Integrated GWAS and Gene Expression Suggest ORM1 as a Potential Regulator of Plasma Levels of Cell-Free DNA and Thrombosis Risk

Sonia Lopez (Lead / Corresponding author), Angel Martinez-Perez, Alba Rodriguez-Rius, Ana Viñuela, Andrew A. Brown, Laura Martin-Fernandez, Noelia Vilalta, Marc Arús, Nikolaos I. Panousis, Alfonso Buil, Maria Sabater-Lleal, Juan Carlos Souto, Emmanouil T. Dermitzakis, Jose Manuel Soria

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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.

Original languageEnglish
Pages (from-to)1027-1039
Number of pages13
JournalThrombosis and Haemostasis
Volume122
Issue number6
Early online date10 Mar 2022
DOIs
Publication statusPublished - 2022

Keywords

  • expression quantitative trait loci
  • immunothrombosis
  • neutrophil extracellular traps
  • α-1-acid glycoprotein 1

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