Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH

Genome Medicine

Johannes Karten¹  Allan Lawrie²  Richard C. Trembath³  Emilia M. Swietlik⁴  Tobias Tilly⁴  Divya Pandya⁴  Carmen M. Treacy⁴  Stefan Gräf⁵  Jennifer M. Martin⁶  Nicholas W. Morrell⁷  Usha Krishnan⁸  Carrie L. Welch⁸  Erika B. Rosenzweig⁸  Xueya Zhou⁹  Jacob J. Hagen⁹  Na Zhu⁹  Wendy K. Chung^1,10  Yicheng Guo^1,11  Yufeng Shen^1,12  Anna W. Coleman^1,13  Katie A. Lutz^1,13  William C. Nichols^1,14  Michael W. Pauciulo^1,14  Martin R. Wilkins^1,15  Claudia Gonzaga-Jauregui^1,16 

[1] 42Genetics, Belfast, Ireland;Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK;Department of Medical and Molecular Genetics, King’s College London, London, UK;Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK;Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK;Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK;NIHR BioResource for Translational Research, Cambridge Biomedical Campus, Cambridge, UK;Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK;NIHR BioResource for Translational Research, Cambridge Biomedical Campus, Cambridge, UK;Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK;NIHR BioResource for Translational Research, Cambridge Biomedical Campus, Cambridge, UK;Addenbrooke’s Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK;Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK;Department of Pediatrics, Columbia University Irving Medical Center, 1150 St. Nicholas Avenue, Room 620, 10032, New York, NY, USA;Department of Pediatrics, Columbia University Irving Medical Center, 1150 St. Nicholas Avenue, Room 620, 10032, New York, NY, USA;Department of Systems Biology, Columbia University, New York, NY, USA;Department of Pediatrics, Columbia University Irving Medical Center, 1150 St. Nicholas Avenue, Room 620, 10032, New York, NY, USA;Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA;Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA;Department of Systems Biology, Columbia University, New York, NY, USA;Department of Systems Biology, Columbia University, New York, NY, USA;Department of Biomedical Informatics, Columbia University, New York, NY, USA;Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA;Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA;Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA;National Heart & Lung Institute, Imperial College London, London, UK;Regeneron Pharmaceuticals, New York, NY, USA;

关键词: Genetics;    Pulmonary arterial hypertension;    Exome sequencing;    Genome sequencing;    Case-control association testing;    De novo variant analysis;   

DOI  :  10.1186/s13073-021-00891-1

来源: Springer

【 摘 要 】

BackgroundPulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by pathogenic remodeling of pulmonary arterioles leading to increased pulmonary pressures, right ventricular hypertrophy, and heart failure. PAH can be associated with other diseases (APAH: connective tissue diseases, congenital heart disease, and others) but often the etiology is idiopathic (IPAH). Mutations in bone morphogenetic protein receptor 2 (BMPR2) are the cause of most heritable cases but the vast majority of other cases are genetically undefined.MethodsTo identify new risk genes, we utilized an international consortium of 4241 PAH cases with exome or genome sequencing data from the National Biological Sample and Data Repository for PAH, Columbia University Irving Medical Center, and the UK NIHR BioResource – Rare Diseases Study. The strength of this combined cohort is a doubling of the number of IPAH cases compared to either national cohort alone. We identified protein-coding variants and performed rare variant association analyses in unrelated participants of European ancestry, including 1647 IPAH cases and 18,819 controls. We also analyzed de novo variants in 124 pediatric trios enriched for IPAH and APAH-CHD.ResultsSeven genes with rare deleterious variants were associated with IPAH with false discovery rate smaller than 0.1: three known genes (BMPR2, GDF2, and TBX4), two recently identified candidate genes (SOX17, KDR), and two new candidate genes (fibulin 2, FBLN2; platelet-derived growth factor D, PDGFD). The new genes were identified based solely on rare deleterious missense variants, a variant type that could not be adequately assessed in either cohort alone. The candidate genes exhibit expression patterns in lung and heart similar to that of known PAH risk genes, and most variants occur in conserved protein domains. For pediatric PAH, predicted deleterious de novo variants exhibited a significant burden compared to the background mutation rate (2.45×, p = 2.5e−5). At least eight novel pediatric candidate genes carrying de novo variants have plausible roles in lung/heart development.ConclusionsRare variant analysis of a large international consortium identified two new candidate genes—FBLN2 and PDGFD. The new genes have known functions in vasculogenesis and remodeling. Trio analysis predicted that ~ 15% of pediatric IPAH may be explained by de novo variants.

【 授权许可】

CC BY