longer significant (Table 1). In the context of assessing effects of AF risk variants on cardiac conduction, we have also recently shown that p.Arg721Trp associates with many ECG measures corresponding to a widespread effect on electrical function of the heart32 (see Supplementary material online, Figure S3).

Table 1
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Association of p.Arg721Trp with congenital heart defects and various cardiac phenotypes

NaffNcontrOR/effect (95% CI)aP-value
Congenital heart defects
 Coarctation of the aorta120355 11644.2 (20.5 to 95.5)5.0 × 10−22
 Bicuspid aortic valve208293 34610.5 (2.6 to 38.0)7.3 × 10−8
 Ventricular septal defect715357 6414.4 (1.9 to 10.0)3.7 × 10−4
 Patent ductus arteriosus594357 7624.9 (2.1 to 11.6)2.3 × 10−4
 Atrial septal defect657353 0963.3 (1.5 to 7.1)0.0026
Cardiac conditions
 Sick sinus syndrome3310346 0828.7 (6.8 to 11.2)6.2 × 10−64
 Atrial fibrillation13 471374 9392.4 (1.9 to 3.0)1.1 × 10−14
 Aortic valve stenosis2457349 3422.7 (1.8 to 4.0)1.8 × 10−6
 Heart failure10 480353 5081.8 (1.4 to 2.3)2.3 × 10−6
 Ischaemic stroke8948369 6241.5 (1.1 to 2.0)0.0029
 High degree atrioventricular block1303361 9192.1 (1.2 to 3.5)0.0092
 Coronary artery disease37 782318 8451.2 (1.0 to 1.5)0.056
 Hypertrophic cardiomyopathy163239 2930.0 (0.0 to 4.5)0.15
 Thoracic aortic aneurysm353302 4581.8 (0.6 to 5.3)0.31
 Hypertension54 974324 8031.1 (0.9 to 1.3)0.44
Echocardiogram
 Left atrial diameter19 3800.3 (0.1 to 0.5)2.6 × 10−4
 Aortic root diameter19 506−0.1 (−0.2 to 0.1)0.41
 LVEDDb57010.0 (−0.3 to 0.3)0.93
NaffNcontrOR/effect (95% CI)aP-value
Congenital heart defects
 Coarctation of the aorta120355 11644.2 (20.5 to 95.5)5.0 × 10−22
 Bicuspid aortic valve208293 34610.5 (2.6 to 38.0)7.3 × 10−8
 Ventricular septal defect715357 6414.4 (1.9 to 10.0)3.7 × 10−4
 Patent ductus arteriosus594357 7624.9 (2.1 to 11.6)2.3 × 10−4
 Atrial septal defect657353 0963.3 (1.5 to 7.1)0.0026
Cardiac conditions
 Sick sinus syndrome3310346 0828.7 (6.8 to 11.2)6.2 × 10−64
 Atrial fibrillation13 471374 9392.4 (1.9 to 3.0)1.1 × 10−14
 Aortic valve stenosis2457349 3422.7 (1.8 to 4.0)1.8 × 10−6
 Heart failure10 480353 5081.8 (1.4 to 2.3)2.3 × 10−6
 Ischaemic stroke8948369 6241.5 (1.1 to 2.0)0.0029
 High degree atrioventricular block1303361 9192.1 (1.2 to 3.5)0.0092
 Coronary artery disease37 782318 8451.2 (1.0 to 1.5)0.056
 Hypertrophic cardiomyopathy163239 2930.0 (0.0 to 4.5)0.15
 Thoracic aortic aneurysm353302 4581.8 (0.6 to 5.3)0.31
 Hypertension54 974324 8031.1 (0.9 to 1.3)0.44
Echocardiogram
 Left atrial diameter19 3800.3 (0.1 to 0.5)2.6 × 10−4
 Aortic root diameter19 506−0.1 (−0.2 to 0.1)0.41
 LVEDDb57010.0 (−0.3 to 0.3)0.93

Shown are the number of affected individuals and control individuals used in the association analysis for each of the traits.

a

Estimated odds ratio (OR) or the effect in standard deviation and the 95% confidence interval (CI) for the association with p.Arg721Trp.

b

Left ventricular end-diastolic diameter.

Table 1
Open in new tab

Association of p.Arg721Trp with congenital heart defects and various cardiac phenotypes

NaffNcontrOR/effect (95% CI)aP-value
Congenital heart defects
 Coarctation of the aorta120355 11644.2 (20.5 to 95.5)5.0 × 10−22
 Bicuspid aortic valve208293 34610.5 (2.6 to 38.0)7.3 × 10−8
 Ventricular septal defect715357 6414.4 (1.9 to 10.0)3.7 × 10−4
 Patent ductus arteriosus594357 7624.9 (2.1 to 11.6)2.3 × 10−4
 Atrial septal defect657353 0963.3 (1.5 to 7.1)0.0026
Cardiac conditions
 Sick sinus syndrome3310346 0828.7 (6.8 to 11.2)6.2 × 10−64
 Atrial fibrillation13 471374 9392.4 (1.9 to 3.0)1.1 × 10−14
 Aortic valve stenosis2457349 3422.7 (1.8 to 4.0)1.8 × 10−6
 Heart failure10 480353 5081.8 (1.4 to 2.3)2.3 × 10−6
 Ischaemic stroke8948369 6241.5 (1.1 to 2.0)0.0029
 High degree atrioventricular block1303361 9192.1 (1.2 to 3.5)0.0092
 Coronary artery disease37 782318 8451.2 (1.0 to 1.5)0.056
 Hypertrophic cardiomyopathy163239 2930.0 (0.0 to 4.5)0.15
 Thoracic aortic aneurysm353302 4581.8 (0.6 to 5.3)0.31
 Hypertension54 974324 8031.1 (0.9 to 1.3)0.44
Echocardiogram
 Left atrial diameter19 3800.3 (0.1 to 0.5)2.6 × 10−4
 Aortic root diameter19 506−0.1 (−0.2 to 0.1)0.41
 LVEDDb57010.0 (−0.3 to 0.3)0.93
NaffNcontrOR/effect (95% CI)aP-value
Congenital heart defects
 Coarctation of the aorta120355 11644.2 (20.5 to 95.5)5.0 × 10−22
 Bicuspid aortic valve208293 34610.5 (2.6 to 38.0)7.3 × 10−8
 Ventricular septal defect715357 6414.4 (1.9 to 10.0)3.7 × 10−4
 Patent ductus arteriosus594357 7624.9 (2.1 to 11.6)2.3 × 10−4
 Atrial septal defect657353 0963.3 (1.5 to 7.1)0.0026
Cardiac conditions
 Sick sinus syndrome3310346 0828.7 (6.8 to 11.2)6.2 × 10−64
 Atrial fibrillation13 471374 9392.4 (1.9 to 3.0)1.1 × 10−14
 Aortic valve stenosis2457349 3422.7 (1.8 to 4.0)1.8 × 10−6
 Heart failure10 480353 5081.8 (1.4 to 2.3)2.3 × 10−6
 Ischaemic stroke8948369 6241.5 (1.1 to 2.0)0.0029
 High degree atrioventricular block1303361 9192.1 (1.2 to 3.5)0.0092
 Coronary artery disease37 782318 8451.2 (1.0 to 1.5)0.056
 Hypertrophic cardiomyopathy163239 2930.0 (0.0 to 4.5)0.15
 Thoracic aortic aneurysm353302 4581.8 (0.6 to 5.3)0.31
 Hypertension54 974324 8031.1 (0.9 to 1.3)0.44
Echocardiogram
 Left atrial diameter19 3800.3 (0.1 to 0.5)2.6 × 10−4
 Aortic root diameter19 506−0.1 (−0.2 to 0.1)0.41
 LVEDDb57010.0 (−0.3 to 0.3)0.93

Shown are the number of affected individuals and control individuals used in the association analysis for each of the traits.

a

Estimated odds ratio (OR) or the effect in standard deviation and the 95% confidence interval (CI) for the association with p.Arg721Trp.

b

Left ventricular end-diastolic diameter.

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