Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism

Sara Lindström^{1

2}, Lu Wang³, Erin N Smith^{4

5}, William Gordon¹, Astrid van Hylckama Vlieg⁶, Mariza de Andrade⁷, Jennifer A Brody⁸, Jack W Pattee⁹, Jeffrey Haessler², Ben M Brumpton^{10

11

12}, Daniel I Chasman^{13

14}, Pierre Suchon^{15

16}, Ming-Huei Chen^{17

18}, Constance Turman¹⁹, Marine Germain²⁰, Kerri L Wiggins⁸, James MacDonald³, Sigrid K Braekkan^{5

21}, Sebastian M Armasu⁷, Nathan Pankratz²², Rebecca D Jackson²³, Jonas B Nielsen²⁴, Franco Giulianini¹³, Marja K Puurunen¹⁸, Manal Ibrahim¹⁵, Susan R Heckbert^{1

25}, Scott M Damrauer^{26

27}, Pradeep Natarajan^{28

29

14

30}, Derek Klarin^{28

31

32}; Million Veteran Program; Paul S de Vries³³, Maria Sabater-Lleal^{34

35}, Jennifer E Huffman³⁶; CHARGE Hemostasis Working Group; Theo K Bammler³, Kelly A Frazer^{4

5

37}, Bryan M McCauley⁷, Kent Taylor³⁸, James S Pankow³⁹, Alexander P Reiner^{1

2}, Maiken E Gabrielsen¹⁰, Jean-François Deleuze^{40

41}, Chris J O'Donnell^{17

18

42}, Jihye Kim¹⁹, Barbara McKnight^{2

43}, Peter Kraft¹⁹, John-Bjarne Hansen^{5

21}, Frits R Rosendaal⁶, John A Heit⁷, Bruce M Psaty^{25

44}, Weihong Tang³⁹, Charles Kooperberg², Kristian Hveem¹⁰, Paul M Ridker^{13

14}, Pierre-Emmanuel Morange^{15

16

45}, Andrew D Johnson^{17

18}, Christopher Kabrhel^{46

47

48}, David-Alexandre Trégouët²⁰, Nicholas L Smith^{1

25

49}

Affiliations

¹ Department of Epidemiology, University of Washington, Seattle, WA.
² Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
³ Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA.
⁴ Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA.
⁵ K.G. Jebsen Thrombosis Research and Expertise Center, Department of Clinical Medicine, UiT-The Arctic University of Norway, Tromsø, Norway.
⁶ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
⁷ Department of Health Sciences Research, Mayo Clinic, Rochester, MN.
⁸ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA.
⁹ Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN.
¹⁰ K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
¹¹ Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
¹² Clinic of Thoracic and Occupational Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
¹³ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA.
¹⁴ Department of Medicine, Harvard Medical School, Boston, MA.
¹⁵ Laboratory of Haematology, La Timone Hospital, Marseille, France.
¹⁶ Center for CardioVascular and Nutrition research (C2VN), Universite Aix-Marseille, Institut National de la Recherche Agronomique (INRA), INSERM, Marseille, France.
¹⁷ Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Framingham, MA.
¹⁸ The Framingham Heart Study, Framingham, MA.
¹⁹ Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA.
²⁰ INSERM UMR_S 1219, Bordeaux Population Health Research Center, University of Bordeaux, Bordeaux, France.
²¹ Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway.
²² Department of Laboratory Medicine and Pathology, School of Medicine, University of Minnesota, Minneapolis, MN.
²³ Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University, Columbus OH.
²⁴ Division of Cardiology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI.
²⁵ Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA.
²⁶ Department of Surgery, Corporal Michael Crescenz VA Medical Center, Philadelphia, PA.
²⁷ Department of Surgery, Perleman School of Medicine, University of Pennsylvania, Philadelphia, PA.
²⁸ Boston VA Healthcare System, Boston, MA.
²⁹ Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA.
³⁰ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA.
³¹ Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
³² Department of Surgery, Massachusetts General Hospital, Boston, MA.
³³ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX.
³⁴ Unit of Genomics of Complex Diseases, Institut de Recerca de l'Hospital de Sant Pau, IIB-Sant Pau, Barcelona, Spain.
³⁵ Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
³⁶ Center for Population Genomics, MAVERIC, VA Boston Healthcare System, Boston, MA.
³⁷ Institute of Genomic Medicine, University of California San Diego, La Jolla, CA.
³⁸ Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor-University of California Los Angeles Medical Center, Torrence CA.
³⁹ Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN.
⁴⁰ Centre National de Recherche en Génomique Humaine, Direction de la Recherche Fondamentale, Le Commissariat à l'énergie atomique et aux énergies alternatives, Evry, France.
⁴¹ The Centre d'Etude du Polymorphism Humain (CEPH), Fondation Jean Dausset, Paris, France.
⁴² Million Veteran Program, Veteran's Administration, Boston, MA.
⁴³ Department of Biostatistics, University of Washington, Seattle, WA.
⁴⁴ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA.
⁴⁵ Centre de Ressources Biologiques Assistance Publique-Hôpitaux de Marseille, HemoVasc, Marseille, France.
⁴⁶ Center for Vascular Emergencies, Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA.
⁴⁷ Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA.
⁴⁸ Department of Emergency Medicine, Harvard Medical School, Boston, MA; and.
⁴⁹ Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, WA.

PMID: 31420334
PMCID: PMC6871304
DOI: 10.1182/blood.2019000435

Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism

Sara Lindström et al. Blood. 2019.

. 2019 Nov 7;134(19):1645-1657.

doi: 10.1182/blood.2019000435.

Authors

Affiliations

¹ Department of Epidemiology, University of Washington, Seattle, WA.
² Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
³ Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA.
⁴ Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA.
⁵ K.G. Jebsen Thrombosis Research and Expertise Center, Department of Clinical Medicine, UiT-The Arctic University of Norway, Tromsø, Norway.
⁶ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
⁷ Department of Health Sciences Research, Mayo Clinic, Rochester, MN.
⁸ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA.
⁹ Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN.
¹⁰ K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
¹¹ Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
¹² Clinic of Thoracic and Occupational Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
¹³ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA.
¹⁴ Department of Medicine, Harvard Medical School, Boston, MA.
¹⁵ Laboratory of Haematology, La Timone Hospital, Marseille, France.
¹⁶ Center for CardioVascular and Nutrition research (C2VN), Universite Aix-Marseille, Institut National de la Recherche Agronomique (INRA), INSERM, Marseille, France.
¹⁷ Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Framingham, MA.
¹⁸ The Framingham Heart Study, Framingham, MA.
¹⁹ Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA.
²⁰ INSERM UMR_S 1219, Bordeaux Population Health Research Center, University of Bordeaux, Bordeaux, France.
²¹ Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway.
²² Department of Laboratory Medicine and Pathology, School of Medicine, University of Minnesota, Minneapolis, MN.
²³ Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University, Columbus OH.
²⁴ Division of Cardiology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI.
²⁵ Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA.
²⁶ Department of Surgery, Corporal Michael Crescenz VA Medical Center, Philadelphia, PA.
²⁷ Department of Surgery, Perleman School of Medicine, University of Pennsylvania, Philadelphia, PA.
²⁸ Boston VA Healthcare System, Boston, MA.
²⁹ Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA.
³⁰ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA.
³¹ Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
³² Department of Surgery, Massachusetts General Hospital, Boston, MA.
³³ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX.
³⁴ Unit of Genomics of Complex Diseases, Institut de Recerca de l'Hospital de Sant Pau, IIB-Sant Pau, Barcelona, Spain.
³⁵ Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
³⁶ Center for Population Genomics, MAVERIC, VA Boston Healthcare System, Boston, MA.
³⁷ Institute of Genomic Medicine, University of California San Diego, La Jolla, CA.
³⁸ Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor-University of California Los Angeles Medical Center, Torrence CA.
³⁹ Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN.
⁴⁰ Centre National de Recherche en Génomique Humaine, Direction de la Recherche Fondamentale, Le Commissariat à l'énergie atomique et aux énergies alternatives, Evry, France.
⁴¹ The Centre d'Etude du Polymorphism Humain (CEPH), Fondation Jean Dausset, Paris, France.
⁴² Million Veteran Program, Veteran's Administration, Boston, MA.
⁴³ Department of Biostatistics, University of Washington, Seattle, WA.
⁴⁴ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA.
⁴⁵ Centre de Ressources Biologiques Assistance Publique-Hôpitaux de Marseille, HemoVasc, Marseille, France.
⁴⁶ Center for Vascular Emergencies, Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA.
⁴⁷ Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA.
⁴⁸ Department of Emergency Medicine, Harvard Medical School, Boston, MA; and.
⁴⁹ Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, WA.

PMID: 31420334
PMCID: PMC6871304
DOI: 10.1182/blood.2019000435

Abstract

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.

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Figures

**Figure 1.**
Manhattan plot of the association of 12 923 718 variants by chromosome and their association with VTE.

**Figure 2.**
GRS distribution for VTE cases and controls.

See this image and copyright information in PMC

Comment in

Genetics of venous thromboembolism revised.
Zöller B. Zöller B. Blood. 2019 Nov 7;134(19):1568-1570. doi: 10.1182/blood.2019002597. Blood. 2019. PMID: 31698420 Free PMC article. No abstract available.

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Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism

Affiliations

Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism

Authors

Affiliations

Abstract

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Comment in

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

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Miscellaneous