Antithrombin, protein C and protein S: Genome and transcriptome wide association studies identify 7 novel loci regulating plasma levels Article Swipe
Yuekai Ji
,
Gerard Temprano‐Sagrera
,
Lori A. Holle
,
Allison Bebo
,
Jennifer A. Brody
,
Ngoc‐Quynh Le
,
Michael R. Brown
,
Ángel Martínez-Pérez
,
Colleen M. Sitlani
,
Pierre Suchon
,
Marcus E. Kleber
,
David Emmert
,
Ayse Bilge Ozel
,
Dre’Von A. Dobson
,
Weihong Tang
,
Dolors Llobet
,
Russell P. Tracy
,
Jean‐François Deleuze
,
Graciela E. Delgado
,
Martin Gögele
,
Kerri L. Wiggins
,
Juan Carlos Souto
,
James S. Pankow
,
Kent D. Taylor
,
David‐Alexandre Trégouët
,
Angela P. Moissl
,
Christian Fuchsberger
,
Frits R. Rosendaal
,
Alanna C. Morrison
,
José Manuel Soria
,
Mary Cushman
,
Pierre‐Emmanuel Morange
,
Winfried März
,
Andrew A. Hicks
,
Karl C. Desch
,
Andrew D. Johnson
,
Paul S. de Vries
,
Alisa S. Wolberg
,
Nicholas L. Smith
,
Maria Sabater‐Lleal
·
YOU?
·
· 2022
· Open Access
·
· DOI: https://doi.org/10.1101/2022.11.01.22281689
YOU?
·
· 2022
· Open Access
·
· DOI: https://doi.org/10.1101/2022.11.01.22281689
Objective Antithrombin, protein C (PC) and protein S (PS) are circulating natural-anticoagulant proteins that regulate hemostasis and of which partial deficiencies are causes of venous thromboembolism. Previous genetic association studies involving antithrombin, PC, and PS were limited by modest sample sizes or by being restricted to candidate genes. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, we meta-analyzed across ancestries the results from 10 genome-wide association studies (GWAS) of plasma levels of antithrombin, PC, PS free and PS total. Approach and Results Study participants were of European and African ancestries and genotype data were imputed to TOPMed, a dense multi-ancestry reference panel. Each of 10 studies conducted a GWAS for each phenotype and summary results were meta-analyzed, stratified by ancestry. We also conducted transcriptome-wide association analyses and multi-phenotype analysis to discover additional associations. Novel GWAS findings were validated by in vitro functional experiments. Mendelian randomization was performed to assess the causal relationship between these proteins and cardiovascular outcomes. GWAS meta-analyses identified 4 newly associated loci: 3 with antithrombin levels ( GCKR, BAZ1B , and HP-TXNL4B ) and 1 with PS levels ( ORM1 - ORM2 ). TWAS identified 3 newly associated genes: 1 with antithrombin level ( FCGRT ), 1 with PC ( GOLM2 ), and 1 with PS ( MYL7 ). In addition, we replicated 7 independent loci reported in previous studies. Functional experiments provided evidence for the involvement of GCKR, SNX17 , and HP genes in antithrombin regulation. Conclusion The use of larger sample sizes, diverse populations, and a denser imputation reference panel allowed the detection of 7 novel genomic loci associated with plasma antithrombin, PC, and PS levels.
Related Topics
Concepts
Genome-wide association study
Genetic association
Mendelian randomization
Antithrombin
Biology
Genetics
Phenotype
Genetic epidemiology
Gene
Genotype
Computational biology
Single-nucleotide polymorphism
Genetic variants
Heparin
Biochemistry
Metadata
- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1101/2022.11.01.22281689
- https://www.medrxiv.org/content/medrxiv/early/2022/11/02/2022.11.01.22281689.full.pdf
- OA Status
- green
- Cited By
- 2
- References
- 97
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4308259187
All OpenAlex metadata
Raw OpenAlex JSON
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https://openalex.org/W4308259187Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1101/2022.11.01.22281689Digital Object Identifier
- Title
-
Antithrombin, protein C and protein S: Genome and transcriptome wide association studies identify 7 novel loci regulating plasma levelsWork title
- Type
-
preprintOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2022Year of publication
- Publication date
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2022-11-02Full publication date if available
- Authors
-
Yuekai Ji, Gerard Temprano‐Sagrera, Lori A. Holle, Allison Bebo, Jennifer A. Brody, Ngoc‐Quynh Le, Michael R. Brown, Ángel Martínez-Pérez, Colleen M. Sitlani, Pierre Suchon, Marcus E. Kleber, David Emmert, Ayse Bilge Ozel, Dre’Von A. Dobson, Weihong Tang, Dolors Llobet, Russell P. Tracy, Jean‐François Deleuze, Graciela E. Delgado, Martin Gögele, Kerri L. Wiggins, Juan Carlos Souto, James S. Pankow, Kent D. Taylor, David‐Alexandre Trégouët, Angela P. Moissl, Christian Fuchsberger, Frits R. Rosendaal, Alanna C. Morrison, José Manuel Soria, Mary Cushman, Pierre‐Emmanuel Morange, Winfried März, Andrew A. Hicks, Karl C. Desch, Andrew D. Johnson, Paul S. de Vries, Alisa S. Wolberg, Nicholas L. Smith, Maria Sabater‐LlealList of authors in order
- Landing page
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https://doi.org/10.1101/2022.11.01.22281689Publisher landing page
- PDF URL
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https://www.medrxiv.org/content/medrxiv/early/2022/11/02/2022.11.01.22281689.full.pdfDirect link to full text PDF
- Open access
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YesWhether a free full text is available
- OA status
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greenOpen access status per OpenAlex
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https://www.medrxiv.org/content/medrxiv/early/2022/11/02/2022.11.01.22281689.full.pdfDirect OA link when available
- Concepts
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Genome-wide association study, Genetic association, Mendelian randomization, Antithrombin, Biology, Genetics, Phenotype, Genetic epidemiology, Gene, Genotype, Computational biology, Single-nucleotide polymorphism, Genetic variants, Heparin, BiochemistryTop concepts (fields/topics) attached by OpenAlex
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2Total citation count in OpenAlex
- Citations by year (recent)
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2025: 1, 2024: 1Per-year citation counts (last 5 years)
- References (count)
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97Number of works referenced by this work
- Related works (count)
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10Other works algorithmically related by OpenAlex
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| abstract_inverted_index.functional | 149 |
| abstract_inverted_index.hemostasis | 16 |
| abstract_inverted_index.identified | 168, 195 |
| abstract_inverted_index.imputation | 260 |
| abstract_inverted_index.replicated | 223 |
| abstract_inverted_index.restricted | 45 |
| abstract_inverted_index.stratified | 125 |
| abstract_inverted_index.association | 29, 73, 132 |
| abstract_inverted_index.circulating | 11 |
| abstract_inverted_index.consortium, | 63 |
| abstract_inverted_index.experiments | 232 |
| abstract_inverted_index.genome-wide | 72 |
| abstract_inverted_index.independent | 225 |
| abstract_inverted_index.involvement | 237 |
| abstract_inverted_index.regulation. | 247 |
| abstract_inverted_index.Epidemiology | 62 |
| abstract_inverted_index.antithrombin | 175, 202, 246 |
| abstract_inverted_index.deficiencies | 21 |
| abstract_inverted_index.experiments. | 150 |
| abstract_inverted_index.participants | 91 |
| abstract_inverted_index.populations, | 256 |
| abstract_inverted_index.relationship | 159 |
| abstract_inverted_index.Antithrombin, | 2 |
| abstract_inverted_index.antithrombin, | 32, 80, 274 |
| abstract_inverted_index.associations. | 140 |
| abstract_inverted_index.meta-analyses | 167 |
| abstract_inverted_index.meta-analyzed | 65 |
| abstract_inverted_index.randomization | 152 |
| abstract_inverted_index.cardiovascular | 164 |
| abstract_inverted_index.meta-analyzed, | 124 |
| abstract_inverted_index.multi-ancestry | 107 |
| abstract_inverted_index.multi-phenotype | 135 |
| abstract_inverted_index.thromboembolism. | 26 |
| abstract_inverted_index.transcriptome-wide | 131 |
| abstract_inverted_index.natural-anticoagulant | 12 |
| cited_by_percentile_year.max | 95 |
| cited_by_percentile_year.min | 90 |
| corresponding_author_ids | https://openalex.org/A5061057305, https://openalex.org/A5101789217 |
| countries_distinct_count | 7 |
| institutions_distinct_count | 40 |
| corresponding_institution_ids | https://openalex.org/I150117356, https://openalex.org/I201448701, https://openalex.org/I2801795740, https://openalex.org/I2801987317, https://openalex.org/I28166907 |
| sustainable_development_goals[0].id | https://metadata.un.org/sdg/3 |
| sustainable_development_goals[0].score | 0.8299999833106995 |
| sustainable_development_goals[0].display_name | Good health and well-being |
| citation_normalized_percentile.value | 0.63014237 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | False |