Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve

Bo Yang; Wei Zhou; Jiao Jiao; Jonas B Nielsen; Michael R Mathis; Mahyar Heydarpour; Guillaume Lettre; Lasse Folkersen; Siddharth Prakash; Claudia Schurmann; Lars Fritsche; Gregory A Farnum; Maoxuan Lin; Mohammad Othman; Whitney Hornsby; Anisa Driscoll; Alexandra Levasseur; Marc Thomas; Linda Farhat; Marie-Pierre Dubé; Eric M Isselbacher; Anders Franco-Cereceda; Dong-Chuan Guo; Erwin P Bottinger; G Michael Deeb; Anna Booher; Sachin Kheterpal; Y Eugene Chen; Hyun Min Kang; Jacob Kitzman; Heather J Cordell; Bernard D Keavney; Judith A Goodship; Santhi K Ganesh; Gonçalo Abecasis; Kim A Eagle; Alan P Boyle; Ruth J F Loos; Per Eriksson; Jean-Claude Tardif; Chad M Brummett; Dianna M Milewicz; Simon C Body; Cristen J Willer

doi:10.1038/ncomms15481

Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve

Nat Commun. 2017 May 25:8:15481. doi: 10.1038/ncomms15481.

Authors

Bo Yang^{1

2}, Wei Zhou³, Jiao Jiao¹, Jonas B Nielsen⁴, Michael R Mathis⁵, Mahyar Heydarpour⁶, Guillaume Lettre^{7

8}, Lasse Folkersen^{9

10}, Siddharth Prakash¹¹, Claudia Schurmann¹², Lars Fritsche^{13

14}, Gregory A Farnum³, Maoxuan Lin⁴, Mohammad Othman¹⁵, Whitney Hornsby², Anisa Driscoll², Alexandra Levasseur², Marc Thomas², Linda Farhat², Marie-Pierre Dubé^{7

8}, Eric M Isselbacher⁶, Anders Franco-Cereceda¹⁶, Dong-Chuan Guo¹¹, Erwin P Bottinger¹², G Michael Deeb^{1

2}, Anna Booher^{2

4}, Sachin Kheterpal⁵, Y Eugene Chen^{1

2

4}, Hyun Min Kang¹³, Jacob Kitzman^{3

17}, Heather J Cordell¹⁸, Bernard D Keavney^{19

20}, Judith A Goodship¹⁸, Santhi K Ganesh^{2

4

17}, Gonçalo Abecasis¹³, Kim A Eagle^{2

4}, Alan P Boyle^{3

17}, Ruth J F Loos^{12

21}, Per Eriksson⁹, Jean-Claude Tardif^{7

8}, Chad M Brummett⁵, Dianna M Milewicz¹¹, Simon C Body⁶, Cristen J Willer^{2

3

4

17}

Affiliations

¹ Department of Cardiac Surgery, University of Michigan, Ann Arbor, Michigan 48109, USA.
² Frankel Cardiovascular Center, University of Michigan, Ann Arbor, Michigan 48109, USA.
³ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA.
⁴ Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
⁵ Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
⁶ Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
⁷ Montreal Heart Institute, Montreal, Quebec, Canada HIT 1C8.
⁸ Department of Medicine, Université de Montréal, Montreal, Quebec, Canada QC H3T 1J4.
⁹ Cardiovascular Medicine Unit, Center for Molecular Medicine, Department of Medicine, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm SE-171 76, Sweden.
¹⁰ Center for Biological Sequence Analysis, Technical University of Denmark, Copenhagen DK-2800, Denmark.
¹¹ Department of Internal Medicine, Division of Medical Genetics, University of Texas Health Science Center at Houston McGovern Medical School, Houston, Texas 77030, USA.
¹² The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
¹³ Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.
¹⁴ Norwegian University of Science and Technology, Trondheim 7491, Norway.
¹⁵ Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan 48105, USA.
¹⁶ Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm SE-171 76, Sweden.
¹⁷ Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
¹⁸ Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne NE1 3BZ, UK.
¹⁹ Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, UK.
²⁰ Manchester Heart Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WL, UK.
²¹ The Mindich Child Health Development Institute, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.

Abstract

Bicuspid aortic valve (BAV) is a heritable congenital heart defect and an important risk factor for valvulopathy and aortopathy. Here we report a genome-wide association scan of 466 BAV cases and 4,660 age, sex and ethnicity-matched controls with replication in up to 1,326 cases and 8,103 controls. We identify association with a noncoding variant 151 kb from the gene encoding the cardiac-specific transcription factor, GATA4, and near-significance for p.Ser377Gly in GATA4. GATA4 was interrupted by CRISPR-Cas9 in induced pluripotent stem cells from healthy donors. The disruption of GATA4 significantly impaired the transition from endothelial cells into mesenchymal cells, a critical step in heart valve development.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Substitution
Aortic Valve / abnormalities*
Aortic Valve / embryology
Aortic Valve / metabolism
Bicuspid Aortic Valve Disease
CRISPR-Cas Systems
Case-Control Studies
Cell Transdifferentiation / genetics
Female
GATA4 Transcription Factor / deficiency
GATA4 Transcription Factor / genetics*
GATA4 Transcription Factor / metabolism
Gene Regulatory Networks
Genetic Variation*
Genome-Wide Association Study
Heart Defects, Congenital / genetics
Heart Valve Diseases / embryology
Heart Valve Diseases / genetics*
Heart Valve Diseases / metabolism
Humans
Induced Pluripotent Stem Cells / metabolism
Induced Pluripotent Stem Cells / pathology
Male
Mutation, Missense
Phenotype
RNA, Untranslated / genetics

Substances

GATA4 Transcription Factor
GATA4 protein, human
RNA, Untranslated

Abstract

Publication types

MeSH terms

Substances

Grants and funding