Zhu, N;
Swietlik, EM;
Welch, CL;
Pauciulo, MW;
Hagen, JJ;
Zhou, X;
Guo, Y;
Karten, J;
Pandya, D;
Tilly, T;
et al.
Zhu, N; Swietlik, EM; Welch, CL; Pauciulo, MW; Hagen, JJ; Zhou, X; Guo, Y; Karten, J; Pandya, D; Tilly, T; Lutz, KA; Martin, JM; Treacy, CM; Rosenzweig, EB; Krishnan, U; Coleman, AW; Gonzaga-Jauregui, C; Lawrie, A; Trembath, RC; Wilkins, MR; Regeneron Genetics Center; PAH Biobank Enrolling Centers’ Investigators; NIHR BioResource for Translational Research - Rare Diseases; National Cohort Study of Idiopathic and Heritable PAH; Morrell, NW; Shen, Y; Gräf, S; Nichols, WC; Chung, WK
(2021)
Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH.
Genome Med, 13 (1).
p. 80.
ISSN 1756-994X
https://doi.org/10.1186/s13073-021-00891-1
SGUL Authors: Southgate, Laura
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Abstract
BACKGROUND: Pulmonary 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. METHODS: To 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. RESULTS: Seven 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. CONCLUSIONS: Rare 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.
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Additional Information: | © The Author(s). 2021, corrected publication 2021. Open Access This article is licensed under a Creative Commons Attribution4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Correction available at https://doi.org/10.1186/s13073-021-00915-w | ||||||||||||||||||||||||||||||||||||||||||
Keywords: | Case-control association testing, De novo variant analysis, Exome sequencing, Genetics, Genome sequencing, Pulmonary arterial hypertension, Regeneron Genetics Center, PAH Biobank Enrolling Centers’ Investigators, NIHR BioResource for Translational Research - Rare Diseases, National Cohort Study of Idiopathic and Heritable PAH, 0604 Genetics, 1103 Clinical Sciences | ||||||||||||||||||||||||||||||||||||||||||
SGUL Research Institute / Research Centre: | Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) | ||||||||||||||||||||||||||||||||||||||||||
Journal or Publication Title: | Genome Med | ||||||||||||||||||||||||||||||||||||||||||
ISSN: | 1756-994X | ||||||||||||||||||||||||||||||||||||||||||
Language: | eng | ||||||||||||||||||||||||||||||||||||||||||
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Publisher License: | Creative Commons: Attribution 4.0 | ||||||||||||||||||||||||||||||||||||||||||
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PubMed ID: | 33971972 | ||||||||||||||||||||||||||||||||||||||||||
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URI: | https://openaccess.sgul.ac.uk/id/eprint/113408 | ||||||||||||||||||||||||||||||||||||||||||
Publisher's version: | https://doi.org/10.1186/s13073-021-00891-1 |
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