Integrated GWAS and Gene Expression Suggest ORM1 as a Potential Regulator of Plasma Levels of Cell-Free DNA and Thrombosis Risk
López, Sonia (Institut d'Investigació Biomèdica Sant Pau)
Martinez-Perez, Angel (Institut d'Investigació Biomèdica Sant Pau)
Rodriguez-Rius, Alba (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Viñuela, Ana (Biosciences Institute. Faculty of Medicine. Newcastle University)
Brown, Andrew A. (Population Health and Genomics. University of Dundee)
Martin-Fernandez, Laura (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Vilalta, Noelia (Institut d'Investigació Biomèdica Sant Pau)
Arús, Marc (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Panousis, Nikolaos I. (Department of Genetic Medicine and Development. University of Geneva)
Buil, Alfonso (Institute of Biological Psychiatry. Mental Health Sct. Hans Hospital)
Sabater-Lleal, Maria (Institut d'Investigació Biomèdica Sant Pau)
Souto, Juan Carlos (Institut d'Investigació Biomèdica Sant Pau)
Dermitzakis, Emmanouil T (University of Geneva Medical School)
Soria Fernández, José Manuel (Institut d'Investigació Biomèdica Sant Pau)
Universitat Autònoma de Barcelona

Date:	2022
Abstract:	Plasma cell-free DNA (cfDNA) is a surrogate marker of neutrophil extracellular traps (NETs) that contribute to immunothrombosis. There is growing interest about the mechanisms underlying NET formation and elevated cfDNA, but little is known about the factors involved. We aimed to identify genes involved in the regulation of cfDNA levels using data from the Genetic Analysis of Idiopathic Thrombophilia (GAIT-2) Project. Imputed genotypes, whole blood RNA-Seq data, and plasma cfDNA quantification were available for 935 of the GAIT-2 participants from 35 families with idiopathic thrombophilia. We performed heritability and GWAS analysis for cfDNA. The heritability of cfDNA was 0. 26 (p 3. 7106), while the GWAS identified a significant association (rs1687391, p 3. 551010) near the ORM1 gene, on chromosome 9. An eQTL (expression quantitative trait loci) analysis revealed a significant association between the lead GWAS variant and the expression of ORM1 in whole blood (p 6. 14109). Additionally, ORM1 expression correlated with levels of cfDNA (p 4. 38104). Finally, genetic correlation analysis between cfDNA and thrombosis identified a suggestive association (?g 0. 43, p 0. 089). All in all, we show evidence of the role of ORM1 in regulating cfDNA levels in plasma, which might contribute to the susceptibility to thrombosis through mechanisms of immunothrombosis.
Grants:	Instituto de Salud Carlos III PI14/00582 Instituto de Salud Carlos III PI17/00059 Instituto de Salud Carlos III CP17/00142 Agència de Gestió d'Ajuts Universitaris i de Recerca SGR1736 Agència de Gestió d'Ajuts Universitaris i de Recerca FI2017B_00673
Note:	Altres ajuts: CERCA Programme, Generalitat de Catalunya; Fundación Española de Trombosis y Hemostasia; European Social Fund.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Immunothrombosis ; Neutrophil extracellular traps ; α-1-acid glycoprotein 1 ; Expression quantitative trait loci
Published in:	Thrombosis and Haemostasis, Vol. 122 Núm. 6 (january 2022) , p. 1027-1039, ISSN 2567-689X

DOI: 10.1055/s-0041-1742169
PMID: 35272364

13 p, 2.5 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
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