Integrated GWAS and Gene Expression Suggest ORM1 as a Potential Regulator of Plasma Levels of Cell-Free DNA and Thrombosis Risk
Por:
Lopez, S, Martinez-Perez, A, Rodriguez-Rius, A, Vinuela, A, Brown, AA, Martin-Fernandez, L, Vilalta, N, Arus, M, Panousis, NI, Buil, A, Sabater-Lleal, M, Souto, JC, Dermitzakis, ET, Soria, JM
Publicada:
1 jun 2022
Ahead of Print:
1 mar 2022
Resumen:
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 = 3.7 x 10(-6)), while the GWAS identified a significant association (rs1687391, p = 3.55 x 10(-10)) 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 = 6.14 x 10(-9)). Additionally, ORM1 expression correlated with levels of cfDNA (p = 4.38 x 10(-4)). Finally, genetic correlation analysis between cfDNA and thrombosis identified a suggestive association (rho(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.
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Filiaciones:
Lopez, S:
IIB St Pau, Res Inst Hosp Santa Creu & St Pau, Genom Complex Dis Unit, St Quinti 77-79,3rd Floor, Barcelona 08041, Spain
Martinez-Perez, A:
IIB St Pau, Res Inst Hosp Santa Creu & St Pau, Genom Complex Dis Unit, St Quinti 77-79,3rd Floor, Barcelona 08041, Spain
Rodriguez-Rius, A:
IIB St Pau, Res Inst Hosp Santa Creu & St Pau, Genom Complex Dis Unit, St Quinti 77-79,3rd Floor, Barcelona 08041, Spain
Vinuela, A:
Newcastle Univ, Fac Med, Biosci Inst, Newcastle Upon Tyne, Tyne & Wear, England
Brown, AA:
Univ Dundee, Populat Hlth & Genom, Dundee, Scotland
Martin-Fernandez, L:
IIB St Pau, Res Inst Hosp Santa Creu & St Pau, Genom Complex Dis Unit, St Quinti 77-79,3rd Floor, Barcelona 08041, Spain
Fdn Espanola Trombosis & Hemostasia FETH, Madrid, Spain
Banc Sang & Teixits, Congenital Coagulopathies Lab, Barcelona, Spain
Univ Autonoma Barcelona VHIR UAB, Vall dHebron Res Inst, Transfus Med, Barcelona, Spain
Vilalta, N:
Hosp Santa Creu & Sant Pau, Haemostasis & Thrombosis Unit, Dept Hematol, Barcelona, Spain
Arus, M:
Hosp Santa Creu & Sant Pau, Haemostasis & Thrombosis Unit, Dept Hematol, Barcelona, Spain
Panousis, NI:
Wellcome Sanger Inst, Wellcome Genome Campus, Hinxton, South Cambridge, England
Univ Geneva, Dept Genet Med & Dev, Geneva, Switzerland
Buil, A:
Mental Hlth Sct Hans Hosp, Inst Biol Psychiat, Roskilde, Denmark
Sabater-Lleal, M:
IIB St Pau, Res Inst Hosp Santa Creu & St Pau, Genom Complex Dis Unit, St Quinti 77-79,3rd Floor, Barcelona 08041, Spain
Karolinska Inst, Ctr Mol Med, Dept Med, Cardiovasc Med Unit, Stockholm, Sweden
Souto, JC:
Hosp Santa Creu & Sant Pau, Haemostasis & Thrombosis Unit, Dept Hematol, Barcelona, Spain
Dermitzakis, ET:
Univ Geneva, Dept Genet Med & Dev, Geneva, Switzerland
Soria, JM:
IIB St Pau, Res Inst Hosp Santa Creu & St Pau, Genom Complex Dis Unit, St Quinti 77-79,3rd Floor, Barcelona 08041, Spain
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