Genome-wide association study in European patients with congenital heart disease identifies risk loci for transposition of the great arteries and anomalies of the thoracic arteries and veins and expression of discovered candidate genes in the developing heart

Lahm, Harald; Jia, Ming; Dreßen, Martina; Wirth, Fabian; Puluca, Nazan; Gilsbach, Ralf; Bd, Keavney; Cleuziou, Julie; Beck, Nicole; Bondareva, Olga; Dzilic, Elda; Burri, Melchior; Kc, König; Ja, Ziegelmüller; Abou‐Ajram, Claudia; I, Neb; Z, Zhang; Sa, Doppler; Mastantuono, Elisa; Lichtner, Peter; Eckstein, Gertrud; Hörer, Jürgen; Ewert, Peter; Priest,; Hein, Lutz; Lange, Rüdiger; Meitinger, Thomas; Cordell, Heather J.; Müller‐Myhsok, Bertram; Krane, Markus

doi:10.1101/2020.06.19.161067

Cited by 3 publications

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References 67 publications

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“…Previously identified in GWAS of blood pressure(37, 38) and aortic root diameter(38), the two variants in GOSR2 identified in systole (rs6504673) and diastole (rs533030436) display essentially no linkage in European populations (R2 0.02) and arise from different haplotypes [Figure S9]. The variant rs533030436 identified in diastolic measures is in strong linkage with rs11874 (R 2 0.84) recently identified in congenital cardiovascular malformations(39) as well as rs17608766 (R 2 0.76) identified in Aortic valve stenosis(27) in the same UK Biobank MRI dataset. The cusps and annulus of the mitral valve are composed primarily of endothelial cells and valvular interstitial cells which may differentiate to myofibroblasts in disease states(40).…”

Section: Discussionmentioning

confidence: 87%

Computational estimates of mitral annular diameter in systole and diastole cardiac cycle reveal novel genetic determinants of valve function and disease

Tcheandjieu

Georges

et al. 2020

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The fibrous annulus of the mitral valve defines the functional orifice and anchors the anterior and posterior leaflets, playing an important role in normal cardiovascular physiology and valvular function. We derived automated estimates of mitral valve annular diameter in the 4-chamber view from 32,220 MRI images from the UK Biobank at ventricular systole and diastole as the basis for genome wide association studies. Mitral annular dimensions correspond to previously described anatomical norms and GWAS inclusive of four population strata identify ten loci, including novel loci (GOSR2, ERBB4, MCTP2, MCPH1) and genes related to cardiac contractility (BAG3, TTN, RBFOX1). ATAC-seq of primary mitral valve tissue localize multiple variants to regions of open chromatin in biologically relevant cell types and rs17608766 to an algorithmically predicted enhancer element in GOSR2. We observed strong genetic correlation with measures of contractility and mitral valve disease, and clinical correlations with heart failure, cerebrovascular disease, and ventricular arrythmias. A polygenic score of mitral valve annular diameter in systole was predictive of risk mitral valve prolapse across four cohorts (Odds ratio 1.19 per SD increase in polygenic score, 95% confidence interval 1.14 to 1.24, p=4.9E-11). In summary genetic and clinical studies of mitral valve annular diameter reveal new genetic determinants of mitral valve biology while highlighting known and previously unrecognized clinical associations. Polygenic determinants of mitral valve annular diameter may represent an independent risk-factor for mitral prolapse. Overall, computationally estimated phenotypes derived at scale from medical imaging represent an important substrate for genetic discovery and clinical risk prediction.

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Section: Discussionmentioning

confidence: 87%

Computational estimates of mitral annular diameter in systole and diastole cardiac cycle reveal novel genetic determinants of valve function and disease

Tcheandjieu

Georges

et al. 2020

Preprint

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“…ZBTB10 encodes a telomere-associated protein [23]. Lately, a GWAS involving 4,000 unrelated Caucasian patients diagnosed with CHD indicated that ZBTB10 was associated with TGA, since two highly signi cant SNPs (rs148563140 and rs143638934) closely located to this gene [24]. Furthermore, they suggested strong cell-type speci city in murine cardiac development for Zbtb10.…”

Section: Discussionmentioning

confidence: 99%

Rare Copy Number Variation Analysis in Chinese Children of Complete Atrioventricular Canal and Single Ventricle 

Zhang

Wang

You

et al. 2021

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Background: Congenital heart disease (CHD) is the most common birth defects. Copy number variations (CNVs) have been proved to be important genetic factors that contribute to CHD. Here, we screened pathogenic CNVs in Chinese children with two rare types of CHD, complete atrioventricular canal (CAVC) and single ventricle (SV) .Methods：We screened CNVs in 262 sporadic CAVC cases and 259 sporadic SV cases respectively, using a customized SNP array. The detected CNVs were annotated and filtered using available databases.Results: Among 262 CAVC patients, we identified 44 rare CNVs in 43 individuals (16.4 %, 43/262), including 2 syndrome-related CNVs (7q11.23 and 8q24.3 deletion). Surprisingly, 88.6% rare CNVs (39/44) were duplications of 21q11.2-21q22.3, which were categorized as trisomy 21 (Down syndrome, DS). In CAVC with DS patients, the female to male ratio was 1.6:1 (24:15), and the rate of pulmonary hypertension (PH) was 41% (16/39). Additionally, 6 rare CNVs were identified in the SV patients (2.3%, 6/259), and none of them was trisomy 21.Conclusions: Our study identified 50 rare CNVs in 262 CAVC and 259 SV patients, representing the largest cohort of these two rare CHD types in Chinese population. The results provided strong correlation between CAVC and DS, which also showed sex difference and higher incidence of PH. The presence of rare CNVs suggests the etiology of complex CHD is incredibly diverse, and CHD candidate genes remain to be discovered.

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“…ZBTB10 encodes a telomere-associated protein [41]. Lately, a GWAS involving 4,000 unrelated Caucasian patients diagnosed with CHD indicated that ZBTB10 was associated with TGA, since two highly significant SNPs (rs148563140 and rs143638934) closely located to this gene [42]. Furthermore, they suggested strong cell-type specificity in murine cardiac development for Zbtb10.…”

Section: Discussionmentioning

confidence: 99%

Copy number variation analysis in Chinese children with complete atrioventricular canal and single ventricle

et al. 2021

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Background Congenital heart disease (CHD) is one of the most common birth defects. Copy number variations (CNVs) have been proved to be important genetic factors that contribute to CHD. Here we screened genome-wide CNVs in Chinese children with complete atrioventricular canal (CAVC) and single ventricle (SV), since there were scarce researches dedicated to these two types of CHD. Methods We screened CNVs in 262 sporadic CAVC cases and 259 sporadic SV cases respectively, using a customized SNP array. The detected CNVs were annotated and filtered using available databases. Results Among 262 CAVC patients, we identified 6 potentially-causative CNVs in 43 individuals (16.41%, 43/262), including 2 syndrome-related CNVs (7q11.23 and 8q24.3 deletion). Surprisingly, 90.70% CAVC patients with detected CNVs (39/43) were found to carry duplications of 21q11.2–21q22.3, which were recognized as trisomy 21 (Down syndrome, DS). In CAVC with DS patients, the female to male ratio was 1.6:1.0 (24:15), and the rate of pulmonary hypertension (PH) was 41.03% (16/39). Additionally, 6 potentially-causative CNVs were identified in the SV patients (2.32%, 6/259), and none of them was trisomy 21. Most CNVs identified in our cohort were classified as rare (< 1%), occurring just once among CAVC or SV individuals except the 21q11.2–21q22.3 duplication (14.89%) in CAVC cohort. Conclusions Our study identified 12 potentially-causative CNVs in 262 CAVC and 259 SV patients, representing the largest cohort of these two CHD types in Chinese population. The results provided strong correlation between CAVC and DS, which also showed sex difference and high incidence of PH. The presence of potentially-causative CNVs suggests the etiology of complex CHD is incredibly diverse, and CHD candidate genes remain to be discovered.

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Genome-wide association study in European patients with congenital heart disease identifies risk loci for transposition of the great arteries and anomalies of the thoracic arteries and veins and expression of discovered candidate genes in the developing heart

Cited by 3 publications

References 67 publications

Computational estimates of mitral annular diameter in systole and diastole cardiac cycle reveal novel genetic determinants of valve function and disease

Computational estimates of mitral annular diameter in systole and diastole cardiac cycle reveal novel genetic determinants of valve function and disease

Rare Copy Number Variation Analysis in Chinese Children of Complete Atrioventricular Canal and Single Ventricle

Copy number variation analysis in Chinese children with complete atrioventricular canal and single ventricle

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Genome-wide association study in European patients with congenital heart disease identifies risk loci for transposition of the great arteries and anomalies of the thoracic arteries and veins and expression of discovered candidate genes in the developing heart

Cited by 3 publications

References 67 publications

Computational estimates of mitral annular diameter in systole and diastole cardiac cycle reveal novel genetic determinants of valve function and disease

Computational estimates of mitral annular diameter in systole and diastole cardiac cycle reveal novel genetic determinants of valve function and disease

Rare Copy Number Variation Analysis in Chinese Children of Complete Atrioventricular Canal and Single Ventricle&nbsp;

Copy number variation analysis in Chinese children with complete atrioventricular canal and single ventricle

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Rare Copy Number Variation Analysis in Chinese Children of Complete Atrioventricular Canal and Single Ventricle