A large-scale exome array analysis of venous thromboembolism

Sara Lindström^{1

2}, Jennifer A Brody³, Constance Turman⁴, Marine Germain⁵, Traci M Bartz^{3

6}, Erin N Smith^{7

8}, Ming-Huei Chen⁹, Marja Puurunen¹⁰, Daniel Chasman¹¹, Jeffrey Hassler², Nathan Pankratz¹², Saonli Basu¹³, Weihua Guan¹³, Beata Gyorgy^{14

15}, Manal Ibrahim^{16

17

18}, Jean-Philippe Empana^{19

20}, Robert Olaso²¹, Rebecca Jackson²², Sigrid K Braekkan²³, Barbara McKnight⁶, Jean-Francois Deleuze²¹, Cristopher J O'Donnell²⁴, Xavier Jouven^{19

25}, Kelly A Frazer^{7

8

26}, Bruce M Psaty^{1

3

27

28}, Kerri L Wiggins³, Kent Taylor²⁹, Alexander P Reiner¹, Susan R Heckbert¹, Charles Kooperberg², Paul Ridker¹¹, John-Bjarne Hansen^{8

23}, Weihong Tang³⁰, Andrew D Johnson⁹, Pierre-Emmanuel Morange^{16

17

18}, David A Trégouët⁵, Peter Kraft^{4

31}, Nicholas L Smith^{1

28

32}, Christopher Kabrhel^{33

34

35}; INVENT Consortium

Affiliations

¹ Department of Epidemiology, University of Washington, Seattle, Washington.
² Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
³ Department of Medicine, University of Washington, Seattle, Washington.
⁴ Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, Massachusetts.
⁵ University of Bordeaux, Inserm 1219, Bordeaux Population Health Research Center, Bordeaux, France.
⁶ Department of Biostatistics, University of Washington, Seattle, Washington.
⁷ Department of Pediatrics, Rady Children's Hospital, University of California, San Diego, California.
⁸ Department of Clinical Medicine, UiT-The Arctic University of Norway, K.G. Jebsen Thrombosis Research and Expertise Center (TREC), Tromsø, Norway.
⁹ Population Sciences Branch, National Heart, Lung and Blood Institute's The Framingham Heart Study, Framingham, Massachusetts.
¹⁰ School of Medicine, Boston University, Boston, Massachusetts.
¹¹ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
¹² Department of Laboratory Medicine and Pathology, School of Medicine, University of Minnesota, Minneapolis, Minnesota.
¹³ Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota.
¹⁴ Team Genomics & Pathophysiology of Cardiovascular Diseases, Sorbonne Universités, UPMC Univ. Paris 06, INSERM, UMR_S 1166, Paris, France.
¹⁵ ICAN Institute for Cardiometabolism and Nutrition, Paris, France.
¹⁶ Laboratory of Haematology, La Timone Hospital, Marseille, France.
¹⁷ Aix-Marseille University, INSERM, INSERM, INRA, C2VN, Marseille, France.
¹⁸ CRB Assistance Publique Hopitaux de Marseille HemoVasc, Marseille, France.
¹⁹ Department of Epidemiology, Université Paris Descartes, Sorbonne Paris Cité, INSERM UMR_S 970, Paris, France.
²⁰ Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
²¹ Centre National de Recherche en Génomique Humaine (CNRGH), Direction de la Recherche Fondamentale, CEA, Institut de Biologie François Jacob, Evry, France.
²² Ohio State University, Columbus, Ohio.
²³ Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway.
²⁴ Department of Cardiology, Boston Veteran's Administration Healthcare, Boston, Massachusetts.
²⁵ Department of Cardiology, Georges Pompidou European Hospital, APHP, Paris, France.
²⁶ Institute for Genomic Medicine, University of California, San Diego, California.
²⁷ Department of Health Services, University of Washington, Seattle, Washington.
²⁸ Kaiser Permanente Washington Research Institute, Seattle, Washington.
²⁹ LA BioMed, Torrance, California.
³⁰ Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota.
³¹ Department of Biostatistics, Harvard TH Chan School of Public Health, Boston, Massachusetts.
³² Department of Veteran Affairs Office of Research and Development, Seattle Epidemiologic Research and Information Center, Seattle, Washington.
³³ Department of Emergency Medicine, Center for Vascular Emergencies, Massachusetts General Hospital, Boston, Massachusetts.
³⁴ Channing Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
³⁵ Harvard Medical School, Boston, Massachusetts.

PMID: 30659681
PMCID: PMC6520188
DOI: 10.1002/gepi.22187

Meta-Analysis

A large-scale exome array analysis of venous thromboembolism

Sara Lindström et al. Genet Epidemiol. 2019 Jun.

. 2019 Jun;43(4):449-457.

doi: 10.1002/gepi.22187. Epub 2019 Jan 19.

Authors

Affiliations

¹ Department of Epidemiology, University of Washington, Seattle, Washington.
² Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
³ Department of Medicine, University of Washington, Seattle, Washington.
⁴ Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, Massachusetts.
⁵ University of Bordeaux, Inserm 1219, Bordeaux Population Health Research Center, Bordeaux, France.
⁶ Department of Biostatistics, University of Washington, Seattle, Washington.
⁷ Department of Pediatrics, Rady Children's Hospital, University of California, San Diego, California.
⁸ Department of Clinical Medicine, UiT-The Arctic University of Norway, K.G. Jebsen Thrombosis Research and Expertise Center (TREC), Tromsø, Norway.
⁹ Population Sciences Branch, National Heart, Lung and Blood Institute's The Framingham Heart Study, Framingham, Massachusetts.
¹⁰ School of Medicine, Boston University, Boston, Massachusetts.
¹¹ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
¹² Department of Laboratory Medicine and Pathology, School of Medicine, University of Minnesota, Minneapolis, Minnesota.
¹³ Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota.
¹⁴ Team Genomics & Pathophysiology of Cardiovascular Diseases, Sorbonne Universités, UPMC Univ. Paris 06, INSERM, UMR_S 1166, Paris, France.
¹⁵ ICAN Institute for Cardiometabolism and Nutrition, Paris, France.
¹⁶ Laboratory of Haematology, La Timone Hospital, Marseille, France.
¹⁷ Aix-Marseille University, INSERM, INSERM, INRA, C2VN, Marseille, France.
¹⁸ CRB Assistance Publique Hopitaux de Marseille HemoVasc, Marseille, France.
¹⁹ Department of Epidemiology, Université Paris Descartes, Sorbonne Paris Cité, INSERM UMR_S 970, Paris, France.
²⁰ Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
²¹ Centre National de Recherche en Génomique Humaine (CNRGH), Direction de la Recherche Fondamentale, CEA, Institut de Biologie François Jacob, Evry, France.
²² Ohio State University, Columbus, Ohio.
²³ Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway.
²⁴ Department of Cardiology, Boston Veteran's Administration Healthcare, Boston, Massachusetts.
²⁵ Department of Cardiology, Georges Pompidou European Hospital, APHP, Paris, France.
²⁶ Institute for Genomic Medicine, University of California, San Diego, California.
²⁷ Department of Health Services, University of Washington, Seattle, Washington.
²⁸ Kaiser Permanente Washington Research Institute, Seattle, Washington.
²⁹ LA BioMed, Torrance, California.
³⁰ Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota.
³¹ Department of Biostatistics, Harvard TH Chan School of Public Health, Boston, Massachusetts.
³² Department of Veteran Affairs Office of Research and Development, Seattle Epidemiologic Research and Information Center, Seattle, Washington.
³³ Department of Emergency Medicine, Center for Vascular Emergencies, Massachusetts General Hospital, Boston, Massachusetts.
³⁴ Channing Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
³⁵ Harvard Medical School, Boston, Massachusetts.

PMID: 30659681
PMCID: PMC6520188
DOI: 10.1002/gepi.22187

Abstract

Although recent Genome-Wide Association Studies have identified novel associations for common variants, there has been no comprehensive exome-wide search for low-frequency variants that affect the risk of venous thromboembolism (VTE). We conducted a meta-analysis of 11 studies comprising 8,332 cases and 16,087 controls of European ancestry and 382 cases and 1,476 controls of African American ancestry genotyped with the Illumina HumanExome BeadChip. We used the seqMeta package in R to conduct single variant and gene-based rare variant tests. In the single variant analysis, we limited our analysis to the 64,794 variants with at least 40 minor alleles across studies (minor allele frequency [MAF] ~0.08%). We confirmed associations with previously identified VTE loci, including ABO, F5, F11, and FGA. After adjusting for multiple testing, we observed no novel significant findings in single variant or gene-based analysis. Given our sample size, we had greater than 80% power to detect minimum odds ratios greater than 1.5 and 1.8 for a single variant with MAF of 0.01 and 0.005, respectively. Larger studies and sequence data may be needed to identify novel low-frequency and rare variants associated with VTE risk.

Keywords: exome; genetic association; venous thromboembolism.

PubMed Disclaimer

Conflict of interest statement

CONFLICT OF INTEREST:

No authors report a conflict of interest related to this work.

Figures

**Figure 1:**
QQ plots for gene burden tests including non-synonymous variants with MAF≤0.01. The WSB test using a broad definition of variant inclusion (upper left panel), the WSB test using a strict definition of variant inclusion (upper right panel), the SKAT test using a broad definition of variant inclusion (lower left panel), the SKAT test using a strict definition of variant inclusion (lower right panel).

See this image and copyright information in PMC

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A large-scale exome array analysis of venous thromboembolism

Affiliations

A large-scale exome array analysis of venous thromboembolism

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

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Miscellaneous