Genome-wide association study of multiple congenital heart disease phenotypes identifies a susceptibility locus for atrial septal defect at chromosome 4p16

被引：108

作者：

Cordell, Heather J. ^{[1
]}

Bentham, Jamie ^{[2
]}

Topf, Ana ^{[1
]}

Zelenika, Diana ^{[3
,4
]}

Heath, Simon ^{[3
,5
]}

Mamasoula, Chrysovalanto ^{[1
]}

Cosgrove, Catherine ^{[2
]}

Blue, Gillian ^{[6
]}

Granados-Riveron, Javier ^{[7
]}

Setchfield, Kerry ^{[7
]}

Thornborough, Chris ^{[8
]}

Breckpot, Jeroen ^{[9
]}

Soemedi, Rachel ^{[1
]}

Martin, Ruairidh ^{[1
]}

Rahman, Thahira J. ^{[1
]}

Hall, Darroch ^{[1
]}

van Engelen, Klaartje ^{[10
]}

Moorman, Antoon F. M. ^{[11
]}

Zwinderman, Aelko H. ^{[12
]}

Barnett, Phil ^{[11
]}

Koopmann, Tamara T. ^{[13
]}

Adriaens, Michiel E. ^{[13
]}

Varro, Andras ^{[14
]}

George, Alfred L., Jr. ^{[15
]}

dos Remedios, Christobal ^{[16
]}

Bishopric, Nanette H. ^{[17
]}

Bezzina, Connie R. ^{[13
]}

O'Sullivan, John ^{[18
]}

Gewillig, Marc ^{[19
]}

Bu'Lock, Frances A. ^{[8
]}

Winlaw, David ^{[6
]}

Bhattacharya, Shoumo ^{[2
]}

Devriendt, Koen ^{[9
]}

Brook, J. David ^{[7
]}

Mulder, Barbara J. M. ^{[20
]}

Mital, Seema ^{[21
]}

Postma, Alex V. ^{[11
]}

Lathrop, G. Mark ^{[3
,4
]}

Farrall, Martin ^{[2
]}

Goodship, Judith A. ^{[1
]}

Keavney, Bernard D. ^{[1
,22
]}

机构：

[1] Newcastle Univ, Inst Med Genet, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[2] Univ Oxford, Dept Cardiovasc Med, Oxford, England

[3] CEA, Inst Genom, Ctr Natl Genotypage, Evry, France

[4] Fdn Jean Dausset, Ctr Etud Polymorphisme Humain, Paris, France

[5] Ctr Nacl Anal Genom, Barcelona, Spain

[6] Childrens Hosp Westmead, Westmead, NSW, Australia

[7] Univ Nottingham, Inst Genet, Nottingham NG7 2RD, England

[8] Univ Hosp Leicester Natl Hlth Serv NHS Trust, East Midlands Congenital Heart Ctr, Leicester, Leics, England

[9] Univ Louvain, Ctr Human Genet, Leuven, Belgium

[10] Univ Amsterdam, Acad Med Ctr, Dept Clin Genet, NL-1105 AZ Amsterdam, Netherlands

[11] Univ Amsterdam, Acad Med Ctr, Heart Failure Res Ctr, NL-1105 AZ Amsterdam, Netherlands

[12] Univ Amsterdam, Acad Med Ctr, Dept Clin Epidemiol Biostat & Bioinformat, NL-1105 AZ Amsterdam, Netherlands

[13] Univ Amsterdam, Acad Med Ctr, Heart Failure Res Ctr, Dept Clin & Expt Cardiol, NL-1105 AZ Amsterdam, Netherlands

[14] Univ Szeged, Fac Med, Dept Pharmacol & Pharmacotherapy, Szeged, Hungary

[15] Vanderbilt Univ, Dept Med, Div Med Genet, Nashville, TN USA

[16] Univ Sydney, Dept Anat, Bosch Inst, Muscle Res Unit, Sydney, NSW 2006, Australia

[17] Univ Miami, Miller Sch Med, Dept Med Mol & Cellular Pharmacol, Miami, FL 33136 USA

[18] Newcastle Hosp NHS Fdn Trust, Newcastle Upon Tyne, Tyne & Wear, England

[19] Univ Louvain, Leuven, Belgium

[20] Univ Amsterdam, Acad Med Ctr, Ctr Heart, NL-1105 AZ Amsterdam, Netherlands

[21] Hosp Sick Children, Toronto, ON M5G 1X8, Canada

[22] Univ Manchester, Inst Cardiovasc Sci, Manchester, Lancs, England

来源：

NATURE GENETICS | 2013年 / 45卷 / 07期

基金：

英国惠康基金; 美国国家卫生研究院;

关键词：

MSX1; TETRALOGY; MUTATION;

D O I：

10.1038/ng.2637

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

We carried out a genome-wide association study (GWAS) of congenital heart disease (CHD). Our discovery cohort comprised 1,995 CHD cases and 5,159 controls and included affected individuals from each of the 3 major clinical CHD categories (with septal, obstructive and cyanotic defects). When all CHD phenotypes were considered together, no region achieved genome-wide significant association. However, a region on chromosome 4p16, adjacent to the MSX1 and STX18 genes, was associated (P = 9.5 x 10(-7)) with the risk of ostium secundum atrial septal defect (ASD) in the discovery cohort (N = 340 cases), and this association was replicated in a further 417 ASD cases and 2,520 controls (replication P = 5.0 x 10(-5); odds ratio (OR) in replication cohort = 1.40, 95% confidence interval (CI) = 1.19-1.65; combined P = 2.6 x 10(-10)). Genotype accounted for similar to 9% of the population-attributable risk of ASD.

引用

页码：822 / U151

页数：5

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