Genome-wide association analysis of self-reported events in 6135 individuals and 252 827 controls identifies 8 loci associated with thrombosis

METASTROKE Consortium, INVENT Consortium, David A. Hinds, Alfonso Buil, Daniel Ziemek, Angel Martinez-Perez, Rainer Malik, Lasse Folkersen, Marine Germain, Anders Mälarstig, Andrew Brown, Jose Manuel Soria, Martin Dichgans, Nan Bing, Anders Franco-Cereceda, Juan Carlos Souto, Emmanouil T. Dermitzakis, Anders Hamsten, Bradford B. Worrall, Joyce Y. Tung & 1 others Maria Sabater-Lleal

Research output: Contribution to journalArticle

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Abstract

Thrombotic diseases are among the leading causes of morbidity and mortality in the world. To add insights into the genetic regulation of thrombotic disease, we conducted a genome-wide association study (GWAS) of 6135 self-reported blood clots events and 252 827 controls of European ancestry belonging to the 23andMe cohort of research participants. Eight loci exceeded genome-wide significance. Among the genome-wide significant results, our study replicated previously known venous thromboembolism (VTE) loci near the F5, FGA-FGG, F11, F2, PROCR and ABO genes, and the more recently discovered locus near SLC44A2 In addition, our study reports for the first time a genome-wide significant association between rs114209171, located upstream of the F8 structural gene, and thrombosis risk. Analyses of expression profiles and expression quantitative trait loci across different tissues suggested SLC44A2, ILF3 and AP1M2 as the three most plausible candidate genes for the chromosome 19 locus, our only genome-wide significant thrombosis-related locus that does not harbor likely coagulation-related genes. In addition, we present data showing that this locus also acts as a novel risk factor for stroke and coronary artery disease (CAD). In conclusion, our study reveals novel common genetic risk factors for VTE, stroke and CAD and provides evidence that self-reported data on blood clots used in a GWAS yield results that are comparable with those obtained using clinically diagnosed VTE. This observation opens up the potential for larger meta-analyses, which will enable elucidation of the genetics of thrombotic diseases, and serves as an example for the genetic study of other diseases.

Original languageEnglish
Pages (from-to)1867-1874
Number of pages8
JournalHuman Molecular Genetics
Volume25
Issue number9
Early online date9 Feb 2016
DOIs
Publication statusPublished - 1 May 2016

Fingerprint

Genome-Wide Association Study
Venous Thromboembolism
Thrombosis
Genome
Genes
Coronary Artery Disease
Stroke
Chromosomes, Human, Pair 19
Inborn Genetic Diseases
Quantitative Trait Loci
Meta-Analysis
Morbidity
Mortality
Research

Keywords

  • Adaptor Protein Complex 1/genetics
  • Adaptor Protein Complex mu Subunits/genetics
  • Adolescent
  • Adult
  • Biomarkers/metabolism
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Female
  • Genetic Loci/genetics
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Membrane Glycoproteins/genetics
  • Membrane Transport Proteins/genetics
  • Middle Aged
  • Nuclear Factor 90 Proteins/genetics
  • Polymorphism, Single Nucleotide/genetics
  • Risk Factors
  • Self Report
  • Thrombosis/genetics
  • Young Adult

Cite this

METASTROKE Consortium, INVENT Consortium, Hinds, D. A., Buil, A., Ziemek, D., Martinez-Perez, A., ... Sabater-Lleal, M. (2016). Genome-wide association analysis of self-reported events in 6135 individuals and 252 827 controls identifies 8 loci associated with thrombosis. Human Molecular Genetics, 25(9), 1867-1874. https://doi.org/10.1093/hmg/ddw037
METASTROKE Consortium ; INVENT Consortium ; Hinds, David A. ; Buil, Alfonso ; Ziemek, Daniel ; Martinez-Perez, Angel ; Malik, Rainer ; Folkersen, Lasse ; Germain, Marine ; Mälarstig, Anders ; Brown, Andrew ; Soria, Jose Manuel ; Dichgans, Martin ; Bing, Nan ; Franco-Cereceda, Anders ; Souto, Juan Carlos ; Dermitzakis, Emmanouil T. ; Hamsten, Anders ; Worrall, Bradford B. ; Tung, Joyce Y. ; Sabater-Lleal, Maria. / Genome-wide association analysis of self-reported events in 6135 individuals and 252 827 controls identifies 8 loci associated with thrombosis. In: Human Molecular Genetics. 2016 ; Vol. 25, No. 9. pp. 1867-1874.
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abstract = "Thrombotic diseases are among the leading causes of morbidity and mortality in the world. To add insights into the genetic regulation of thrombotic disease, we conducted a genome-wide association study (GWAS) of 6135 self-reported blood clots events and 252 827 controls of European ancestry belonging to the 23andMe cohort of research participants. Eight loci exceeded genome-wide significance. Among the genome-wide significant results, our study replicated previously known venous thromboembolism (VTE) loci near the F5, FGA-FGG, F11, F2, PROCR and ABO genes, and the more recently discovered locus near SLC44A2 In addition, our study reports for the first time a genome-wide significant association between rs114209171, located upstream of the F8 structural gene, and thrombosis risk. Analyses of expression profiles and expression quantitative trait loci across different tissues suggested SLC44A2, ILF3 and AP1M2 as the three most plausible candidate genes for the chromosome 19 locus, our only genome-wide significant thrombosis-related locus that does not harbor likely coagulation-related genes. In addition, we present data showing that this locus also acts as a novel risk factor for stroke and coronary artery disease (CAD). In conclusion, our study reveals novel common genetic risk factors for VTE, stroke and CAD and provides evidence that self-reported data on blood clots used in a GWAS yield results that are comparable with those obtained using clinically diagnosed VTE. This observation opens up the potential for larger meta-analyses, which will enable elucidation of the genetics of thrombotic diseases, and serves as an example for the genetic study of other diseases.",
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METASTROKE Consortium, INVENT Consortium, Hinds, DA, Buil, A, Ziemek, D, Martinez-Perez, A, Malik, R, Folkersen, L, Germain, M, Mälarstig, A, Brown, A, Soria, JM, Dichgans, M, Bing, N, Franco-Cereceda, A, Souto, JC, Dermitzakis, ET, Hamsten, A, Worrall, BB, Tung, JY & Sabater-Lleal, M 2016, 'Genome-wide association analysis of self-reported events in 6135 individuals and 252 827 controls identifies 8 loci associated with thrombosis', Human Molecular Genetics, vol. 25, no. 9, pp. 1867-1874. https://doi.org/10.1093/hmg/ddw037

Genome-wide association analysis of self-reported events in 6135 individuals and 252 827 controls identifies 8 loci associated with thrombosis. / METASTROKE Consortium; INVENT Consortium; Hinds, David A.; Buil, Alfonso; Ziemek, Daniel; Martinez-Perez, Angel; Malik, Rainer; Folkersen, Lasse; Germain, Marine; Mälarstig, Anders; Brown, Andrew; Soria, Jose Manuel; Dichgans, Martin; Bing, Nan; Franco-Cereceda, Anders; Souto, Juan Carlos; Dermitzakis, Emmanouil T.; Hamsten, Anders; Worrall, Bradford B.; Tung, Joyce Y.; Sabater-Lleal, Maria (Lead / Corresponding author).

In: Human Molecular Genetics, Vol. 25, No. 9, 01.05.2016, p. 1867-1874.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genome-wide association analysis of self-reported events in 6135 individuals and 252 827 controls identifies 8 loci associated with thrombosis

AU - METASTROKE Consortium

AU - INVENT Consortium

AU - Hinds, David A.

AU - Buil, Alfonso

AU - Ziemek, Daniel

AU - Martinez-Perez, Angel

AU - Malik, Rainer

AU - Folkersen, Lasse

AU - Germain, Marine

AU - Mälarstig, Anders

AU - Brown, Andrew

AU - Soria, Jose Manuel

AU - Dichgans, Martin

AU - Bing, Nan

AU - Franco-Cereceda, Anders

AU - Souto, Juan Carlos

AU - Dermitzakis, Emmanouil T.

AU - Hamsten, Anders

AU - Worrall, Bradford B.

AU - Tung, Joyce Y.

AU - Sabater-Lleal, Maria

N1 - © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

PY - 2016/5/1

Y1 - 2016/5/1

N2 - Thrombotic diseases are among the leading causes of morbidity and mortality in the world. To add insights into the genetic regulation of thrombotic disease, we conducted a genome-wide association study (GWAS) of 6135 self-reported blood clots events and 252 827 controls of European ancestry belonging to the 23andMe cohort of research participants. Eight loci exceeded genome-wide significance. Among the genome-wide significant results, our study replicated previously known venous thromboembolism (VTE) loci near the F5, FGA-FGG, F11, F2, PROCR and ABO genes, and the more recently discovered locus near SLC44A2 In addition, our study reports for the first time a genome-wide significant association between rs114209171, located upstream of the F8 structural gene, and thrombosis risk. Analyses of expression profiles and expression quantitative trait loci across different tissues suggested SLC44A2, ILF3 and AP1M2 as the three most plausible candidate genes for the chromosome 19 locus, our only genome-wide significant thrombosis-related locus that does not harbor likely coagulation-related genes. In addition, we present data showing that this locus also acts as a novel risk factor for stroke and coronary artery disease (CAD). In conclusion, our study reveals novel common genetic risk factors for VTE, stroke and CAD and provides evidence that self-reported data on blood clots used in a GWAS yield results that are comparable with those obtained using clinically diagnosed VTE. This observation opens up the potential for larger meta-analyses, which will enable elucidation of the genetics of thrombotic diseases, and serves as an example for the genetic study of other diseases.

AB - Thrombotic diseases are among the leading causes of morbidity and mortality in the world. To add insights into the genetic regulation of thrombotic disease, we conducted a genome-wide association study (GWAS) of 6135 self-reported blood clots events and 252 827 controls of European ancestry belonging to the 23andMe cohort of research participants. Eight loci exceeded genome-wide significance. Among the genome-wide significant results, our study replicated previously known venous thromboembolism (VTE) loci near the F5, FGA-FGG, F11, F2, PROCR and ABO genes, and the more recently discovered locus near SLC44A2 In addition, our study reports for the first time a genome-wide significant association between rs114209171, located upstream of the F8 structural gene, and thrombosis risk. Analyses of expression profiles and expression quantitative trait loci across different tissues suggested SLC44A2, ILF3 and AP1M2 as the three most plausible candidate genes for the chromosome 19 locus, our only genome-wide significant thrombosis-related locus that does not harbor likely coagulation-related genes. In addition, we present data showing that this locus also acts as a novel risk factor for stroke and coronary artery disease (CAD). In conclusion, our study reveals novel common genetic risk factors for VTE, stroke and CAD and provides evidence that self-reported data on blood clots used in a GWAS yield results that are comparable with those obtained using clinically diagnosed VTE. This observation opens up the potential for larger meta-analyses, which will enable elucidation of the genetics of thrombotic diseases, and serves as an example for the genetic study of other diseases.

KW - Adaptor Protein Complex 1/genetics

KW - Adaptor Protein Complex mu Subunits/genetics

KW - Adolescent

KW - Adult

KW - Biomarkers/metabolism

KW - Case-Control Studies

KW - Child

KW - Child, Preschool

KW - Female

KW - Genetic Loci/genetics

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Infant

KW - Infant, Newborn

KW - Male

KW - Membrane Glycoproteins/genetics

KW - Membrane Transport Proteins/genetics

KW - Middle Aged

KW - Nuclear Factor 90 Proteins/genetics

KW - Polymorphism, Single Nucleotide/genetics

KW - Risk Factors

KW - Self Report

KW - Thrombosis/genetics

KW - Young Adult

U2 - 10.1093/hmg/ddw037

DO - 10.1093/hmg/ddw037

M3 - Article

VL - 25

SP - 1867

EP - 1874

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 9

ER -