Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH
Creators: name: Zhu, Na
name: Swietlik, Emilia M.
name: Welch, Carrie L.
name: Pauciulo, Michael W.
name: Hagen, Jacob J.
name: Zhou, Xueya
name: Guo, Yicheng
name: Karten, Johannes
name: Pandya, Divya
name: Tilly, Tobias
name: Lutz, Katie A.
name: Martin, Jennifer M.
name: Treacy, Carmen M.
name: Rosenzweig, Erika B.
name: Krishnan, Usha
name: Coleman, Anna W.
name: Gonzaga-Juaregui, Claudia
name: Lawrie, Allan
name: Trembath, Richard C.
name: Wilkins, Martin R.
name: Morrell, Nicholas W.
name: Shen, Yufeng
name: Gräf, Stefan
name: Nichols, William C.
name: Chung, Wendy K.
name: Hirsch, Russel
name: White, R. James
name: Simon, Marc
name: Badesch, David
name: Rosenzweig, Erika
name: Burger, Charles
name: Chakinala, Murali
name: Thenappan, Thenappan
name: Elliott, Greg
name: Simms, Robert
name: Farber, Harrison
name: Frantz, Robert
name: Elwing, Jean
name: Hill, Nicholas
name: Ivy, Dunbar
name: Klinger, James
name: Nathan, Steven
name: Oudiz, Ronald
name: Robbins, Ivan
name: Schilz, Robert
name: Fortin, Terry
name: Wilt, Jeffrey
name: Yung, Delphine
name: Austin, Eric
name: Ahmad, Ferhaan
name: Bhatt, Nitin
name: Lahm, Tim
name: Frost, Adaani
name: Safdar, Zeenat
name: Rehman, Zia
name: Walter, Robert
name: Torres, Fernando
name: Bakshi, Sahil
name: Archer, Stephen
name: Argula, Rahul
name: Barnett, Christopher
name: Benza, Raymond
name: Desai, Ankit
name: Maddipati, Veeranna
name: Bogaard, Harm J.
name: Church, Colin
name: Coghlin, Gerry
name: Condliffe, Robin
name: Eyries, Mélanie
name: Gall, Henning
name: Ghio, Stefano
name: Girerd, Barbara
name: Holden, Simon
name: Howard, Luke
name: Humbert, Marc
name: Kiely, David G.
name: Kovacs, Gabor
name: Lordan, Jim
name: Machado, Rajiv D.
name: MacKenzie Ross, Robert V.
name: McCabe, Colm
name: Moledina, Shahin
name: Montani, David
name: Olschewski, Horst
name: Penkett, Christopher J.
name: Pepke-Zaba, Joanna
name: Price, Laura
name: Rhodes, Christopher J.
name: Seeger, Werner
name: Soubrier, Florent
name: Southgate, Laura
name: Suntharalingam, Jay
name: Swift, Andrew J.
name: Toshner, Mark R.
name: Noordegraaf, Anton Vonk
name: Wharton, John
name: Wild, Jim
name: Wort, Stephen John
Publisher: name: Apollo - University of Cambridge Repository
Year: 2021
Subjects: subject: Research
subject: Genetics
subject: FOS: Biological sciences
subject: FOS: Biological sciences
subject: Pulmonary arterial hypertension
subject: Exome sequencing
subject: Genome sequencing
subject: Case-control association testing
subject: De novo variant analysis

description: 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.