Imperial College London
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Professor Martin Wilkins

Faculty of Medicine, National Heart & Lung Institute

Professor of Clinical Pharmacology
 
 
 
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Contact

 

+44 (0)20 3313 6101m.wilkins Website

 
 
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Assistant

 

Mrs Elizabeth O'Brien +44 (0)20 3313 6101

 
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Location

 

NIHR Imperial Clinical Research FacilityICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Zhu:2021:10.1186/s13073-021-00891-1,
author = {Zhu, N and Swietlik, EM and Welch, CL and Pauciulo, MW and Hagen, JJ and Zhou, X and Guo, Y and Karten, J and Pandya, D and Tilly, T and Lutz, KA and Martin, JM and Treacy, CM and Rosenzweig, EB and Krishnan, U and Coleman, AW and Gonzaga-Juaregui, C and Lawrie, A and Trembath, RC and Wilkins, MR and Morrell, NW and Shen, Y and Graf, S and Nichols, WC and Chung, WK},
doi = {10.1186/s13073-021-00891-1},
journal = {Genome Medicine: medicine in the post-genomic era},
pages = {1--18},
title = {Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH},
url = {http://dx.doi.org/10.1186/s13073-021-00891-1},
volume = {13},
year = {2021}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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×
AU  - Zhu,N
AU  - Swietlik,EM
AU  - Welch,CL
AU  - Pauciulo,MW
AU  - Hagen,JJ
AU  - Zhou,X
AU  - Guo,Y
AU  - Karten,J
AU  - Pandya,D
AU  - Tilly,T
AU  - Lutz,KA
AU  - Martin,JM
AU  - Treacy,CM
AU  - Rosenzweig,EB
AU  - Krishnan,U
AU  - Coleman,AW
AU  - Gonzaga-Juaregui,C
AU  - Lawrie,A
AU  - Trembath,RC
AU  - Wilkins,MR
AU  - Morrell,NW
AU  - Shen,Y
AU  - Graf,S
AU  - Nichols,WC
AU  - Chung,WK
DO  - 10.1186/s13073-021-00891-1
EP  - 18
PY  - 2021///
SN  - 1756-994X
SP  - 1
TI  - Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH
T2  - Genome Medicine: medicine in the post-genomic era
UR  - http://dx.doi.org/10.1186/s13073-021-00891-1
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000656212700001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-021-00891-1
UR  - http://hdl.handle.net/10044/1/94568
VL  - 13
ER  -
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