Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries

Doris Skoric-Milosavljevic; Rafik Tadros; Fernanda M Bosada; Federico Tessadori; Jan Hendrik van Weerd; Odilia Ilse Woudstra; Fleur V.Y. Tjong; Najim Lahrouchi; FANNY BAJOLLE; Heather J Cordell; AJ Agopian; Gillian M Blue; Daniela QCM Barge-Schaapveld; Marc H Gewillig; Christoph Preuss; Elisabeth M Lodder; Phil Barnett; Aho Ilgun; Leander Beekman; Karel van Duijvenboden; Regina Bokenkamp; Martina Müller-Nurasyid; Hubert W Vliegen; Thelma C Konings; Joost P van Melle; Arie van Dijk; Roland RJ van Kimmenade; Jolien W Roos-Hesselink; Gertjan Sieswerda; Folkert Meijboom; Hashim Abdul-Khaliq; Felix Berger; Sven Dittrich; Marc-Phillip Hitz; Julia Moosmann; Frank-Thomas Riede; Stephan Schubert; Pilar Galan; G Mark Lathrop; Hans Markus Munter; Ammar Al-Chalabi; Christopher E. Shaw; Pamela J. Shaw; Karen E. Morrison; Jan H. Veldink; Leonard H van den Berg; Sylvia M Evans; Marcelo A Nobrega; Ivy Aneas; Milena Radivojkov-Blagojevic; Thomas Meitinger; Erwin Oechslin; Tapas Mondal; M Lynn Bergin; John F Smythe; Luis Altamirano-Diaz; Jane Lougheed; Berto J Bouma; Marie A Chaix; Jennie Kline; Anne Susan Bassett; Gregor Andelfinger; Roel LF van der Palen; Patrice Bouvagnet; Sally-Ann B Clur; Jeroen Breckpot; Wilhelmina S. Kerstjens-Frederikse; David S Winlaw; Ulrike Bauer; Seema Mital; Elizabeth Goldmuntz; Bernard D Keavney; Damien Bonnet; Barbara J. Mulder; Michael Tanck; Jeroen Bakkers; Vincent M Christoffels; Cornelis J Boogerd; Alex V Postma; Connie R Bezzina

doi:10.1161/circresaha.120.317107

Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries

Doris Skoric-Milosavljevic, Rafik Tadros, Fernanda M Bosada, Federico Tessadori, Jan Hendrik van Weerd, Odilia Ilse Woudstra, Fleur V.Y. Tjong, Najim Lahrouchi, FANNY BAJOLLE, Heather J Cordell, AJ Agopian, Gillian M Blue, Daniela QCM Barge-Schaapveld, Marc H Gewillig, Christoph Preuss, Elisabeth M Lodder, Phil Barnett, Aho Ilgun, Leander Beekman, Karel van DuijvenbodenRegina Bokenkamp, Martina Müller-Nurasyid, Hubert W Vliegen, Thelma C Konings, Joost P van Melle, Arie van Dijk, Roland RJ van Kimmenade, Jolien W Roos-Hesselink, Gertjan Sieswerda, Folkert Meijboom, Hashim Abdul-Khaliq, Felix Berger, Sven Dittrich, Marc-Phillip Hitz, Julia Moosmann, Frank-Thomas Riede, Stephan Schubert, Pilar Galan, G Mark Lathrop, Hans Markus Munter, Ammar Al-Chalabi, Christopher E. Shaw, Pamela J. Shaw, Karen E. Morrison, Jan H. Veldink, Leonard H van den Berg, Sylvia M Evans, Marcelo A Nobrega, Ivy Aneas, Milena Radivojkov-Blagojevic, Thomas Meitinger, Erwin Oechslin, Tapas Mondal, M Lynn Bergin, John F Smythe, Luis Altamirano-Diaz, Jane Lougheed, Berto J Bouma, Marie A Chaix, Jennie Kline, Anne Susan Bassett, Gregor Andelfinger, Roel LF van der Palen, Patrice Bouvagnet, Sally-Ann B Clur, Jeroen Breckpot, Wilhelmina S. Kerstjens-Frederikse, David S Winlaw, Ulrike Bauer, Seema Mital, Elizabeth Goldmuntz, Bernard D Keavney, Damien Bonnet, Barbara J. Mulder, Michael Tanck, Jeroen Bakkers, Vincent M Christoffels, Cornelis J Boogerd, Alex V Postma, Connie R Bezzina

School of Nursing and Midwifery

Research output: Contribution to journal › Article › peer-review

Abstract

Background: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. Methods: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10-10, OR=0.69 per C allele). Results: SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10-5). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A, which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart. Conclusions: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A. Genomic and functional data support a causal role of WNT5A at the locus.

Original language	English
Journal	Circulation Research
Early online date	10 Dec 2021
DOIs	https://doi.org/10.1161/circresaha.120.317107
Publication status	Early online date - 10 Dec 2021

Keywords

Cardiology and Cardiovascular Medicine
Physiology

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10.1161/circresaha.120.317107Licence: CC BY-NC-ND

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Skoric-Milosavljevic, D., Tadros, R., Bosada, F. M., Tessadori, F., van Weerd, J. H., Woudstra, O. I., Tjong, F. V. Y., Lahrouchi, N., BAJOLLE, FANNY., Cordell, H. J., Agopian, AJ., Blue, G. M., Barge-Schaapveld, D. QCM., Gewillig, M. H., Preuss, C., Lodder, E. M., Barnett, P., Ilgun, A., Beekman, L., ... Bezzina, C. R. (2021). Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries. Circulation Research. https://doi.org/10.1161/circresaha.120.317107

@article{7bab00a47d1f4485a517ce2aa858387f,

title = "Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries",

abstract = "Background: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. Methods: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10-10, OR=0.69 per C allele). Results: SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10-5). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A, which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart. Conclusions: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A. Genomic and functional data support a causal role of WNT5A at the locus.",

keywords = "Cardiology and Cardiovascular Medicine, Physiology",

author = "Doris Skoric-Milosavljevic and Rafik Tadros and Bosada, {Fernanda M} and Federico Tessadori and {van Weerd}, {Jan Hendrik} and Woudstra, {Odilia Ilse} and Tjong, {Fleur V.Y.} and Najim Lahrouchi and FANNY BAJOLLE and Cordell, {Heather J} and AJ Agopian and Blue, {Gillian M} and Barge-Schaapveld, {Daniela QCM} and Gewillig, {Marc H} and Christoph Preuss and Lodder, {Elisabeth M} and Phil Barnett and Aho Ilgun and Leander Beekman and {van Duijvenboden}, Karel and Regina Bokenkamp and Martina M{\"u}ller-Nurasyid and Vliegen, {Hubert W} and Konings, {Thelma C} and {van Melle}, {Joost P} and {van Dijk}, Arie and {van Kimmenade}, {Roland RJ} and Roos-Hesselink, {Jolien W} and Gertjan Sieswerda and Folkert Meijboom and Hashim Abdul-Khaliq and Felix Berger and Sven Dittrich and Marc-Phillip Hitz and Julia Moosmann and Frank-Thomas Riede and Stephan Schubert and Pilar Galan and Lathrop, {G Mark} and Munter, {Hans Markus} and Ammar Al-Chalabi and Shaw, {Christopher E.} and Shaw, {Pamela J.} and Morrison, {Karen E.} and Veldink, {Jan H.} and {van den Berg}, {Leonard H} and Evans, {Sylvia M} and Nobrega, {Marcelo A} and Ivy Aneas and Milena Radivojkov-Blagojevic and Thomas Meitinger and Erwin Oechslin and Tapas Mondal and Bergin, {M Lynn} and Smythe, {John F} and Luis Altamirano-Diaz and Jane Lougheed and Bouma, {Berto J} and Chaix, {Marie A} and Jennie Kline and Bassett, {Anne Susan} and Gregor Andelfinger and {van der Palen}, {Roel LF} and Patrice Bouvagnet and Clur, {Sally-Ann B} and Jeroen Breckpot and Kerstjens-Frederikse, {Wilhelmina S.} and Winlaw, {David S} and Ulrike Bauer and Seema Mital and Elizabeth Goldmuntz and Keavney, {Bernard D} and Damien Bonnet and Mulder, {Barbara J.} and Michael Tanck and Jeroen Bakkers and Christoffels, {Vincent M} and Boogerd, {Cornelis J} and Postma, {Alex V} and Bezzina, {Connie R}",

year = "2021",

month = dec,

day = "10",

doi = "10.1161/circresaha.120.317107",

language = "English",

journal = "Circulation Research",

issn = "0009-7330",

publisher = "Lippincott Williams and Wilkins",

}

Skoric-Milosavljevic, D, Tadros, R, Bosada, FM, Tessadori, F, van Weerd, JH, Woudstra, OI, Tjong, FVY, Lahrouchi, N, BAJOLLE, FANNY, Cordell, HJ, Agopian, AJ, Blue, GM, Barge-Schaapveld, DQCM, Gewillig, MH, Preuss, C, Lodder, EM, Barnett, P, Ilgun, A, Beekman, L, van Duijvenboden, K, Bokenkamp, R, Müller-Nurasyid, M, Vliegen, HW, Konings, TC, van Melle, JP, van Dijk, A, van Kimmenade, RRJ, Roos-Hesselink, JW, Sieswerda, G, Meijboom, F, Abdul-Khaliq, H, Berger, F, Dittrich, S, Hitz, M-P, Moosmann, J, Riede, F-T, Schubert, S, Galan, P, Lathrop, GM, Munter, HM, Al-Chalabi, A, Shaw, CE, Shaw, PJ, Morrison, KE, Veldink, JH, van den Berg, LH, Evans, SM, Nobrega, MA, Aneas, I, Radivojkov-Blagojevic, M, Meitinger, T, Oechslin, E, Mondal, T, Bergin, ML, Smythe, JF, Altamirano-Diaz, L, Lougheed, J, Bouma, BJ, Chaix, MA, Kline, J, Bassett, AS, Andelfinger, G, van der Palen, RLF, Bouvagnet, P, Clur, S-AB, Breckpot, J, Kerstjens-Frederikse, WS, Winlaw, DS, Bauer, U, Mital, S, Goldmuntz, E, Keavney, BD, Bonnet, D, Mulder, BJ, Tanck, M, Bakkers, J, Christoffels, VM, Boogerd, CJ, Postma, AV & Bezzina, CR 2021, 'Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries', Circulation Research. https://doi.org/10.1161/circresaha.120.317107

TY - JOUR

T1 - Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries

AU - Skoric-Milosavljevic, Doris

AU - Tadros, Rafik

AU - Bosada, Fernanda M

AU - Tessadori, Federico

AU - van Weerd, Jan Hendrik

AU - Woudstra, Odilia Ilse

AU - Tjong, Fleur V.Y.

AU - Lahrouchi, Najim

AU - BAJOLLE, FANNY

AU - Cordell, Heather J

AU - Agopian, AJ

AU - Blue, Gillian M

AU - Barge-Schaapveld, Daniela QCM

AU - Gewillig, Marc H

AU - Preuss, Christoph

AU - Lodder, Elisabeth M

AU - Barnett, Phil

AU - Ilgun, Aho

AU - Beekman, Leander

AU - van Duijvenboden, Karel

AU - Bokenkamp, Regina

AU - Müller-Nurasyid, Martina

AU - Vliegen, Hubert W

AU - Konings, Thelma C

AU - van Melle, Joost P

AU - van Dijk, Arie

AU - van Kimmenade, Roland RJ

AU - Roos-Hesselink, Jolien W

AU - Sieswerda, Gertjan

AU - Meijboom, Folkert

AU - Abdul-Khaliq, Hashim

AU - Berger, Felix

AU - Dittrich, Sven

AU - Hitz, Marc-Phillip

AU - Moosmann, Julia

AU - Riede, Frank-Thomas

AU - Schubert, Stephan

AU - Galan, Pilar

AU - Lathrop, G Mark

AU - Munter, Hans Markus

AU - Al-Chalabi, Ammar

AU - Shaw, Christopher E.

AU - Shaw, Pamela J.

AU - Morrison, Karen E.

AU - Veldink, Jan H.

AU - van den Berg, Leonard H

AU - Evans, Sylvia M

AU - Nobrega, Marcelo A

AU - Aneas, Ivy

AU - Radivojkov-Blagojevic, Milena

AU - Meitinger, Thomas

AU - Oechslin, Erwin

AU - Mondal, Tapas

AU - Bergin, M Lynn

AU - Smythe, John F

AU - Altamirano-Diaz, Luis

AU - Lougheed, Jane

AU - Bouma, Berto J

AU - Chaix, Marie A

AU - Kline, Jennie

AU - Bassett, Anne Susan

AU - Andelfinger, Gregor

AU - van der Palen, Roel LF

AU - Bouvagnet, Patrice

AU - Clur, Sally-Ann B

AU - Breckpot, Jeroen

AU - Kerstjens-Frederikse, Wilhelmina S.

AU - Winlaw, David S

AU - Bauer, Ulrike

AU - Mital, Seema

AU - Goldmuntz, Elizabeth

AU - Keavney, Bernard D

AU - Bonnet, Damien

AU - Mulder, Barbara J.

AU - Tanck, Michael

AU - Bakkers, Jeroen

AU - Christoffels, Vincent M

AU - Boogerd, Cornelis J

AU - Postma, Alex V

AU - Bezzina, Connie R

PY - 2021/12/10

Y1 - 2021/12/10

N2 - Background: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. Methods: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10-10, OR=0.69 per C allele). Results: SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10-5). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A, which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart. Conclusions: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A. Genomic and functional data support a causal role of WNT5A at the locus.

AB - Background: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. Methods: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10-10, OR=0.69 per C allele). Results: SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10-5). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A, which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart. Conclusions: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A. Genomic and functional data support a causal role of WNT5A at the locus.

KW - Cardiology and Cardiovascular Medicine

KW - Physiology

U2 - 10.1161/circresaha.120.317107

DO - 10.1161/circresaha.120.317107

M3 - Article

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

ER -

Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries

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