. 2024 Sep 3;33(18):1584-1591.

doi: 10.1093/hmg/ddae097.

Multi-ancestry polygenic risk scores for venous thromboembolism

Yon Ho Jee¹, Florian Thibord^{2

3}, Alicia Dominguez⁴, Corriene Sept⁵, Kristin Boulier⁶, Vidhya Venkateswaran⁷, Yi Ding⁶, Tess Cherlin⁸, Shefali Setia Verma⁸, Valeria Lo Faro^{9

10}, Traci M Bartz¹¹, Anne Boland^{12

13}, Jennifer A Brody¹⁴, Jean-Francois Deleuze^{12

13

15}, Joseph Emmerich^{16

17}, Marine Germain¹⁸, Andrew D Johnson^{2

3}, Charles Kooperberg¹⁹, Pierre-Emmanuel Morange²⁰, Nathan Pankratz²¹, Bruce M Psaty^{14

22

23}, Alexander P Reiner^{19

22}, David M Smadja^{24

25}, Colleen M Sitlani¹⁴, Pierre Suchon²⁰, Weihong Tang²⁶, David-Alexandre Trégouët¹⁸, Sebastian Zöllner⁴, Bogdan Pasaniuc⁷, Scott M Damrauer^{27

28

29}, Serena Sanna^{30

31}, Harold Snieder⁹; Lifelines Cohort Study; Christopher Kabrhel³², Nicholas L Smith^{23

33

34}, Peter Kraft³⁵; INVENT Consortium

Collaborators, Affiliations

Collaborators

Raul Aguirre-Gamboa, Patrick Deelen, Lude Franke, Jan A Kuivenhoven, Esteban A Lopera Maya, Ilja M Nolte, Serena Sanna, Harold Snieder, Morris A Swertz, Peter M Visscher, Judith M Vonk, Cisca Wijmenga, Naomi Wray

Affiliations

¹ Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Ave, Boston, MA 02115, United States.
² Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, 31 Center Drive, Bethesda, MD 20892, United States.
³ Framingham Heart Study, Boston University and National Heart, Lung, and Blood Institute, Framingham, 73 Mt. Wayte Ave, Suite #2, Framingham, MA 01702, United States.
⁴ Department of Biostatistics, University of Michigan, 1415 Washington Heights, Ann Arbor, MI 48109, United States.
⁵ Department of Biostatistics, Harvard T.H. Chan School of Public Health, 677 Huntington Ave, Boston, MA 02115, United States.
⁶ Bioinformatics Interdepartmental Program, University of California Los Angeles, 611 Charles E. Young Drive East, Los Angeles, CA 90095-1570, United States.
⁷ Department of Oral Biology, University of California Los Angeles School of Dentistry, 13-089 CHS, Box 951668, Box 951570, Los Angeles, CA 90095-1668, United States.
⁸ Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, 3400 Spruce St. Philadelphia, PA 19104-4238, United States.
⁹ Department of Epidemiology, University of Groningen, University Medical Center Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands.
¹⁰ Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Dag Hammarskjölds väg 20751 85 Uppsala, Sweden.
¹¹ Cardiovascular Health Research Unit, Departments of Biostatistics and Medicine, University of Washington, 4333 Brooklyn Ave, Seattle, WA 98195, United States.
¹² Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, 91057 Evry, France.
¹³ Laboratory of Excellence in Medical Genomics, GENMED, F-91057 Evry, France.
¹⁴ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, 4333 Brooklyn Ave, Seattle, WA 98195, United States.
¹⁵ Centre d'Etude du Polymorphisme Humain, Fondation Jean Dausset, 27 rue Juliette Dodu, 75010 Paris, France.
¹⁶ Department of Vascular Medicine, Paris Saint-Joseph Hospital Group, University of Paris, 75014 Paris, France.
¹⁷ INSERM CRESS UMR 1153, F-75005, Paris, France.
¹⁸ Bordeaux Population Health Research Center, University of Bordeaux, INSERM, UMR 1219, Bordeaux, France.
¹⁹ Division of Public Health Sciences, Fred Hutchinbson Cancer Center, PO Box 19024, Seattle, WA 98109, United States.
²⁰ Aix-Marseille University, INSERM, INRAE, Centre de Recherche en CardioVasculaire et Nutrition, Laboratory of Haematology, CRB Assistance Publique - Hôpitaux de Marseille, HemoVasc, 27, boulevard Jean Moulin, 13005 Marseille, France.
²¹ Department of Laboratory Medicine and Pathology, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455, United States.
²² Department of Epidemiology, University of Washington, 4333 Brooklyn Ave, Seattle, WA 98195, United States.
²³ Department of Health Systems and Population Health, University of Washington, 4333 Brooklyn Ave, Seattle, WA 98195, United States.
²⁴ Innovative Therapies in Hemostasis, Université de Paris, INSERM, F-75006, Paris, France.
²⁵ Hematology Department and Biosurgical Research Lab (Carpentier Foundation), Assistance Publique Hôpitaux de Paris, Centre-Université de Paris (APHP-CUP), F-75015, Paris, France.
²⁶ Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, 1300 S. 2nd St., Minneapolis, MN 55454, United States.
²⁷ Department of Genetics, University of Pennsylvania Perelman School of Medicine, 415 Curie Blvd, Philadelphia, PA 19104, United States.
²⁸ Department of Surgery, Department of Genetics, and Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Building 421, Philadelphia, PA 19104, United States.
²⁹ Department of Surgery, Corporal Michael Crescenz VA Medical Center, 3900 Woodland Ave, Philadelphia, PA 19104, United States.
³⁰ Department of Genetics, University of Groningen, University Medical Center Groningen (UMCG), PO Box 30.001, 9700 RB Groningen, The Netherlands.
³¹ Institute for Genetics and Biomedical Research, National Research Council, SS 554 Km 4,500, 09042 Monserrato CA, Italy.
³² Center for Vascular Emergencies, Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, United States.
³³ Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, 1730 Minor Ave, Seattle, WA 98101, United States.
³⁴ Department of Veterans Affairs Office of Research and Development, Seattle Epidemiologic Research and Information Center, 1660 S Columbian Way, S-152-E, Seattle, WA 98108, United States.
³⁵ Transdivisional Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Dr, Rockville, MD 20850, United States.

PMID: 38879759
PMCID: PMC11373328
DOI: 10.1093/hmg/ddae097

Multi-ancestry polygenic risk scores for venous thromboembolism

Yon Ho Jee et al. Hum Mol Genet. 2024.

. 2024 Sep 3;33(18):1584-1591.

doi: 10.1093/hmg/ddae097.

Authors

Collaborators

Raul Aguirre-Gamboa, Patrick Deelen, Lude Franke, Jan A Kuivenhoven, Esteban A Lopera Maya, Ilja M Nolte, Serena Sanna, Harold Snieder, Morris A Swertz, Peter M Visscher, Judith M Vonk, Cisca Wijmenga, Naomi Wray

Affiliations

¹ Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Ave, Boston, MA 02115, United States.
² Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, 31 Center Drive, Bethesda, MD 20892, United States.
³ Framingham Heart Study, Boston University and National Heart, Lung, and Blood Institute, Framingham, 73 Mt. Wayte Ave, Suite #2, Framingham, MA 01702, United States.
⁴ Department of Biostatistics, University of Michigan, 1415 Washington Heights, Ann Arbor, MI 48109, United States.
⁵ Department of Biostatistics, Harvard T.H. Chan School of Public Health, 677 Huntington Ave, Boston, MA 02115, United States.
⁶ Bioinformatics Interdepartmental Program, University of California Los Angeles, 611 Charles E. Young Drive East, Los Angeles, CA 90095-1570, United States.
⁷ Department of Oral Biology, University of California Los Angeles School of Dentistry, 13-089 CHS, Box 951668, Box 951570, Los Angeles, CA 90095-1668, United States.
⁸ Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, 3400 Spruce St. Philadelphia, PA 19104-4238, United States.
⁹ Department of Epidemiology, University of Groningen, University Medical Center Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands.
¹⁰ Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Dag Hammarskjölds väg 20751 85 Uppsala, Sweden.
¹¹ Cardiovascular Health Research Unit, Departments of Biostatistics and Medicine, University of Washington, 4333 Brooklyn Ave, Seattle, WA 98195, United States.
¹² Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, 91057 Evry, France.
¹³ Laboratory of Excellence in Medical Genomics, GENMED, F-91057 Evry, France.
¹⁴ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, 4333 Brooklyn Ave, Seattle, WA 98195, United States.
¹⁵ Centre d'Etude du Polymorphisme Humain, Fondation Jean Dausset, 27 rue Juliette Dodu, 75010 Paris, France.
¹⁶ Department of Vascular Medicine, Paris Saint-Joseph Hospital Group, University of Paris, 75014 Paris, France.
¹⁷ INSERM CRESS UMR 1153, F-75005, Paris, France.
¹⁸ Bordeaux Population Health Research Center, University of Bordeaux, INSERM, UMR 1219, Bordeaux, France.
¹⁹ Division of Public Health Sciences, Fred Hutchinbson Cancer Center, PO Box 19024, Seattle, WA 98109, United States.
²⁰ Aix-Marseille University, INSERM, INRAE, Centre de Recherche en CardioVasculaire et Nutrition, Laboratory of Haematology, CRB Assistance Publique - Hôpitaux de Marseille, HemoVasc, 27, boulevard Jean Moulin, 13005 Marseille, France.
²¹ Department of Laboratory Medicine and Pathology, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455, United States.
²² Department of Epidemiology, University of Washington, 4333 Brooklyn Ave, Seattle, WA 98195, United States.
²³ Department of Health Systems and Population Health, University of Washington, 4333 Brooklyn Ave, Seattle, WA 98195, United States.
²⁴ Innovative Therapies in Hemostasis, Université de Paris, INSERM, F-75006, Paris, France.
²⁵ Hematology Department and Biosurgical Research Lab (Carpentier Foundation), Assistance Publique Hôpitaux de Paris, Centre-Université de Paris (APHP-CUP), F-75015, Paris, France.
²⁶ Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, 1300 S. 2nd St., Minneapolis, MN 55454, United States.
²⁷ Department of Genetics, University of Pennsylvania Perelman School of Medicine, 415 Curie Blvd, Philadelphia, PA 19104, United States.
²⁸ Department of Surgery, Department of Genetics, and Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Building 421, Philadelphia, PA 19104, United States.
²⁹ Department of Surgery, Corporal Michael Crescenz VA Medical Center, 3900 Woodland Ave, Philadelphia, PA 19104, United States.
³⁰ Department of Genetics, University of Groningen, University Medical Center Groningen (UMCG), PO Box 30.001, 9700 RB Groningen, The Netherlands.
³¹ Institute for Genetics and Biomedical Research, National Research Council, SS 554 Km 4,500, 09042 Monserrato CA, Italy.
³² Center for Vascular Emergencies, Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, United States.
³³ Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, 1730 Minor Ave, Seattle, WA 98101, United States.
³⁴ Department of Veterans Affairs Office of Research and Development, Seattle Epidemiologic Research and Information Center, 1660 S Columbian Way, S-152-E, Seattle, WA 98108, United States.
³⁵ Transdivisional Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Dr, Rockville, MD 20850, United States.

PMID: 38879759
PMCID: PMC11373328
DOI: 10.1093/hmg/ddae097

Abstract

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality, with large disparities in incidence rates between Black and White Americans. Polygenic risk scores (PRSs) limited to variants discovered in genome-wide association studies in European-ancestry samples can identify European-ancestry individuals at high risk of VTE. However, there is limited evidence on whether high-dimensional PRS constructed using more sophisticated methods and more diverse training data can enhance the predictive ability and their utility across diverse populations. We developed PRSs for VTE using summary statistics from the International Network against Venous Thrombosis (INVENT) consortium genome-wide association studies meta-analyses of European- (71 771 cases and 1 059 740 controls) and African-ancestry samples (7482 cases and 129 975 controls). We used LDpred2 and PRS-CSx to construct ancestry-specific and multi-ancestry PRSs and evaluated their performance in an independent European- (6781 cases and 103 016 controls) and African-ancestry sample (1385 cases and 12 569 controls). Multi-ancestry PRSs with weights tuned in European-ancestry samples slightly outperformed ancestry-specific PRSs in European-ancestry test samples (e.g. the area under the receiver operating curve [AUC] was 0.609 for PRS-CSx_combinedEUR and 0.608 for PRS-CSxEUR [P = 0.00029]). Multi-ancestry PRSs with weights tuned in African-ancestry samples also outperformed ancestry-specific PRSs in African-ancestry test samples (PRS-CSxAFR: AUC = 0.58, PRS-CSx_combined AFR: AUC = 0.59), although this difference was not statistically significant (P = 0.34). The highest fifth percentile of the best-performing PRS was associated with 1.9-fold and 1.68-fold increased risk for VTE among European- and African-ancestry subjects, respectively, relative to those in the middle stratum. These findings suggest that the multi-ancestry PRS might be used to improve performance across diverse populations to identify individuals at highest risk for VTE.

Keywords: genetic; polygenic risk score; risk prediction; venous thromboembolism; venous thrombosis.

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Figures

**Figure 1**
Overview of development and validation of population-specific and multi-ancestry PRS for venous thromboembolism.

**Figure 2**
AUC and OR for population-specific and multiancestry PRS across populations.

**Figure 3**
Distribution of relative risk of VTE by PRS across populations.

See this image and copyright information in PMC

Update of

Multi-ancestry polygenic risk scores for venous thromboembolism.
Jee YH, Thibord F, Dominguez A, Sept C, Boulier K, Venkateswaran V, Ding Y, Cherlin T, Verma SS, Faro VL, Bartz TM, Boland A, Brody JA, Deleuze JF, Emmerich J, Germain M, Johnson AD, Kooperberg C, Morange PE, Pankratz N, Psaty BM, Reiner AP, Smadja DM, Sitlani CM, Suchon P, Tang W, Trégouët DA, Zöllner S, Pasaniuc B, Damrauer SM, Sanna S, Snieder H; Lifelines Cohort Study; Kabrhel C, Smith NL, Kraft P; INVENT Consortium. Jee YH, et al. medRxiv [Preprint]. 2024 Jan 10:2024.01.09.24300914. doi: 10.1101/2024.01.09.24300914. medRxiv. 2024. Update in: Hum Mol Genet. 2024 Sep 3;33(18):1584-1591. doi: 10.1093/hmg/ddae097. PMID: 38260294 Free PMC article. Updated. Preprint.

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Multi-ancestry polygenic risk scores for venous thromboembolism

Collaborators

Affiliations

Multi-ancestry polygenic risk scores for venous thromboembolism

Authors

Collaborators

Affiliations

Abstract

Figures

Update of

References

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