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

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 recurr...

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Autores principales: Škorić-Milosavljević, Doris, Tadros, Rafik, Bosada, Fernanda M., Tessadori, Federico, van Weerd, Jan Hendrik, Woudstra, Odilia I., Tjong, Fleur V.Y., Lahrouchi, Najim, Bajolle, Fanny, Cordell, Heather J., Agopian, A.J., Blue, Gillian M., Barge-Schaapveld, Daniela Q.C.M., Gewillig, Marc, Preuss, Christoph, Lodder, Elisabeth M., Barnett, Phil, Ilgun, Aho, Beekman, Leander, van Duijvenboden, Karel, Bokenkamp, Regina, Müller-Nurasyid, Martina, Vliegen, Hubert W., Konings, Thelma C., van Melle, Joost P., van Dijk, Arie P.J., van Kimmenade, Roland R.J., Roos-Hesselink, Jolien W., Sieswerda, Gertjan T., Meijboom, Folkert, Abdul-Khaliq, Hashim, Berger, Felix, Dittrich, Sven, Hitz, Marc-Phillip, Moosmann, Julia, Riede, Frank-Thomas, Schubert, Stephan, Galan, Pilar, Lathrop, Mark, Munter, Hans M., Al-Chalabi, Ammar, Shaw, Christopher E., Shaw, Pamela J., Morrison, Karen E., Veldink, Jan H., van den Berg, Leonard H., Evans, Sylvia, Nobrega, Marcelo A., Aneas, Ivy, Radivojkov-Blagojević, Milena, Meitinger, Thomas, Oechslin, Erwin, Mondal, Tapas, Bergin, Lynn, Smythe, John F., Altamirano-Diaz, Luis, Lougheed, Jane, Bouma, Berto J., Chaix, Marie-A., Kline, Jennie, Bassett, Anne S., Andelfinger, Gregor, van der Palen, Roel L.F., Bouvagnet, Patrice, Clur, Sally-Ann B., Breckpot, Jeroen, Kerstjens-Frederikse, Wilhelmina S., Winlaw, David S., Bauer, Ulrike M.M., Mital, Seema, Goldmuntz, Elizabeth, Keavney, Bernard, Bonnet, Damien, Mulder, Barbara J., Tanck, Michael W.T., Bakkers, Jeroen, Christoffels, Vincent M., Boogerd, Cornelis J., Postma, Alex V., Bezzina, Connie R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8768504/
https://www.ncbi.nlm.nih.gov/pubmed/34886679
http://dx.doi.org/10.1161/CIRCRESAHA.120.317107
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author Škorić-Milosavljević, Doris
Tadros, Rafik
Bosada, Fernanda M.
Tessadori, Federico
van Weerd, Jan Hendrik
Woudstra, Odilia I.
Tjong, Fleur V.Y.
Lahrouchi, Najim
Bajolle, Fanny
Cordell, Heather J.
Agopian, A.J.
Blue, Gillian M.
Barge-Schaapveld, Daniela Q.C.M.
Gewillig, Marc
Preuss, Christoph
Lodder, Elisabeth M.
Barnett, Phil
Ilgun, Aho
Beekman, Leander
van Duijvenboden, Karel
Bokenkamp, Regina
Müller-Nurasyid, Martina
Vliegen, Hubert W.
Konings, Thelma C.
van Melle, Joost P.
van Dijk, Arie P.J.
van Kimmenade, Roland R.J.
Roos-Hesselink, Jolien W.
Sieswerda, Gertjan T.
Meijboom, Folkert
Abdul-Khaliq, Hashim
Berger, Felix
Dittrich, Sven
Hitz, Marc-Phillip
Moosmann, Julia
Riede, Frank-Thomas
Schubert, Stephan
Galan, Pilar
Lathrop, Mark
Munter, Hans M.
Al-Chalabi, Ammar
Shaw, Christopher E.
Shaw, Pamela J.
Morrison, Karen E.
Veldink, Jan H.
van den Berg, Leonard H.
Evans, Sylvia
Nobrega, Marcelo A.
Aneas, Ivy
Radivojkov-Blagojević, Milena
Meitinger, Thomas
Oechslin, Erwin
Mondal, Tapas
Bergin, Lynn
Smythe, John F.
Altamirano-Diaz, Luis
Lougheed, Jane
Bouma, Berto J.
Chaix, Marie-A.
Kline, Jennie
Bassett, Anne S.
Andelfinger, Gregor
van der Palen, Roel L.F.
Bouvagnet, Patrice
Clur, Sally-Ann B.
Breckpot, Jeroen
Kerstjens-Frederikse, Wilhelmina S.
Winlaw, David S.
Bauer, Ulrike M.M.
Mital, Seema
Goldmuntz, Elizabeth
Keavney, Bernard
Bonnet, Damien
Mulder, Barbara J.
Tanck, Michael W.T.
Bakkers, Jeroen
Christoffels, Vincent M.
Boogerd, Cornelis J.
Postma, Alex V.
Bezzina, Connie R.
author_facet Škorić-Milosavljević, Doris
Tadros, Rafik
Bosada, Fernanda M.
Tessadori, Federico
van Weerd, Jan Hendrik
Woudstra, Odilia I.
Tjong, Fleur V.Y.
Lahrouchi, Najim
Bajolle, Fanny
Cordell, Heather J.
Agopian, A.J.
Blue, Gillian M.
Barge-Schaapveld, Daniela Q.C.M.
Gewillig, Marc
Preuss, Christoph
Lodder, Elisabeth M.
Barnett, Phil
Ilgun, Aho
Beekman, Leander
van Duijvenboden, Karel
Bokenkamp, Regina
Müller-Nurasyid, Martina
Vliegen, Hubert W.
Konings, Thelma C.
van Melle, Joost P.
van Dijk, Arie P.J.
van Kimmenade, Roland R.J.
Roos-Hesselink, Jolien W.
Sieswerda, Gertjan T.
Meijboom, Folkert
Abdul-Khaliq, Hashim
Berger, Felix
Dittrich, Sven
Hitz, Marc-Phillip
Moosmann, Julia
Riede, Frank-Thomas
Schubert, Stephan
Galan, Pilar
Lathrop, Mark
Munter, Hans M.
Al-Chalabi, Ammar
Shaw, Christopher E.
Shaw, Pamela J.
Morrison, Karen E.
Veldink, Jan H.
van den Berg, Leonard H.
Evans, Sylvia
Nobrega, Marcelo A.
Aneas, Ivy
Radivojkov-Blagojević, Milena
Meitinger, Thomas
Oechslin, Erwin
Mondal, Tapas
Bergin, Lynn
Smythe, John F.
Altamirano-Diaz, Luis
Lougheed, Jane
Bouma, Berto J.
Chaix, Marie-A.
Kline, Jennie
Bassett, Anne S.
Andelfinger, Gregor
van der Palen, Roel L.F.
Bouvagnet, Patrice
Clur, Sally-Ann B.
Breckpot, Jeroen
Kerstjens-Frederikse, Wilhelmina S.
Winlaw, David S.
Bauer, Ulrike M.M.
Mital, Seema
Goldmuntz, Elizabeth
Keavney, Bernard
Bonnet, Damien
Mulder, Barbara J.
Tanck, Michael W.T.
Bakkers, Jeroen
Christoffels, Vincent M.
Boogerd, Cornelis J.
Postma, Alex V.
Bezzina, Connie R.
author_sort Škorić-Milosavljević, Doris
collection PubMed
description 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. OBJECTIVE: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. METHODS AND RESULTS: 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). 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.
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spelling pubmed-87685042022-01-21 Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries Škorić-Milosavljević, Doris Tadros, Rafik Bosada, Fernanda M. Tessadori, Federico van Weerd, Jan Hendrik Woudstra, Odilia I. Tjong, Fleur V.Y. Lahrouchi, Najim Bajolle, Fanny Cordell, Heather J. Agopian, A.J. Blue, Gillian M. Barge-Schaapveld, Daniela Q.C.M. Gewillig, Marc Preuss, Christoph Lodder, Elisabeth M. Barnett, Phil Ilgun, Aho Beekman, Leander van Duijvenboden, Karel Bokenkamp, Regina Müller-Nurasyid, Martina Vliegen, Hubert W. Konings, Thelma C. van Melle, Joost P. van Dijk, Arie P.J. van Kimmenade, Roland R.J. Roos-Hesselink, Jolien W. Sieswerda, Gertjan T. Meijboom, Folkert Abdul-Khaliq, Hashim Berger, Felix Dittrich, Sven Hitz, Marc-Phillip Moosmann, Julia Riede, Frank-Thomas Schubert, Stephan Galan, Pilar Lathrop, Mark Munter, Hans M. Al-Chalabi, Ammar Shaw, Christopher E. Shaw, Pamela J. Morrison, Karen E. Veldink, Jan H. van den Berg, Leonard H. Evans, Sylvia Nobrega, Marcelo A. Aneas, Ivy Radivojkov-Blagojević, Milena Meitinger, Thomas Oechslin, Erwin Mondal, Tapas Bergin, Lynn Smythe, John F. Altamirano-Diaz, Luis Lougheed, Jane Bouma, Berto J. Chaix, Marie-A. Kline, Jennie Bassett, Anne S. Andelfinger, Gregor van der Palen, Roel L.F. Bouvagnet, Patrice Clur, Sally-Ann B. Breckpot, Jeroen Kerstjens-Frederikse, Wilhelmina S. Winlaw, David S. Bauer, Ulrike M.M. Mital, Seema Goldmuntz, Elizabeth Keavney, Bernard Bonnet, Damien Mulder, Barbara J. Tanck, Michael W.T. Bakkers, Jeroen Christoffels, Vincent M. Boogerd, Cornelis J. Postma, Alex V. Bezzina, Connie R. Circ Res Original Research 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. OBJECTIVE: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. METHODS AND RESULTS: 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). 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. Lippincott Williams & Wilkins 2021-12-10 2022-01-21 /pmc/articles/PMC8768504/ /pubmed/34886679 http://dx.doi.org/10.1161/CIRCRESAHA.120.317107 Text en © 2021 The Authors. https://creativecommons.org/licenses/by-nc-nd/4.0/Circulation Research is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.
spellingShingle Original Research
Škorić-Milosavljević, Doris
Tadros, Rafik
Bosada, Fernanda M.
Tessadori, Federico
van Weerd, Jan Hendrik
Woudstra, Odilia I.
Tjong, Fleur V.Y.
Lahrouchi, Najim
Bajolle, Fanny
Cordell, Heather J.
Agopian, A.J.
Blue, Gillian M.
Barge-Schaapveld, Daniela Q.C.M.
Gewillig, Marc
Preuss, Christoph
Lodder, Elisabeth M.
Barnett, Phil
Ilgun, Aho
Beekman, Leander
van Duijvenboden, Karel
Bokenkamp, Regina
Müller-Nurasyid, Martina
Vliegen, Hubert W.
Konings, Thelma C.
van Melle, Joost P.
van Dijk, Arie P.J.
van Kimmenade, Roland R.J.
Roos-Hesselink, Jolien W.
Sieswerda, Gertjan T.
Meijboom, Folkert
Abdul-Khaliq, Hashim
Berger, Felix
Dittrich, Sven
Hitz, Marc-Phillip
Moosmann, Julia
Riede, Frank-Thomas
Schubert, Stephan
Galan, Pilar
Lathrop, Mark
Munter, Hans M.
Al-Chalabi, Ammar
Shaw, Christopher E.
Shaw, Pamela J.
Morrison, Karen E.
Veldink, Jan H.
van den Berg, Leonard H.
Evans, Sylvia
Nobrega, Marcelo A.
Aneas, Ivy
Radivojkov-Blagojević, Milena
Meitinger, Thomas
Oechslin, Erwin
Mondal, Tapas
Bergin, Lynn
Smythe, John F.
Altamirano-Diaz, Luis
Lougheed, Jane
Bouma, Berto J.
Chaix, Marie-A.
Kline, Jennie
Bassett, Anne S.
Andelfinger, Gregor
van der Palen, Roel L.F.
Bouvagnet, Patrice
Clur, Sally-Ann B.
Breckpot, Jeroen
Kerstjens-Frederikse, Wilhelmina S.
Winlaw, David S.
Bauer, Ulrike M.M.
Mital, Seema
Goldmuntz, Elizabeth
Keavney, Bernard
Bonnet, Damien
Mulder, Barbara J.
Tanck, Michael W.T.
Bakkers, Jeroen
Christoffels, Vincent M.
Boogerd, Cornelis J.
Postma, Alex V.
Bezzina, Connie R.
Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries
title Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries
title_full Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries
title_fullStr Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries
title_full_unstemmed Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries
title_short Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries
title_sort common genetic variants contribute to risk of transposition of the great arteries
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8768504/
https://www.ncbi.nlm.nih.gov/pubmed/34886679
http://dx.doi.org/10.1161/CIRCRESAHA.120.317107
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