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

Lookup NU author(s): Professor Bernard Keavney, Professor Heather Cordell


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Copyright: © 2021, American Society for Clinical Investigation.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.

Publication metadata

Author(s): Lahm H, Jia M, Dressen M, Wirth F, Puluca N, Gilsbach R, Keavney BD, Cleuziou J, Beck N, Bondareva O, Dzilic E, Burri M, Konig KC, Ziegelmuller JA, Abou-Ajram C, Neb I, Zhang Z, Doppler SA, Mastantuono E, Lichtner P, Eckstein G, Horer J, Ewert P, Priest JR, Hein L, Lange R, Meitinger T, Cordell HJ, Muller-Myhsok B, Krane M

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Investigation

Year: 2021

Volume: 131

Issue: 2

Print publication date: 19/01/2021

Online publication date: 17/11/2020

Acceptance date: 12/11/2020

ISSN (print): 0021-9738

ISSN (electronic): 1558-8238

Publisher: American Society for Clinical Investigation


DOI: 10.1172/JCI141837

PubMed id: 33201861


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