Bayesian Inference Associates Rare
KDR
Variants With Specific Phenotypes in Pulmonary Arterial Hypertension
Authors: Swietlik Emilia M. , Greene Daniel , Zhu Na , Megy Karyn , Cogliano Marcella , Rajaram Smitha , Pandya Divya , Tilly Tobias , Lutz Katie A. , Welch Carrie C.L. , Pauciulo Michael W. , Southgate Laura , Martin Jennifer M. , Treacy Carmen M. , Penkett Christopher J. , Stephens Jonathan C. , Bogaard Harm J. , Church Colin , Coghlan Gerry , Coleman Anna W. , Condliffe Robin , Eichstaedt Christina A. , Eyries Mélanie , Gall Henning , Ghio Stefano , Girerd Barbara , Grünig Ekkehard , Holden Simon , Howard Luke , Humbert Marc , Kiely David G. , Kovacs Gabor , Lordan Jim , Machado Rajiv D. , MacKenzie Ross Robert V. , McCabe Colm , Moledina Shahin , Montani David , Olschewski Horst , Pepke-Zaba Joanna , Price Laura , Rhodes Christopher J. , Seeger Werner , Soubrier Florent , Suntharalingam Jay , Toshner Mark R. , Vonk Noordegraaf Anton , Wharton John , Wild James M. , Wort Stephen John , Lawrie Allan , Wilkins Martin R. , Trembath Richard C. , Shen Yufeng , Chung Wendy K. , Swift Andrew J. , Nichols William C. , Morrell Nicholas W. , Gräf Stefan , Abbs Stephen , Abulhoul Lara , Adlard Julian , Ahmed Munaza , Aitman Timothy J. , Alachkar Hana , Allsup David J. , Ancliff Philip , Antrobus Richard , Armstrong Ruth , Arno Gavin , Ashford Sofie , Astle William J. , Attwood Anthony , Aurora Paul , Babbs Christian , Bacchelli Chiara , Bakchoul Tamam , Banka Siddharth , Bariana Tadbir , Barwell Julian , Batista Joana , Baxendale Helen E. , Beales Phil L. , Bennett David L. , Bierzynska Agnieszka , Biss Tina , Bitner-Glindzicz Maria A.K. , Black Graeme C. , Bleda Marta , Blesneac Iulia , Bockenhauer Detlef , Boyce Sara , Bradley John R. , Breen Gerome , Brennan Paul , Brewer Carole , Brown Matthew , Browning Andrew C. , Browning Michael J. , Buchan Rachel J. , Buckland Matthew S. , Bueser Teofila , Diz Carmen Bugarin , Burn John , Burns Siobhan O. , Burren Oliver S. , Burrows Nigel , Campbell Carolyn , Carr-White Gerald , Carss Keren , Casey Ruth , Caulfield Mark J. , Chambers Jenny , Chambers John , Chan Melanie M.Y. , Cheng Floria , Chinnery Patrick F. , Chitre Manali , Christian Martin T. , Clayton-Smith Jill , Cleary Maureen , Brod Naomi Clements , Colby Elizabeth , Cole Trevor R.P. , Collins Janine , Collins Peter W. , Compton Cecilia J. , Cook H. Terence , Cook Stuart , Cooper Nichola , Corris Paul A. , Curry Nicola S. , Daniels Matthew J. , Dattani Mehul , Daugherty Louise C. , Davis John , De Soyza Anthony , Deevi Sri V.V. , Dent Timothy , Deshpande Charu , Dewhurst Eleanor F. , Dixon Peter H. , Douzgou Sofia , Downes Kate , Drazyk Anna M. , Drewe Elizabeth , Duarte Daniel , Dutt Tina , Edgar J. David M. , Edwards Karen , Egner William , Ekani Melanie N. , Elliott Perry , Erber Wendy N. , Erwood Marie , Estiu Maria C. , Evans Dafydd Gareth , Evans Gillian , Everington Tamara , Fassihi Hiva , Favier Remi , Fletcher Debra , Flinter Frances A. , Floto R. Andres , Fowler Tom , Fox James , Frary Amy J. , French Courtney E. , Freson Kathleen , Frontini Mattia , Furnell Abigail , Gale Daniel P. , Ganesan Vijeya , Gattens Michael , Ghofrani Hossein-Ardeschir , Gibbs J. Simon R. , Gibson Kate , Gilmour Kimberly C. , Gleadall Nicholas S. , Goddard Sarah , Gomez Keith , Gordins Pavels , Gosal David , Graham Jodie , Grassi Luigi , Greenhalgh Lynn , Greinacher Andreas , Gresele Paolo , Griffiths Philip , Grigoriadou Sofia , Grozeva Detelina , Gurnell Mark , Hackett Scott , Hadinnapola Charaka , Hague Rosie , Hague William M. , Haimel Matthias , Hall Matthew , Hanson Helen L. , Haque Eshika , Harkness Kirsty , Harper Andrew R. , Harris Claire L. , Hart Daniel , Hassan Ahamad , Hayman Grant , Henderson Alex , Herwadkar Archana , Hoffman Jonathan , Horvath Rita , Houlden Henry , Houweling Arjan C. , Hu Fengyuan , Hudson Gavin , Huissoon Aarnoud P. , Hurles Matthew , Irving Melita , Izatt Louise , James Roger , Johnson Sally A. , Jolles Stephen , Jolley Jennifer , Josifova Dragana , Jurkute Neringa , Kasanicki Mary A. , Kazkaz Hanadi , Kazmi Rashid , Kelleher Peter , Kelly Anne M , Kelsall Wilf , Kempster Carly , Kingston Nathalie , Koelling Nils , Kostadima Myrto , Koziell Ania , Kreuzhuber Roman , Kuijpers Taco W. , Kumar Ajith , Kumararatne Dinakantha , Kurian Manju A. , Laffan Michael A. , Lalloo Fiona , Lambert Michele , Allen Hana Lango , Layton D. Mark , Lentaigne Claire , Lester Tracy , Levine Adam P. , Linger Rachel , Longhurst Hilary , Lorenzo Lorena E. , Louka Eleni , Lyons Paul A. , Madan Bella , Maher Eamonn R. , Maimaris Jesmeen , Malka Samantha , Mangles Sarah , Mapeta Rutendo , Marchbank Kevin J. , Marks Stephen , Markus Hugh S. , Marschall Hanns-Ulrich , Marshall Andrew , Mathias Mary , Matthews Emma , Maxwell Heather , McAlinden Paul , McCarthy Mark I. , McKinney Harriet , Meacham Stuart , Mead Adam J. , Mehta Sarju G. , Michaelides Michel , Millar Carolyn , Mohammed Shehla N. , Moore Anthony T. , Mozere Monika , Muir Keith W. , Mumford Andrew D. , Nemeth Andrea H. , Newman William G. , Newnham Michael , Noorani Sadia , Nurden Paquita , O’Sullivan Jennifer , Obaji Samya , Odhams Chris , Okoli Steven , Olschewski Andrea , Ong Kai Ren , Oram S. Helen , Ormondroyd Elizabeth , Ouwehand Willem H. , Palles Claire , Papadia Sofia , Park Soo-Mi , Parry David , Patel Smita , Paterson Joan , Peacock Andrew , Pearce Simon H. , Peerlinck Kathelijne , Petersen Romina , Pilkington Clarissa , Poole Kenneth E.S. , Psaila Bethan , Pyle Angela , Quinton Richard , Rahman Shamima , Rao Anupama , Raymond F. Lucy , Rayner-Matthews Paula J. , Rendon Augusto , Renton Tara , Rice Andrew S.C. , Richter Alex , Robert Leema , Roberts Irene , Rose Sarah J. , Ross-Russell Robert , Roughley Catherine , Roy Noemi B.A. , Ruddy Deborah M. , Sadeghi-Alavijeh Omid , Saleem Moin A. , Samani Nilesh , Samarghitean Crina , Sanchis-Juan Alba , Sargur Ravishankar B. , Sarkany Robert N. , Satchell Simon , Savic Sinisa , Sayer Genevieve , Sayer John A. , Scelsi Laura , Schaefer Andrew M. , Schulman Sol , Scott Richard , Scully Marie , Searle Claire , Sen Arjune , Sewell W.A. Carrock , Seyres Denis , Shah Neil , Shamardina Olga , Shapiro Susan E. , Shaw Adam C. , Sibson Keith , Side Lucy , Simeoni Ilenia , Simpson Michael A. , Sims Matthew C. , Sivapalaratnam Suthesh , Smedley Damian , Smith Katherine R. , Smith Kenneth G.C. , Snape Katie , Soranzo Nicole , Spasic-Boskovic Olivera , Staines Simon , Staples Emily , Stark Hannah , Stirrups Kathleen E. , Stuckey Alex , Syrris Petros , Tait R. Campbell , Talks Kate , Tan Rhea Y.Y. , Taylor Jenny C. , Taylor John M. , Thaventhiran James E. , Themistocleous Andreas C. , Thomas David , Thomas Ellen , Thomas Moira J. , Thomas Patrick , Thomson Kate , Thrasher Adrian J. , Thys Chantal , Tischkowitz Marc , Titterton Catherine , Toh Cheng-Hock , Tomlinson Ian P. , Traylor Matthew , Treadaway Paul , Tuna Salih , Turro Ernest , Twiss Philip , Vale Tom , Van Geet Chris , van Zuydam Natalie , Vandersteen Anthony M , Vazquez-Lopez Marta , von Ziegenweidt Julie , Wagner Annette , Waisfisz Quinten , Walker Neil , Walker Suellen M. , Ware James S. , Watkins Hugh , Watt Christopher , Webster Andrew R. , Wedderburn Lucy , Wei Wei , Welch Steven B. , Wessels Julie , Westbury Sarah K. , Westwood John-Paul , Whitehorn Deborah , Whitworth James , Wilkie Andrew O.M. , Williamson Catherine , Wilson Brian T. , Wong Edwin K.S. , Wood Nicholas , Wood Yvette , Woods Christopher Geoffrey , Woodward Emma R. , Worth Austen , Wright Michael , Yates Katherine , Yong Patrick F.K. , Young Timothy , Yu Ping , Yu-Wai-Man Patrick , Zlamalova Eliska , Hirsch Russel , White R. James , Simon Marc , Badesch David , Rosenzweig Erika , Burger Charles , Chakinala Murali , Thenappan Thenappan , Elliott Greg , Simms Robert , Farber Harrison , Frantz Robert , Elwing Jean , Hill Nicholas , Ivy Dunbar , Klinger James , Nathan Steven , Oudiz Ronald , Robbins Ivan , Schilz Robert , Fortin Terry , Wilt Jeffrey , Yung Delphine , Austin Eric , Ahmad Ferhaan , Bhatt Nitin , Lahm Tim , Frost Adaani , Safdar Zeenat , Rehman Zia , Walter Robert , Torres Fernando , Bakshi Sahil , Archer Stephen , Argula Rahul , Barnett Christopher , Benza Raymond , Desai Ankit , Maddipati Veeranna 
Published: December 2020

Background:
Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH, we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics.

Methods:
We analyzed 13 037 participants enrolled in the NBR study (NIHR BioResource—Rare Diseases), of which 1148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension, we used the Bayesian rare variant association method BeviMed.

Results:

Heterozygous, high impact, likely loss-of-function variants in the kinase insert domain receptor (
KDR
) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (posterior probability=0.989) and older age at diagnosis (posterior probability=0.912). We also provide evidence for familial segregation of a rare nonsense
KDR
variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the 5 patients harboring these predicted deleterious variants in
KDR
. Four additional PAH cases with rare likely loss-of-function variants in
KDR
were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics.

Conclusions:

The Bayesian inference approach allowed us to independently validate
KDR
, which encodes for the VEGFR2 (vascular endothelial growth factor receptor 2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for
KDR
being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.