Congenital heart disease risk loci identified by genome-wide association study in European patients
Harald Lahm, … , Bertram Müller-Myhsok, Markus Krane
Harald Lahm, … , Bertram Müller-Myhsok, Markus Krane
Published November 17, 2020
Citation Information: J Clin Invest. 2021;131(2):e141837. https://doi.org/10.1172/JCI141837.
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Research Article Cardiology Genetics

Congenital heart disease risk loci identified by genome-wide association study in European patients

Abstract

Genetic factors undoubtedly affect the development of congenital heart disease (CHD) but still remain ill defined. We sought to identify genetic risk factors associated with CHD and to accomplish a functional analysis of SNP-carrying genes. We performed a genome-wide association study (GWAS) of 4034 White patients with CHD and 8486 healthy controls. One SNP on chromosome 5q22.2 reached genome-wide significance across all CHD phenotypes and was also indicative for septal defects. One region on chromosome 20p12.1 pointing to the MACROD2 locus identified 4 highly significant SNPs in patients with transposition of the great arteries (TGA). Three highly significant risk variants on chromosome 17q21.32 within the GOSR2 locus were detected in patients with anomalies of thoracic arteries and veins (ATAV). Genetic variants associated with ATAV are suggested to influence the expression of WNT3, and the variant rs870142 related to septal defects is proposed to influence the expression of MSX1. We analyzed the expression of all 4 genes during cardiac differentiation of human and murine induced pluripotent stem cells in vitro and by single-cell RNA-Seq analyses of developing murine and human hearts. Our data show that MACROD2, GOSR2, WNT3, and MSX1 play an essential functional role in heart development at the embryonic and newborn stages.

Authors

Harald Lahm, Meiwen Jia, Martina Dreßen, Felix Wirth, Nazan Puluca, Ralf Gilsbach, Bernard D. Keavney, Julie Cleuziou, Nicole Beck, Olga Bondareva, Elda Dzilic, Melchior Burri, Karl C. König, Johannes A. Ziegelmüller, Claudia Abou-Ajram, Irina Neb, Zhong Zhang, Stefanie A. Doppler, Elisa Mastantuono, Peter Lichtner, Gertrud Eckstein, Jürgen Hörer, Peter Ewert, James R. Priest, Lutz Hein, Rüdiger Lange, Thomas Meitinger, Heather J. Cordell, Bertram Müller-Myhsok, Markus Krane

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Figure 1

Identification of SNPs with genome-wide significance across the entire CHD study group.

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Identification of SNPs with genome-wide significance across the entire C...
(A) Manhattan plot of genome-wide P values for association with the entire CHD study group. (B) LocusZoom plot of the genomic region of rs185531658 on chromosome 5 (chr5). The index SNPs are indicated by a purple diamonds. The forest plot shows the significance of the SNP and the ORs of both collectives separately and together. Circles represent imputed SNPs and triangles represent genotyped SNPs. FE, fixed effects; RE, random effects. Patients with CHD, n = 2594; control participants, n = 8486. –log10 P values were determined by association statistics from the GWAS (logistic regression).