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

被引：46

作者：

Lahm, Harald ^{[1
]}

Jia, Meiwen ^{[2
]}

Dressen, Martina ^{[1
]}

Wirth, Felix ^{[1
]}

Puluca, Nazan ^{[1
]}

Gilsbach, Ralf ^{[3
,4
]}

Keavney, Bernard D. ^{[5
,6
]}

Cleuziou, Julie ^{[7
]}

Beck, Nicole ^{[1
]}

Bondareva, Olga ^{[8
]}

Dzilic, Elda ^{[1
]}

Burri, Melchior ^{[1
]}

Konig, Karl C. ^{[1
]}

Ziegelmuller, Johannes A. ^{[1
]}

Abou-Ajram, Claudia ^{[1
]}

Neb, Irina ^{[1
]}

Zhang, Zhong ^{[1
]}

Doppler, Stefanie A. ^{[1
]}

Mastantuono, Elisa ^{[9
,10
]}

Lichtner, Peter ^{[9
]}

Eckstein, Gertrud ^{[9
]}

Horer, Jurgen ^{[7
]}

Ewert, Peter ^{[11
]}

Priest, James R. ^{[12
]}

Hein, Lutz ^{[8
,13
]}

Lange, Rudiger ^{[1
,14
]}

Meitinger, Thomas ^{[9
,10
,14
]}

Cordell, Heather J. ^{[15
]}

Mueller-Myhsok, Bertram ^{[2
,16
,17
]}

Krane, Markus ^{[1
,14
]}

机构：

[1] German Heart Ctr Munich, Inst Translat Cardiac Surg, Dept Cardiovasc Surg, Div Expt Surg,Inst Insure, Munich, Germany

[2] Max Planck Inst Psychiat Munich, Dept Translat Res Psychiat, Munich, Germany

[3] Goethe Univ, Inst Cardiovasc Physiol, Frankfurt, Germany

[4] DZHK German Ctr Cardiovasc Res, Partner Site RheinMain, Frankfurt, Germany

[5] Univ Manchester, Fac Biol, Sch Med Sci, Div Cardiovasc Sci, Manchester, Lancs, England

[6] Manchester Univ NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Manchester Heart Ctr, Manchester, Lancs, England

[7] German Heart Ctr Munich, Dept Congenital & Paediat Heart Surg, Munich, Germany

[8] Univ Freiburg, Fac Med, Inst Expt & Clin Pharmacol & Toxicol, Freiburg, Germany

[9] German Res Ctr Environm Hlth, Helmholtz Ctr Munich, Inst Human Genet, Neuherberg, Germany

[10] Tech Univ Munich, Inst Human Genet, Klinikum Rechts Isar, Munich, Germany

[11] German Heart Ctr Munich, Dept Pediat Cardiol & Congenital Heart Dis, Munich, Germany

[12] Stanford Univ, Dept Pediat, Div Pediat Cardiol, Sch Med, Palo Alto, CA 94304 USA

[13] Univ Freiburg, Ctr Biol Signaling Studies, BIOSS, Freiburg, Germany

[14] DZHK German Ctr Cardiovasc Res, Partner Site Munich Head Alliance, Munich, Germany

[15] Newcastle Univ, Fac Med Sci, Int Ctr Life, Populat Hlth Sci Inst, Cent Pkwy, Newcastle Upon Tyne, Tyne & Wear, England

[16] SyNergy, Munich Cluster Syst Biol, Munich, Germany

[17] Univ Liverpool, Inst Translat Med, Liverpool, Merseyside, England

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2021年 / 131卷 / 02期

关键词：

COPY-NUMBER VARIANTS; MACROD2; GENE; MUTATIONS; PHENOTYPE; MOUSE;

D O I：

10.1172/JCI141837

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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 MSX7. 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 MSX7 play an essential functional role in heart development at the embryonic and newborn stages.

引用

页数：19

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