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Lahm, H.* ; Jia, M.* ; Dreßen, M.* ; Wirth, F.* ; Puluca, N.* ; Gilsbach, R.* ; Keavney, B.D.* ; Cleuziou, J.* ; Beck, N.* ; Bondareva, O.* ; Dzilic, E.* ; Burri, M.* ; König, K.C.* ; Ziegelmüller, J.A.* ; Abou-Ajram, C.* ; Neb, I.* ; Zhang, Z.* ; Doppler, S.A.* ; Mastantuono, E. ; Lichtner, P. ; Eckstein, G.N. ; Hörer, J.* ; Ewert, P.* ; Priest, J.R.* ; Hein, L.* ; Lange, R.* ; Meitinger, T. ; Cordell, H.J.* ; Müller-Myhsok, B.* ; Krane, M.*

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

J. Clin. Invest. 131:e141837 (2021)
Verlagsversion DOI PMC
Free by publisher
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Copy-number Variants; Macrod2; Mutations; Genetics
ISSN (print) / ISBN 0021-9738
e-ISSN 1558-8238
Zeitschrift Journal of Clinical Investigation
Quellenangaben Band: 131, Heft: 2, Seiten: , Artikelnummer: e141837 Supplement: ,
Verlag American Society of Clinical Investigation
Verlagsort 2015 Manchester Rd, Ann Arbor, Mi 48104 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Human Genetics (IHG)
Förderungen British Heart Foundation
European Union
Deutsche Forschungsgemeinschaft
Deutsches Zentrum fur Herz Kreislauf For-schung
Deutsche Stiftung für Herzforschung
German Federal Ministry of Education and Research (BMBF)
Collaborative Research Centre 992 Medical Epigenetics (DFG grant)