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

Lindström, Sara; Wang, Lu; Smith, Erin N.; Gordon, William W.; Vlieg, Astrid van Hylckama; Andrade, Mariza de; Brody, Jennifer A.; Pattee, Jack; Haessler, Jeffrey; Brumpton, Ben; Chasman, Daniel I.; Suchon, Pierre; Chen, Ming-Huei; Turman, Constance; Germain, Marine; Wiggins, Kerri L.; MacDonald, James W.; Brækkan, Sigrid Kufaas; Armasu, Sebastian M.; Pankratz, Nathan; Jackson, Rebecca D.; Nielsen, Jonas B.; Giulianini, Franco; Puurunen, Marja; Ibrahim, Manal; Heckbert, Susan R.; Damrauer, Scott M.; Natarajan, Pradeep; Klarin, Derek; Vries, Paul S. de; Sabater‐Lleal, Maria; Huffman, Jennifer E.; Bammler, Theo K.; Frazer, Kelly A.; McCauley, Bryan M.; Taylor, Kent D.; Pankow, James S.; Reiner, Alexander P.; Gabrielsen, Maiken Elvestad; Deleuze, Jean; O’Donnell, Chris; Kim, Jihye; McKnight, Barbara; Kraft, Peter; Hansen, John Bjarne; Rosendaal, Frits R.; Heit, John A.; Psaty, Bruce M.; Tang, Weihong; Kooperberg, Charles; Hveem, Kristian; Ridker, Paul M.; Morange, Pierre‐Emmanuel; Johnson, Andrew D.; Kabrhel, Christopher; Trégouët, David‐Alexandre; Smith, Nicholas L.

doi:10.1182/blood.2019000435

Cited by 175 publications

(252 citation statements)

References 95 publications

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“…In Phase 2, an additional round of external replication was performed for lead variants using summary data of up to 15,572 VTE cases and 113,430 disease-free controls from the INVENT consortium's current VTE meta-analysis 13 combined with 2,100 VTE cases and 53,865 controls from MVP 3.0 data. Of note, UK Biobank data was excluded from the summary statistics provided by INVENT.…”

Section: Replicationmentioning

confidence: 99%

“…We combined statistical evidence across MVP and UK Biobank and set a significance threshold of P < 5 ×10 −8 (genome-wide significance), and also required an internal replication P < 0.01 in each of the individual MVP and UK Biobank analyses, with concordant directions of effect, to minimize false positive findings. In Phase 2, an additional round of external replication was performed for lead variants using summary data of up to 15,572 VTE cases and 113,430 disease-free controls from the INVENT consortium 13 combined with 2,100 VTE cases and 53,865 controls from MVP 3.0 data, requiring P < 0.05 with consistent direction of effect for successful replication.…”

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confidence: 99%

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Genome-wide association analysis of venous thromboembolism identifies new risk loci and genetic overlap with arterial vascular disease

et al. 2019

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Venous thromboembolism (VTE) is a significant cause of mortality 1 , yet its genetic determinants remain incompletely defined. We performed a discovery genome-wide association study in the Million Veteran Program and UK Biobank testing ~13 million DNA sequence variants for association with VTE (26,066 cases; 624,053 controls) and meta-analyzed both studies, followed by independent replication with up to 17,672 VTE cases and 167,295 controls. We identified 22 novel loci, bringing the total number of VTE-associated loci to 33 and subsequently fine-mapped these associations. We developed a genome-wide polygenic risk score for VTE that identifies 5% of the population at equivalent incident VTE risk to carriers of the established F5 Leiden (p.R506Q) and prothrombin G20210A mutations. Our data provide new mechanistic insights into the genetic epidemiology of VTE and suggest a greater overlap among venous and arterial cardiovascular disease than previously suggested.

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Section: Replicationmentioning

confidence: 99%

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confidence: 99%

Genome-wide association analysis of venous thromboembolism identifies new risk loci and genetic overlap with arterial vascular disease

et al. 2019

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“…This gene is associated with a number of other traits, including risk factors for COVID-19 morbidity and mortality. For example, genome-wide association studies have associated variants within ABO to activity of the angiotensin converting enzyme 7 , red blood cell count, hemoglobin concentration, hematocrit [8][9][10][11] , von Willebrand factor [12][13][14][15] , myocardial infarction 16,17 , coronary artery disease [17][18][19][20][21] , ischemic stroke 13,19,22 , type 2 diabetes [23][24][25] , and venous thromboembolism [26][27][28][29][30][31][32][33] . A 2012 meta-analysis found that, in addition to individual variants, a non-O blood type is among the most important genetic risk factors for venous thromboembolism 34 .…”

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confidence: 99%

Associations between blood type and COVID-19 infection, intubation, and death

2020

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The rapid global spread of the novel coronavirus SARS-CoV-2 has strained healthcare and testing resources, making the identification and prioritization of individuals most at-risk a critical challenge. Recent evidence suggests blood type may affect risk of severe COVID-19. Here, we use observational healthcare data on 14,112 individuals tested for SARS-CoV-2 with known blood type in the New York Presbyterian (NYP) hospital system to assess the association between ABO and Rh blood types and infection, intubation, and death. We find slightly increased infection prevalence among non-O types. Risk of intubation was decreased among A and increased among AB and B types, compared with type O, while risk of death was increased for type AB and decreased for types A and B. We estimate Rh-negative blood type to have a protective effect for all three outcomes. Our results add to the growing body of evidence suggesting blood type may play a role in COVID-19.

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“…In addition to this L41Q polymorphism, two recent genome-wide association studies (GWAS) identified SNPs in GRK5 linked to platelet counts, mean platelet volume (MPV), and platelet volume distribution width (PDW) [93,99]. A recent genomic and transcriptomic association study showed that SNPs in GRK5 also associate with risk of venous thromboembolism (VTE) [100]. It would be interesting to examine whether these SNPs in GRKs mentioned above affect platelet activation and thrombus formation.…”

Section: Grks Polymorphisms and Their Role In Cardiovascular Diseasementioning

confidence: 99%

The Roles of GRKs in Hemostasis and Thrombosis

Chen

Zhao

Cooper

et al. 2020

IJMS

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Along with cancer, cardiovascular and cerebrovascular diseases remain by far the most common causes of death. Heart attacks and strokes are diseases in which platelets play a role, through activation on ruptured plaques and subsequent thrombus formation. Most platelet agonists activate platelets via G protein-coupled receptors (GPCRs), which make these receptors ideal targets for many antiplatelet drugs. However, little is known about the mechanisms that provide feedback regulation on GPCRs to limit platelet activation. Emerging evidence from our group and others strongly suggests that GPCR kinases (GRKs) are critical negative regulators during platelet activation and thrombus formation. In this review, we will summarize recent findings on the role of GRKs in platelet biology and how one specific GRK, GRK6, regulates the hemostatic response to vascular injury. Furthermore, we will discuss the potential role of GRKs in thrombotic disorders, such as thrombotic events in COVID-19 patients. Studies on the function of GRKs during platelet activation and thrombus formation have just recently begun, and a better understanding of the role of GRKs in hemostasis and thrombosis will provide a fruitful avenue for understanding the hemostatic response to injury. It may also lead to new therapeutic options for the treatment of thrombotic and cardiovascular disorders.

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

Abstract: In this work related to familial aggregation of familial venous thromboembolism, the investigators report genomic and transcriptomic association of 16 novel susceptibility loci for venous thromboembolism.

Cited by 175 publications

References 95 publications

Genome-wide association analysis of venous thromboembolism identifies new risk loci and genetic overlap with arterial vascular disease

Genome-wide association analysis of venous thromboembolism identifies new risk loci and genetic overlap with arterial vascular disease

Associations between blood type and COVID-19 infection, intubation, and death

The Roles of GRKs in Hemostasis and Thrombosis

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