Bayesian inference associates rare KDR variants with specific phenotypes in pulmonary arterial hypertension
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 analyz...
Gespeichert in:
| Hauptverfasser: | , , |
|---|---|
| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
2021
|
| In: |
Circulation. Genomic and precision medicine
Year: 2021, Jahrgang: 14, Heft: 1, Pages: ? |
| ISSN: | 2574-8300 |
| DOI: | 10.1161/CIRCGEN.120.003155 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1161/CIRCGEN.120.003155 Verlag, lizenzpflichtig, Volltext: https://www.ahajournals.org/doi/10.1161/CIRCGEN.120.003155 
|
| Verfasserangaben: | Emilia M. Swietlik, Christina A. Eichstaedt, Ekkehard Grünig [und 464 weitere] |
MARC
| LEADER | 00000caa a2200000 c 4500 | ||
|---|---|---|---|
| 001 | 1760565024 | ||
| 003 | DE-627 | ||
| 005 | 20230428014433.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 210616s2021 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1161/CIRCGEN.120.003155 |2 doi | |
| 035 | |a (DE-627)1760565024 | ||
| 035 | |a (DE-599)KXP1760565024 | ||
| 035 | |a (OCoLC)1341416472 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rda | ||
| 041 | |a eng | ||
| 084 | |a 33 |2 sdnb | ||
| 100 | 1 | |a Swietlik, Emilia M. |e VerfasserIn |0 (DE-588)1235547507 |0 (DE-627)1760567884 |4 aut | |
| 245 | 1 | 0 | |a Bayesian inference associates rare KDR variants with specific phenotypes in pulmonary arterial hypertension |c Emilia M. Swietlik, Christina A. Eichstaedt, Ekkehard Grünig [und 464 weitere] |
| 264 | 1 | |c 2021 | |
| 300 | |a ? | ||
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Originally published 15 Dec 2020 | ||
| 500 | |a Gesehen am 16.06.2021 | ||
| 520 | |a 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. | ||
| 700 | 1 | |a Eichstaedt, Christina |e VerfasserIn |0 (DE-588)1110189419 |0 (DE-627)864806752 |0 (DE-576)47573503X |4 aut | |
| 700 | 1 | |a Grünig, Ekkehard |e VerfasserIn |0 (DE-588)112535801 |0 (DE-627)618892605 |0 (DE-576)31856694X |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Circulation. Genomic and precision medicine |d Philadelphia, Pa. : Lippincott, Williams & Wilkins, 2018 |g 14(2021), 1, Artikel-ID e003155, Seite ? |h Online-Ressource |w (DE-627)1019378298 |w (DE-600)2927603-2 |w (DE-576)502270454 |x 2574-8300 |7 nnas |a Bayesian inference associates rare KDR variants with specific phenotypes in pulmonary arterial hypertension |
| 773 | 1 | 8 | |g volume:14 |g year:2021 |g number:1 |g elocationid:e003155 |g pages:? |g extent:? |a Bayesian inference associates rare KDR variants with specific phenotypes in pulmonary arterial hypertension |
| 856 | 4 | 0 | |u https://doi.org/10.1161/CIRCGEN.120.003155 |x Verlag |x Resolving-System |z lizenzpflichtig |3 Volltext |
| 856 | 4 | 0 | |u https://www.ahajournals.org/doi/10.1161/CIRCGEN.120.003155 |x Verlag |z lizenzpflichtig |3 Volltext |
| 951 | |a AR | ||
| 992 | |a 20210616 | ||
| 993 | |a Article | ||
| 994 | |a 2021 | ||
| 998 | |g 112535801 |a Grünig, Ekkehard |m 112535801:Grünig, Ekkehard |d 910000 |d 950000 |d 950900 |e 910000PG112535801 |e 950000PG112535801 |e 950900PG112535801 |k 0/910000/ |k 1/910000/950000/ |k 2/910000/950000/950900/ |p 27 | ||
| 998 | |g 1110189419 |a Eichstaedt, Christina |m 1110189419:Eichstaedt, Christina |d 910000 |d 950000 |d 950900 |e 910000PE1110189419 |e 950000PE1110189419 |e 950900PE1110189419 |k 0/910000/ |k 1/910000/950000/ |k 2/910000/950000/950900/ |p 22 | ||
| 999 | |a KXP-PPN1760565024 |e 3938756985 | ||
| BIB | |a Y | ||
| SER | |a journal | ||
| JSO | |a {"id":{"doi":["10.1161/CIRCGEN.120.003155"],"eki":["1760565024"]},"origin":[{"dateIssuedKey":"2021","dateIssuedDisp":"2021"}],"person":[{"display":"Swietlik, Emilia M.","given":"Emilia M.","role":"aut","family":"Swietlik"},{"display":"Eichstaedt, Christina","role":"aut","given":"Christina","family":"Eichstaedt"},{"family":"Grünig","given":"Ekkehard","role":"aut","display":"Grünig, Ekkehard"}],"title":[{"title":"Bayesian inference associates rare KDR variants with specific phenotypes in pulmonary arterial hypertension","title_sort":"Bayesian inference associates rare KDR variants with specific phenotypes in pulmonary arterial hypertension"}],"note":["Originally published 15 Dec 2020","Gesehen am 16.06.2021"],"relHost":[{"type":{"media":"Online-Ressource","bibl":"periodical"},"language":["eng"],"titleAlt":[{"title":"Circ Genom Precis Med"}],"physDesc":[{"extent":"Online-Ressource"}],"origin":[{"dateIssuedDisp":"January 16, 2018","publisher":"Lippincott, Williams & Wilkins","publisherPlace":"Philadelphia, Pa."}],"title":[{"partname":"Genomic and precision medicine","title":"Circulation","title_sort":"Circulation"}],"corporate":[{"role":"isb","display":"American Heart Association"}],"disp":"Bayesian inference associates rare KDR variants with specific phenotypes in pulmonary arterial hypertensionCirculation. Genomic and precision medicine","recId":"1019378298","name":{"displayForm":["American Heart Association"]},"pubHistory":["Volume 11 (January 2018)-"],"part":{"issue":"1","volume":"14","pages":"?","extent":"?","text":"14(2021), 1, Artikel-ID e003155, Seite ?","year":"2021"},"id":{"zdb":["2927603-2"],"issn":["2574-8300"],"eki":["1019378298"]}}],"type":{"bibl":"article-journal","media":"Online-Ressource"},"recId":"1760565024","language":["eng"],"physDesc":[{"extent":"? S."}],"name":{"displayForm":["Emilia M. Swietlik, Christina A. Eichstaedt, Ekkehard Grünig [und 464 weitere]"]}} | ||
| SRT | |a SWIETLIKEMBAYESIANIN2021 | ||