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1. Elevated plasma complement factor H related 5 protein is associated with venous thromboembolism

Author

Maria Jesus Iglesias, Laura Sanchez-Rivera, Manal Ibrahim-Kosta, Clément Naudin, Gaëlle Munsch, Louisa Goumidi, Maria Farm, Philip M. Smith, Florian Thibord, Julia Barbara Kral-Pointner, Mun-Gwan Hong, Pierre Suchon, Marine Germain, Waltraud Schrottmaier, Philip Dusart, Anne Boland, David Kotol, Fredrik Edfors, Mine Koprulu, Maik Pietzner, Claudia Langenberg, Scott M. Damrauer, Andrew D. Johnson, Derek M. Klarin, Nicholas L. Smith, David M. Smadja, Margareta Holmström, Maria Magnusson, Angela Silveira, Mathias Uhlén, Thomas Renné, Angel Martinez-Perez, Joseph Emmerich, Jean-Francois Deleuze, Jovan Antovic, Jose Manuel Soria Fernandez, Alice Assinger, Jochen M. Schwenk, Joan Carles Souto Andres, Pierre-Emmanuel Morange, Lynn Marie Butler, David-Alexandre Trégouët, and Jacob Odeberg

Subjects
Science
Abstract

Abstract Venous thromboembolism (VTE) is a common, multi-causal disease with potentially serious short- and long-term complications. In clinical practice, there is a need for improved plasma biomarker-based tools for VTE diagnosis and risk prediction. Here we show, using proteomics profiling to screen plasma from patients with suspected acute VTE, and several case-control studies for VTE, how Complement Factor H Related 5 protein (CFHR5), a regulator of the alternative pathway of complement activation, is a VTE-associated plasma biomarker. In plasma, higher CFHR5 levels are associated with increased thrombin generation potential and recombinant CFHR5 enhanced platelet activation in vitro. GWAS analysis of ~52,000 participants identifies six loci associated with CFHR5 plasma levels, but Mendelian randomization do not demonstrate causality between CFHR5 and VTE. Our results indicate an important role for the regulation of the alternative pathway of complement activation in VTE and that CFHR5 represents a potential diagnostic and/or risk predictive plasma biomarker.

Published
2023
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2. Trends among platelet function, arterial calcium, and vascular function measures

Author

Jason Cunha, Melissa V. Chan, Bongani B. Nkambule, Florian Thibord, Amber Lachapelle, Robin E. Pashek, Ramachandran S. Vasan, Jian Rong, Emelia J. Benjamin, Naomi M. Hamburg, Ming-Huei Chen, Gary F. Mitchell, and Andrew D. Johnson

Subjects
aortic diameter, arterial tonometry, epidemiology, platelet, vascular calcification, Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Arterial tonometry and vascular calcification measures are useful in cardiovascular disease (CVD) risk assessment. Prior studies found associations between tonometry measures, arterial calcium, and CVD risk. Activated platelets release angiopoietin-1 and other factors, which may connect vascular structure and platelet function. We analyzed arterial tonometry, platelet function, aortic, thoracic and coronary calcium, and thoracic and abdominal aorta diameters measured in the Framingham Heart Study Gen3/NOS/OMNI-2 cohorts (n = 3,429, 53.7% women, mean age 54.4 years ±9.3). Platelet reactivity in whole blood or platelet-rich plasma was assessed using 5 assays and 7 agonists. We analyzed linear mixed effects models with platelet reactivity phenotypes as outcomes, adjusting for CVD risk factors and family structure. Higher arterial calcium trended with higher platelet reactivity, whereas larger aortic diameters trended with lower platelet reactivity. Characteristic impedance (Zc) and central pulse pressure positively trended with various platelet traits, while pulse wave velocity and Zc negatively trended with collagen, ADP, and epinephrine traits. All results did not pass a stringent multiple test correction threshold (p

Published
2023
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3. Author Correction: Elevated plasma complement factor H related 5 protein is associated with venous thromboembolism

Author

Maria Jesus Iglesias, Laura Sanchez-Rivera, Manal Ibrahim-Kosta, Clément Naudin, Gaëlle Munsch, Louisa Goumidi, Maria Farm, Philip M. Smith, Florian Thibord, Julia Barbara Kral-Pointner, Mun-Gwan Hong, Pierre Suchon, Marine Germain, Waltraud Schrottmaier, Philip Dusart, Anne Boland, David Kotol, Fredrik Edfors, Mine Koprulu, Maik Pietzner, Claudia Langenberg, Scott M. Damrauer, Andrew D. Johnson, Derek M. Klarin, Nicholas L. Smith, David M. Smadja, Margareta Holmström, Maria Magnusson, Angela Silveira, Mathias Uhlén, Thomas Renné, Angel Martinez-Perez, Joseph Emmerich, Jean-Francois Deleuze, Jovan Antovic, Jose Manuel Soria Fernandez, Alice Assinger, Jochen M. Schwenk, Joan Carles Souto Andres, Pierre-Emmanuel Morange, Lynn Marie Butler, David-Alexandre Trégouët, and Jacob Odeberg

Subjects
Science
Published
2023
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4. A year of COVID-19 GWAS results from the GRASP portal reveals potential genetic risk factors

Author

Florian Thibord, Melissa V. Chan, Ming-Huei Chen, and Andrew D. Johnson

Subjects
COVID-19, genetics, GWAS, trajectory, MUC4, Genetics, QH426-470
Abstract

Host genetic variants influence the susceptibility and severity of several infectious diseases, and the discovery of genetic associations with coronavirus disease 2019 (COVID-19) phenotypes could help to develop new therapeutic strategies to decrease its burden.Between May 2020 and June 2021, we used COVID-19 data released periodically by UK Biobank and performed 65 genome-wide association studies in up to 18 releases of COVID-19 susceptibility (n = 18,481 cases in June 2021), hospitalization (n = 3,260), severe outcomes (n = 1,244), and deaths (n = 1,104), stratified by sex and ancestry.In coherence with previous studies, we observed two independent signals at the chr3p21.31 locus (rs73062389-A, odds ratio [OR], 1.21 (P = 4.26 × 10−15) and rs71325088-C, OR, 1.62 [P = 2.25 × 10−9]) modulating susceptibility and severity, respectively, and a signal influencing susceptibility at the ABO locus (rs9411378-A; OR, 1.10; P = 3.30 × 10−12), suggesting an increased risk of infection in non-O blood groups carriers. Additional signals at the APOE (associated with severity and death) LRMDA (susceptibility in non-European) and chr2q32.3 (susceptibility in women) loci were also identified, but did not replicate in independent datasets. We then devised an approach to extract variants suggestively associated (P < 10−5), exhibiting an increase in significance over time. When applied to the susceptibility, hospitalization and severity analyses, this approach revealed the known RPL24, DPP9, and MAPT loci, respectively, among hundreds of other signals.These results, freely available on the GRASP portal, provide insights on the genetic mechanisms involved in COVID-19 phenotypes.

Published
2022
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6. DNA methylation analysis is used to identify novel genetic loci associated with circulating fibrinogen levels in blood

Author

Julie Hahn, Jan Bressler, Arce Domingo-Relloso, Ming-Huei Chen, Daniel L. McCartney, Alexander Teumer, Jenny van Dongen, Marcus E. Kleber, Dylan Aïssi, Brenton R. Swenson, Jie Yao, Wei Zhao, Jian Huang, Yujing Xia, Michael R. Brown, Ricardo Costeira, Eco J.C. de Geus, Graciela E. Delgado, Dre'Von A. Dobson, Paul Elliott, Hans J. Grabe, Xiuqing Guo, Sarah E. Harris, Jennifer E. Huffman, Sharon L.R. Kardia, Yongmei Liu, Stefan Lorkowski, Riccardo E. Marioni, Matthias Nauck, Scott M. Ratliff, Maria Sabater-Lleal, Tim D. Spector, Pierre Suchon, Kent D. Taylor, Florian Thibord, David-Alexandre Trégouët, Kerri L. Wiggins, Gonneke Willemsen, Jordana T. Bell, Dorret I. Boomsma, Shelley A. Cole, Simon R. Cox, Abbas Dehghan, Andreas Greinacher, Karin Haack, Winfried März, Pierre-Emmanuel Morange, Jerome I. Rotter, Nona Sotoodehnia, Maria Tellez-Plaza, Ana Navas-Acien, Jennifer A. Smith, Andrew D. Johnson, Myriam Fornage, Nicholas L. Smith, Alisa S. Wolberg, Alanna C. Morrison, Paul S. de Vries, Biological Psychology, Amsterdam Reproduction & Development, APH - Mental Health, APH - Personalized Medicine, AMS - Ageing & Vitality, AMS - Sports, APH - Health Behaviors & Chronic Diseases, and APH - Methodology

Subjects
DNA methylation, Hematology, genetics [Fibrinogen], methods [Genome-Wide Association Study], epigenome-wide association study, Epigenesis, Genetic, genetics [Inflammation], SDG 3 - Good Health and Well-being, Genetic Loci, inflammation, Mendelian randomization, Humans, CpG Islands, ddc:610, fibrinogen
Abstract

Background: Fibrinogen plays an essential role in blood coagulation and inflammation. Circulating fibrinogen levels may be determined based on interindividual differences in DNA methylation at cytosine-phosphate-guanine (CpG) sites and vice versa. Objectives: To perform an EWAS to examine an association between blood DNA methylation levels and circulating fibrinogen levels to better understand its biological and pathophysiological actions. Methods: We performed an epigenome-wide association study of circulating fibrinogen levels in 18 037 White, Black, American Indian, and Hispanic participants, representing 14 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. Circulating leukocyte DNA methylation was measured using the Illumina 450K array in 12 904 participants and using the EPIC array in 5133 participants. In each study, an epigenome-wide association study of fibrinogen was performed using linear mixed models adjusted for potential confounders. Study-specific results were combined using array-specific meta-analysis, followed by cross-replication of epigenome-wide significant associations. We compared models with and without CRP adjustment to examine the role of inflammation. Results: We identified 208 and 87 significant CpG sites associated with fibrinogen levels from the 450K (p < 1.03 × 10−7) and EPIC arrays (p < 5.78 × 10−8), respectively. There were 78 associations from the 450K array that replicated in the EPIC array and 26 vice versa. After accounting for overlapping sites, there were 83 replicated CpG sites located in 61 loci, of which only 4 have been previously reported for fibrinogen. The examples of genes located near these CpG sites were SOCS3 and AIM2, which are involved in inflammatory pathways. The associations of all 83 replicated CpG sites were attenuated after CRP adjustment, although many remained significant. Conclusion: We identified 83 CpG sites associated with circulating fibrinogen levels. These associations are partially driven by inflammatory pathways shared by both fibrinogen and CRP.

Published
2023

7. Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors

Author

Florian, Thibord, Derek, Klarin, Jennifer A, Brody, Ming-Huei, Chen, Michael G, Levin, Daniel I, Chasman, Ellen L, Goode, Kristian, Hveem, Maris, Teder-Laving, Angel, Martinez-Perez, Dylan, Aïssi, Delphine, Daian-Bacq, Kaoru, Ito, Pradeep, Natarajan, Pamela L, Lutsey, Girish N, Nadkarni, Paul S, de Vries, Gabriel, Cuellar-Partida, Brooke N, Wolford, Jack W, Pattee, Charles, Kooperberg, Sigrid K, Braekkan, Ruifang, Li-Gao, Noemie, Saut, Corriene, Sept, Marine, Germain, Renae L, Judy, Kerri L, Wiggins, Darae, Ko, Christopher J, O'Donnell, Kent D, Taylor, Franco, Giulianini, Mariza, De Andrade, Therese H, Nøst, Anne, Boland, Jean-Philippe, Empana, Satoshi, Koyama, Thomas, Gilliland, Ron, Do, Jennifer E, Huffman, Xin, Wang, Wei, Zhou, Jose, Manuel Soria, Juan, Carlos Souto, Nathan, Pankratz, Jeffery, Haessler, Kristian, Hindberg, Frits R, Rosendaal, Constance, Turman, Robert, Olaso, Rachel L, Kember, Traci M, Bartz, Julie A, Lynch, Susan R, Heckbert, Sebastian M, Armasu, Ben, Brumpton, David M, Smadja, Xavier, Jouven, Issei, Komuro, Katharine R, Clapham, Ruth J F, Loos, Cristen J, Willer, Maria, Sabater-Lleal, James S, Pankow, Alexander P, Reiner, Vania M, Morelli, Paul M, Ridker, Astrid van Hylckama, Vlieg, Jean-François, Deleuze, Peter, Kraft, Daniel J, Rader, Kyung, Min Lee, Bruce M, Psaty, Anne, Heidi Skogholt, Joseph, Emmerich, Pierre, Suchon, Stephen S, Rich, Ha My T, Vy, Weihong, Tang, Rebecca D, Jackson, John-Bjarne, Hansen, Pierre-Emmanuel, Morange, Christopher, Kabrhel, David-Alexandre, Trégouët, Scott M, Damrauer, Andrew D, Johnson, Nicholas L, Smith, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
genome-wide association study, venous thromboembolism, Quantitative Trait Loci, Thrombosis, Genomics, Venous Thromboembolism, Polymorphism, Single Nucleotide, meta-analysis, Meta-analysis, Physiology (medical), Venous thrombosis, Genetics, Humans, genetics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Genetic Predisposition to Disease, venous thrombosis, Cardiology and Cardiovascular Medicine, Genome-Wide Association Study
Abstract

Background: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources. Methods: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations. Results: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis. Conclusions: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

Published
2022

8. Abstract MP63: Higher Alternative Healthy Eating Index Scores Including Greater EPA and DHA Consumption Are Associated With Attenuated Platelet Function in the Framingham Heart Study

Author

Robin Pashek, Bongani Nkambule, Melissa Chan, Florian Thibord, Amber Lachapelle, Jason Cuhna, Ming-Huei Chen, Paul Jacques, Jiantao Ma, and Andrew Johnson

Subjects
Physiology (medical), Cardiology and Cardiovascular Medicine
Abstract

Introduction: Dietary modification that reflects healthy eating is a notable strategy for CVD prevention on a population level. The cardioprotective role diet plays in hemostasis and thrombosis, particularly in respect to platelet function remains unclear. Hypothesis: Healthier Alternative Healthy Eating Index (AHEI) scores associate with attenuated platelet reactivity in a large-scale population cohort. Methods: Cross-sectional data was obtained from Framingham Heart Study participants (N=3,429). AHEI scores were derived from self-reported Harvard semi-quantitative food frequency questionnaires. Ranging from 0 to 110, higher AHEI scores reflect healthier overall diet quality. Five bioassays measured platelet reactivity traits across several agonists in whole blood and platelet-rich plasma samples. Linear mixed effects models adjusted for age, sex, aspirin use, family relatedness, daily energy intake, and BMI evaluated associations between platelet reactivity and AHEI scores and components. Results: Higher AHEI scores associated with attenuated platelet reactivity among 16 different traits (P Conclusions: We report that higher AHEI scores associate with decreased platelet reactivity. Effects appear strongest for EPA & DHA intake consistent with several small randomized controlled trials. However, we found that a holistic AHEI score reflects a better interpretation of diet as a modulator of platelet function compared to individual components. Our results conclude that the impact of a healthier diet in preventing thrombosis may be partially mediated through a decline in platelet reactivity through multiple independent activation pathways.

Published
2023

9. Whole genome sequence analysis of platelet traits in the NHLBI Trans-Omics for Precision Medicine (TOPMed) initiative

Author

Nauder Faraday, Brian D. Hobbs, Quan Sun, Michael Preuss, Ani Manichaikul, Eric Jorgenson, Ming-Huei Chen, Eric Boerwinkle, Florian Thibord, Arunoday Bhan, Alanna C. Morrison, Ramachandran S. Vasan, Nathan Pankratz, Charles Kooperberg, Deborah A. Nickerson, Joshua P. Lewis, Hélène Choquet, Jee-Young Moon, Jeffrey R. O'Connell, Marsha M. Wheeler, Albert V. Smith, Russell P. Tracy, Nathalie Chami, Ruth J. F. Loos, Alexander P. Reiner, Nicholas L. Smith, Gonçalo R. Abecasis, Laura M. Raffield, Amarise Little, Nancy L. Heard-Costa, Andrew D. Johnson, David C. Glahn, Rasika A. Mathias, Adam S. Butterworth, John Blangero, Joanne E. Curran, Timothy A. Thornton, Laura Almasy, Jerome I. Rotter, Nancy Min, Lisa R. Yanek, Donald M. Lloyd-Jones, Zhe Wang, Matthew P. Conomos, Myriam Fornage, Hua Tang, Lewis C. Becker, Lynette Ekunwe, Cecelia A. Laurie, Adolfo Correa, Jai G. Broome, Terri H. Beaty, Jennifer A. Brody, Caitlin P. McHugh, Yao Hu, Braxton D. Mitchell, Lifang Hou, Yun Li, Kathleen A. Ryan, Paul L. Auer, Stephen S. Rich, Kari E. North, Thomas W. Blackwell, Bruce M. Psaty, Deepti Jain, Paul S Vries, Praveen Surendran, Butterworth, Adam [0000-0002-6915-9015], and Apollo - University of Cambridge Repository

Subjects
Blood Platelets, Platelet disorder, Population, Genome-wide association study, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, Medical and Health Sciences, Genome, 03 medical and health sciences, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, 0302 clinical medicine, Clinical Research, and Blood Institute (U.S.), Genetics, Humans, 2.1 Biological and endogenous factors, Polymorphism, Precision Medicine, Aetiology, Mean platelet volume, education, Hemostatic function, Lung, Molecular Biology, Genetics (clinical), 030304 developmental biology, Blood Platelet Disorders, Genetics & Heredity, 0303 health sciences, education.field_of_study, Human Genome, Single Nucleotide, National Heart, Hematology, General Medicine, Biological Sciences, United States, 3. Good health, Phenotype, Good Health and Well Being, 030220 oncology & carcinogenesis, General Article, National Heart, Lung, and Blood Institute (U.S.), Genome-Wide Association Study, Biotechnology
Abstract

Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing (WGS) from NHLBI’s Trans-Omics for Precision Medicine initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet-related disorder genes influencing variation in platelet traits in TOPMed cohorts (not enriched for blood disorders). For example, association of GP9 with lower PLT and higher MPV was partly driven by a pathogenic Bernard-Soulier syndrome variant (rs5030764, p.Asn61Ser), and the signals at TUBB1 and CD36 were partly driven by loss of function variants not annotated as pathogenic in ClinVar (rs199948010 and rs571975065). However, residual signal remained for these gene-based signals after adjusting for lead variants, suggesting that additional variants in Mendelian genes with impacts in general population cohorts remain to be identified. Gene-based signals were also identified at several genome-wide association study identified loci for genes not annotated for Mendelian platelet disorders (PTPRH, TET2, CHEK2), with somatic variation driving the result at TET2. These results highlight the value of WGS in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits.

Published
2021

10. Multi-phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations

Author

Gerard Temprano‐Sagrera, Colleen M. Sitlani, William P. Bone, Miguel Martin‐Bornez, Benjamin F. Voight, Alanna C. Morrison, Scott M. Damrauer, Paul S. de Vries, Nicholas L. Smith, Maria Sabater‐Lleal, Abbas Dehghan, Adam S Heath, Alanna C Morrison, Alex P Reiner, Andrew Johnson, Anne Richmond, Annette Peters, Astrid van Hylckama Vlieg, Barbara McKnight, Bruce M Psaty, Caroline Hayward, Cavin Ward‐Caviness, Christopher O’Donnell, Daniel Chasman, David P Strachan, David A Tregouet, Dennis Mook‐Kanamori, Dipender Gill, Florian Thibord, Folkert W Asselbergs, Frank W.G. Leebeek, Frits R Rosendaal, Gail Davies, Georg Homuth, Gerard Temprano, Harry Campbell, Herman A Taylor, Jan Bressler, Jennifer E Huffman, Jerome I Rotter, Jie Yao, James F Wilson, Joshua C Bis, Julie M Hahn, Karl C Desch, Kerri L Wiggins, Laura M Raffield, Lawrence F Bielak, Lisa R Yanek, Marcus E Kleber, Martina Mueller, Maryam Kavousi, Massimo Mangino, Melissa Liu, Michael R Brown, Matthew P Conomos, Min‐A Jhun, Ming‐Huei Chen, Moniek P.M. de Maat, Nathan Pankratz, Nicholas L Smith, Patricia A Peyser, Paul Elliot, Paul S de Vries, Peng Wei, Philipp S Wild, Pierre E Morange, Pim van der Harst, Qiong Yang, Ngoc‐Quynh Le, Riccardo Marioni, Ruifang Li, Scott M Damrauer, Simon R Cox, Stella Trompet, Stephan B Felix, Uwe Völker, Weihong Tang, Wolfgang Koenig, J. Wouter Jukema, Xiuqing Guo, Sara Lindstrom, Lu Wang, Erin N Smith, William Gordon, Mariza de Andrade, Jennifer A Brody, Jack W Pattee, Jeffrey Haessler, Ben M Brumpton, Daniel I Chasman, Pierre Suchon, Constance Turman, Marine Germain, James MacDonald, Sigrid K Braekkan, Sebastian M Armasu, Rabecca D Jackson, Jonas B Nielsen, Franco Giulianini, Marja K Puurunen, Manal Ibrahim, Susan R Heckbert, Theo K Bammler, Kelly A Frazer, Bryan M McCauley, Kent Taylor, James S Pankow, Alexander P Reiner, Maiken E Gabrielsen, Jean‐François Deleuze, Chris J O’Donnell, Jihye Kim, Peter Kraft, John‐Bjarne Hansen, John A Heit, Charles Kooperberg, Kristian Hveem, Paul M Ridker, Pierre‐Emmanuel Morange, Andrew D Johnson, Christopher Kabrhel, David‐Alexandre Trégouët, Rainer Malik, Ganesh Chauhan, Matthew Traylor, Muralidharan Sargurupremraj, Yukinori Okada, Aniket Mishra, Loes Rutten‐Jacobs, Anne‐Katrin Giese, Sander W van der Laan, Solveig Gretarsdottir, Christopher D Anderson, Michael Chong, Hieab HH Adams, Tetsuro Ago, Peter Almgren, Philippe Amouyel, Hakan Ay, Traci M Bartz, Oscar R Benavente, Steve Bevan, Giorgio B Boncoraglio, Robert D Brown, Adam S Butterworth, Caty Carrera, Cara L Carty, Wei‐Min Chen, John W Cole, Adolfo Correa, Ioana Cotlarciuc, Carlos Cruchaga, John Danesh, Paul IW de Bakker, Anita L DeStefano, Marcel den Hoed, Qing Duan, Stefan T Engelter, Guido J Falcone, Rebecca F Gottesman, Raji P Grewal, Vilmundur Gudnason, Stefan Gustafsson, Tamara B Harris, Ahamad Hassan, Aki S Havulinna, Elizabeth G Holliday, George Howard, Fang‐Chi Hsu, Hyacinth I Hyacinth, M Arfan Ikram, Erik Ingelsson, Marguerite R Irvin, Xueqiu Jian, Jordi Jiménez‐Conde, Julie A Johnson, J Wouter Jukema, Masahiro Kanai, Keith L Keene, Brett M Kissela, Dawn O Kleindorfer, Michiaki Kubo, Leslie A Lange, Carl D Langefeld, Claudia Langenberg, Lenore J Launer, Jin‐Moo Lee, Robin Lemmens, Didier Leys, Cathryn M Lewis, Wei‐Yu Lin, Arne G Lindgren, Erik Lorentzen, Patrik K Magnusson, Jane Maguire, Ani Manichaikul, Patrick F McArdle, James F Meschia, Braxton D Mitchell, Thomas H Mosley, Michael A Nalls, Toshiharu Ninomiya, Martin J O’Donnell, Sara L Pulit, Kristiina Rannikmäe, Kathryn M Rexrode, Kenneth Rice, Stephen S Rich, Natalia S Rost, Peter M Rothwell, Tatjana Rundek, Ralph L Sacco, Saori Sakaue, Michele M Sale, Veikko Salomaa, Bishwa R Sapkota, Reinhold Schmidt, Carsten O Schmidt, Ulf Schminke, Pankaj Sharma, Agnieszka Slowik, Cathie LM Sudlow, Christian Tanislav, Turgut Tatlisumak, Kent D Taylor, Vincent NS Thijs, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Steffen Tiedt, Christophe Tzourio, Cornelia M van Duijn, Matthew Walters, Nicholas J Wareham, Sylvia Wassertheil‐Smoller, James G Wilson, Salim Yusuf, Najaf Amin, Hugo S Aparicio, Donna K Arnett, John Attia, Alexa S Beiser, Claudine Berr, Julie E Buring, Mariana Bustamante, Valeria Caso, Yu‐Ching Cheng, Seung Hoan Choi, Ayesha Chowhan, Natalia Cullell, Jean‐François Dartigues, Hossein Delavaran, Pilar Delgado, Marcus Dörr, Gunnar Engström, Ian Ford, Wander S Gurpreet, Anders Hamsten, Laura Heitsch, Atsushi Hozawa, Laura Ibanez, Andreea Ilinca, Martin Ingelsson, Motoki Iwasaki, Rebecca D Jackson, Katarina Jood, Pekka Jousilahti, Sara Kaffashian, Lalit Kalra, Masahiro Kamouchi, Takanari Kitazono, Olafur Kjartansson, Manja Kloss, Peter J Koudstaal, Jerzy Krupinski, Daniel L Labovitz, Cathy C Laurie, Christopher R Levi, Linxin Li, Lars Lind, Cecilia M Lindgren, Vasileios Lioutas, Yong Mei Liu, Oscar L Lopez, Hirata Makoto, Nicolas Martinez‐Majander, Koichi Matsuda, Naoko Minegishi, Joan Montaner, Andrew P Morris, Elena Muiño, Martina Müller‐Nurasyid, Bo Norrving, Soichi Ogishima, Eugenio A Parati, Leema Reddy Peddareddygari, Nancy L Pedersen, Joanna Pera, Markus Perola, Alessandro Pezzini, Silvana Pileggi, Raquel Rabionet, Iolanda Riba‐Llena, Marta Ribasés, Jose R Romero, Jaume Roquer, Anthony G Rudd, Antti‐Pekka Sarin, Ralhan Sarju, Chloe Sarnowski, Makoto Sasaki, Claudia L Satizabal, Mamoru Satoh, Naveed Sattar, Norie Sawada, Gerli Sibolt, Ásgeir Sigurdsson, Albert Smith, Kenji Sobue, Carolina Soriano‐Tárraga, Tara Stanne, O Colin Stine, David J Stott, Konstantin Strauch, Takako Takai, Hideo Tanaka, Kozo Tanno, Alexander Teumer, Liisa Tomppo, Nuria P Torres‐Aguila, Emmanuel Touze, Shoichiro Tsugane, Andre G Uitterlinden, Einar M Valdimarsson, Sven J van der Lee, Henry Völzke, Kenji Wakai, David Weir, Stephen R Williams, Charles DA Wolfe, Quenna Wong, Huichun Xu, Taiki Yamaji, Dharambir K Sanghera, Olle Melander, Christina Jern, Daniel Strbian, Israel Fernandez‐Cadenas, W T Longstreth, Arndt Rolfs, Jun Hata, Daniel Woo, Jonathan Rosand, Guillaume Pare, Jemma C Hopewell, Danish Saleheen, Kari Stefansson, Bradford B Worrall, Steven J Kittner, Sudha Seshadri, Myriam Fornage, Hugh S Markus, Joanna MM Howson, Yoichiro Kamatani, Stephanie Debette, Martin Dichgans, and VU University medical center

Subjects
Hemostasis, genome-wide association study, genetic pleiotropy, Hematology, Polymorphism, Single Nucleotide, Hemostatics, blood coagulation, cardiovascular diseases, Phenotype, Cardiovascular Diseases, Tissue Plasminogen Activator, hemostasis, Humans, Genetic Predisposition to Disease, Factor XI, Genome-Wide Association Study
Abstract

Background: Multi-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes. Objectives: To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events. Methods: Summary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi-trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10−9 obtained after applying Bonferroni correction for the number of multi-trait combinations performed (n = 27). Results: Across the 27 multi-trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes. Conclusions: The discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.

Published
2022

11. A year of COVID-19 GWAS results from the GRASP portal reveals potential genetic risk factors

Author

Florian Thibord, Melissa V. Chan, Ming-Huei Chen, and Andrew D. Johnson

Subjects
Molecular Medicine, Genetics (clinical)
Abstract

Host genetic variants influence the susceptibility and severity of several infectious diseases, and the discovery of genetic associations with coronavirus disease 2019 (COVID-19) phenotypes could help to develop new therapeutic strategies to decrease its burden. Between May 2020 and June 2021, we used COVID-19 data released periodically by UK Biobank and performed 65 genome-wide association studies in up to 18 releases of COVID-19 susceptibility (n = 18,481 cases in June 2021), hospitalization (n = 3,260), severe outcomes (n = 1,244), and deaths (n = 1,104), stratified by sex and ancestry. In coherence with previous studies, we observed two independent signals at the chr3p21.31 locus (rs73062389-A, odds ratio [OR], 1.21 (P = 4.26 × 10

Published
2021

12. Serotonin-Affecting Antidepressant Use in Relation to Platelet Reactivity

Author

Joseph Grech, Melissa Victoria Chan, Chinedu Ochin, Amber Lachapelle, Florian Thibord, Zoe Schneider, Bongani Brian Nkambule, Paul Charles John Armstrong, Catherine Wallace de Melendez, Katherine L. Tucker, Mahdi Garelnabi, Timothy David Warner, Ming‐Huei Chen, and Andrew Danner Johnson

Subjects
Pharmacology, Adenosine Diphosphate, Blood Platelets, Serotonin, Aspirin, Platelet Aggregation, Platelet Function Tests, Humans, Pharmacology (medical), Antidepressive Agents, Platelet Aggregation Inhibitors
Abstract

Depression is an independent risk factor of cardiovascular disease morbidity. Serotonin is a key neurotransmitter in depressive pathology, contained within platelets, and is a weak activator of platelets. Our study assessed the link between platelet reactivity traits, depression, and antidepressant (AD) use in a large population sample. Our study was conducted in the Framingham Heart Study (n = 3,140), and AD use (n = 563) and aspirin use (n = 681) were noted. Depression was measured using the Center for Epidemiological Studies-Depression (CES-D) survey. Platelet reactivity traits were measured across multiple agonists using five distinct assays. We utilized a linear mixed effects model to test associations between platelet traits and depression, adjusting for age, sex, aspirin use, and AD use. Similarly, we analyzed trait associations with any AD use, serotonin-affecting ADs, and norepinephrine-affecting ADs, respectively. There were strong associations with reduced platelet function and AD use, particularly with serotonin-affecting medications. This included lower Optimul epinephrine maximal aggregation (P = 4.87E-13), higher U46619 half maximal effective concentration (P = 9.09E-11), lower light transmission aggregometry (LTA) adenosine diphosphate (ADP) final aggregation (P = 1.03E-05), and higher LTA ADP disaggregation (P = 2.28E-05). We found similar associations with serotonin-affecting ADs in an aspirin-taking subset of our sample. There were no significant associations between platelet traits and depression. In the largest study yet of AD use and platelet function we show that antidepressants, particularly serotonin-affecting ADs, inhibit platelets. We did not find evidence that depressive symptomatology in the absence of medication is associated with altered platelet function. Our results are consistent with AD use leading to platelet serotonin depletions, decreased stability of platelet aggregates, and overall decreased aggregation to multiple agonists, which may be a mechanism by which ADs increase risk of bleeding and decrease risk of thrombosis.

Published
2021

13. A year of Covid-19 GWAS results from the GRASP portal reveals potential SARS-CoV-2 modifiers

Author

Melissa V. Chan, Andrew D. Johnson, Ming-Huei Chen, and Florian Thibord

Subjects
Genetics, Apolipoprotein E, Coronavirus disease 2019 (COVID-19), ABO blood group system, Locus (genetics), Genome-wide association study, Biology, Biobank, Phenotype, Genetic association
Abstract

Host genetic variants influence the susceptibility and severity of several infectious diseases, and the discovery of novel genetic associations with Covid-19 phenotypes could help developing new therapeutic strategies to reduce its burden.Between May 2020 and June 2021, we used Covid-19 data released periodically by UK Biobank and performed 65 Genome-Wide Association Studies (GWAS) in up to 18 releases of Covid-19 susceptibility (N=18,481 cases in June 2021), hospitalization (N=3,260), severe outcomes (N=1,244) and death (N=1,104), stratified by sex and ancestry.In coherence with previous studies, we observed 2 independent signals at the chr3p21.31 locus (rs73062389-A, OR=1.21, P=4.26×10−15 and rs71325088-C, OR=1.62, P=2.25×10−9) modulating susceptibility and severity, respectively, and a signal influencing susceptibility at the ABO locus (rs9411378-A, OR=1.10, P=3.30×10−12), suggesting an increased risk of infection in non-O blood groups carriers. Additional signals at the APOE (associated with severity and death) LRMDA (susceptibility in non-European) and chr2q32.3 (susceptibility in women) loci were also identified but did not replicate in independent datasets. We then devised an original approach to extract variants exhibiting an increase in significance over time. When applied to the susceptibility, hospitalization and severity analyses, this approach revealed the known DPP9, RPL24 and MAPT loci, amongst thousands of other signals. Finally, this significance trajectory analysis was applied to the larger Covid-19hgi meta-analyses, where additional loci of interest, related to the immune system, were identified.These results, freely available on the GRASP portal, provide new insights on the genetic mechanisms involved in Covid-19 phenotypes.

Published
2021

14. FGL1 as a modulator of plasma D-dimer levels: exome-wide marker analysis of plasma tPA, PAI-1 and D-dimer

Author

Ci Song, Christopher J. O'Donnell, Weihong Tang, Karl C. Desch, Xiuqing Guo, Aaron R. Folsom, Rasika A. Mathias, David-Alexandre Trégouët, Eleanor M. Simonsick, Jerome I. Rotter, Ming-Huei Chen, Germán D. Carrasquilla, Winfried März, Nicholas L. Smith, Pierre-Emmanuel Morange, Russel Tracy, Maria Sabater-Lleal, Diane M. Becker, Jie Yao, Lisa R. Yanek, Oluf Pedersen, Tuomas O. Kilpeläinen, Hampton L. Leonard, Jennifer A. Brody, Gerard Temprano-Sagrera, Allan Linneberg, Florian Thibord, Torben Hansen, Marcus E. Kleber, Mary Cushman, Jack Pattee, Lewis C. Becker, Hugh Watkins, Niels Grarup, Marta Guindo-Martínez, Nathan Pankratz, Anders Hamsten, Ayse Bilge Ozel, Angela Silveira, Mike A. Nalls, Benjamin Rodriguez, Kent D. Taylor, Laura M. Raffield, Andrew D. Johnson, Paul S. de Vries, Barbara McKnight, Graciela E. Delgado, Alanna C. Morrison, Beata Gyorgy, Bruce M. Psaty, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
medicine.medical_treatment, Clinical Sciences, Locus (genetics), Cardiorespiratory Medicine and Haematology, 030204 cardiovascular system & hematology, Biology, Fibrinogen, Tissue plasminogen activator, Article, Fibrin Fibrinogen Degradation Products, Computational biology, 03 medical and health sciences, computational biology, 0302 clinical medicine, Clinical Research, Plasminogen Activator Inhibitor 1, Fibrinolysis, Genetics, medicine, Humans, Exome, Allele frequency, Gene, Genetic association study, Prevention, Human Genome, Hematology, FGL1, Cardiovascular System & Hematology, Tissue Plasminogen Activator, genetic association study, fibrinolysis, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, fibrinogen, exome, medicine.drug
Abstract

BackgroundUse of targeted exome-arrays with common, rare variants and functionally enriched variation has led to discovery of new genes contributing to population variation in risk factors. Plasminogen activator-inhibitor 1 (PAI-1), tissue plasminogen activator (tPA), and the plasma product D-dimer are important components of the fibrinolytic system. There have been few large-scale genome-wide or exome-wide studies of PAI-1, tPA, and D-dimer.ObjectivesWe sought to discover new genetic loci contributing to variation in these traits using an exome-array approach.MethodsCohort-level analyses and fixed effects meta-analyses of PAI-1 (n=15603), tPA (n=6876,) and D-dimer (n=19306) from 12 cohorts of European ancestry with diverse study design were conducted, including single-variant analyses and gene-based burden testing.ResultsFive variants located in NME7, FGL1, and the fibrinogen locus, all associated with D-dimer levels, achieved genome-wide significance (P&nbsp

Published
2021

15. find-tfbs: a tool to identify functional non-coding variants associated with complex human traits using open chromatin maps and phased whole-genome sequences

Author

Myriam Fornage, James S. Floyd, Jill M. Johnsen, Leslie A. Lange, Paul L. Auer, Jee-Young Moon, John Blangero, Caitlin P. McHugh, Sebastian Meric de Bellefon, Rasika A. Mathias, Guillaume Lettre, Joshua P. Lewis, Florian Thibord, Alexander P. Reiner, Zeynep H. Coban-Akdemir, and Adrienne M. Stilp

Subjects
DNA binding site, Regulatory sequence, Gene expression, Computational biology, Biology, Precision medicine, Genome, Phenotype, DNA sequencing, Chromatin
Abstract

MotivationWhole-genome DNA sequencing (WGS) enables the discovery of non-coding variants, but tools are lacking to prioritize the subset that functionally impacts human phenotypes. DNA sequence variants that disrupt or create transcription factor binding sites (TFBS) can modulate gene expression. find-tfbs efficiently scans phased WGS in large cohorts to identify and count TFBSs in regulatory sequences. This information can then be used in association testing to find putatively functional non-coding variants associated with complex human diseases or traits.ResultsWe applied find-tfbs to discover functional non-coding variants associated with hematological traits in the NHLBI Trans-Omics for Precision Medicine (TOPMed) WGS dataset (Nmax=44,709). We identified >2000 associations at P−9, implicating specific blood cell-types, transcription factors and causal genes. The vast majority of these associations are captured by variants identified in large genome-wide association studies (GWAS) for blood-cell traits. find-tfbs is computationally efficient and robust, allowing for the rapid identification of non-coding variants associated with multiple human phenotypes in very large sample size.Availabilityhttps://github.com/Helkafen/find-tfbs and https://github.com/Helkafen/find-tfbs-demoContactssebastian.meric.de.bellefon@umontreal.ca and guillaume.lettre@umontreal.caSupplementary informationSupplementary data are available.

Published
2020

16. OPTIMIR, a novel algorithm for integrating available genome-wide genotype data into miRNA sequence alignment analysis

Author

Florian Thibord, Pierre Suchon, Pierre-Emmanuel Morange, David-Alexandre Trégouët, Maguelonne Roux, Claire Perret, Marine Germain, Jean-François Deleuze, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU), Laboratoire d'hématologie biologique [Hôpital de la Timone - Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Centre recherche en CardioVasculaire et Nutrition (C2VN), and Gestionnaire, Hal Sorbonne Université

Subjects
Heterozygote, Genotype, Bioinformatics, Computer science, [SDV]Life Sciences [q-bio], Sequence alignment, Genome, 03 medical and health sciences, 0302 clinical medicine, isomiRs, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Databases, Genetic, Genetic variation, microRNA, Humans, Genotyping, Oligonucleotide Array Sequence Analysis, 030304 developmental biology, computer.programming_language, Venous Thrombosis, 0303 health sciences, Base Sequence, Genome, Human, Computational Biology, alignment, Python (programming language), [SDV] Life Sciences [q-bio], MicroRNAs, Allelic Imbalance, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], next-generation sequencing, genetic variations, Sequence Alignment, computer, Algorithm, Algorithms, Software, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Next-generation sequencing is an increasingly popular and efficient approach to characterize the full set of microRNAs (miRNAs) present in human biosamples. MiRNAs’ detection and quantification still remain a challenge as they can undergo different post transcriptional modifications and might harbor genetic variations (polymiRs) that may impact on the alignment step. We present a novel algorithm, OPTIMIR, that incorporates biological knowledge on miRNA editing and genome-wide genotype data available in the processed samples to improve alignment accuracy.OPTIMIR was applied to 391 human plasma samples that had been typed with genome-wide genotyping arrays. OPTIMIR was able to detect genotyping errors, suggested the existence of novel miRNAs and highlighted the allelic imbalance expression of polymiRs in heterozygous carriers.OPTIMIR is written in python, and freely available on the GENMED website (http://www.genmed.fr/index.php/fr/) and on Github (github.com/FlorianThibord/OptimiR).

Published
2019

17. Bayesian Network Analysis of plasma microRNA sequencing data in patients with venous thrombosis

Author

Manal Ibrahim-Kosta, Jean-François Deleuze, Maguelonne Roux, Florian Thibord, Pierre-Emmanuel Morange, Pierre Suchon, Louisa Goumidi, David-Alexandre Trégouët, Claire Perret, Gaëlle Munsch, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Santé publique : épidémiologie & sciences de l'information biomédicale (ED 393), Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire d'hématologie biologique [Hôpital de la Timone - Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Fondation Jean Dausset CEPH, F.T, G.M and M.G were financially supported by the GENMED Laboratory of Excellence on Medical Genomics (ANR-10-LABX-0013). DA.T was financially supported by the «EPIDEMIOM-VTE» Senior Chair from the Initiative of Excellence of the University of Bordeaux. MiRNA sequencing in the MARTHA study was performed on the iGenSeq platform (ICM Institute, Paris) and supported by a grant from the European Society of Cardiology for Medical Research Innovation. Bioinformatics and statistical analyses benefit from the CBiB computing centre of the University of Bordeaux., GENMED consortium, Tregouet, David, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Centre recherche en CardioVasculaire et Nutrition (C2VN), Centre National de Recherche en Génomique Humaine [Evry] (CNRGH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital de la Timone [CHU - APHM] (TIMONE), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre National de Recherche en Génomique Humaine (CNRGH), Centre d'Etude du Polymorphisme Humain (CEPH), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset-Université Paris Cité (UPCité), Admin, Oskar, Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset-Université de Paris (UP)

Subjects
Single-nucleotide polymorphism, Genome-wide association study, [SDV.GEN] Life Sciences [q-bio]/Genetics, 030204 cardiovascular system & hematology, Bioinformatics, Genome Wide Association Study, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, plasma miRNA, Next generation sequencing, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], microRNA, Venous thrombosis, medicine, Trombosis venosa, In patient, 030304 developmental biology, Genetic association, 0303 health sciences, Secuenciación de última generación, [SDV.GEN]Life Sciences [q-bio]/Genetics, Genoma completo, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], MicroRNA sequencing, business.industry, Articles, medicine.disease, Thrombosis, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Biomarcadores, VINTAGE, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Estudio de asociación, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Cardiology and Cardiovascular Medicine, business, Biomarkers
Abstract

MicroRNAs (miRNAs) are small regulatory RNAs participating to several biological processes and known to be involved in various pathologies. Measurable in body fluids, miRNAs have been proposed to serve as efficient biomarkers for diseases and/or associated traits. Here, we performed a next-generation-sequencing based profiling of plasma miRNAs in 344 patients with venous thrombosis (VT) and assessed the association of plasma miRNA levels with several haemostatic traits and the risk of VT recurrence. Among the most significant findings, we detected an association between hsa-miR-199b-3p and haematocrit levels (P = 0.0016), these two markers having both been independently reported to associate with VT risk. We also observed suggestive evidence for association of hsa-miR-370-3p (P = 0.019), hsa-miR-27b-3p (P = 0.016) and hsa-miR-222-3p (P = 0.049) with VT recurrence, the observations at the latter two miRNAs confirming the recent findings of Wang et al. Besides, by conducting Genome-Wide Association Studies on miRNA levels and meta-analyzing our results with some publicly available, we identified 21 new associations of single nucleotide polymorphisms with plasma miRNA levels at the statistical significance threshold of P, Los micro-ARN (miARN) son pequeñas moléculas de ARN reguladoras que participan en varios procesos biológicos y están implicados en diversas patologías. Mensurables en los líquidos corporales, se ha planteado que los miARN pueden ser biomarcadores eficaces para el diagnóstico de enfermedades y/o características asociadas. Aquí hemos llevado a cabo un análisis de miARN plasmático con tecnología de secuenciación de última generación en 344 pacientes con trombosis venosa (TV) y hemos evaluado la asociación de los niveles de miARN con distintas características hemostáticas y el riesgo de recidiva de TV. Entre los hallazgos más significativos, hemos detectado una asociación entre hsa-miR-199b-3p y los niveles de hematocritos (p = 0,0016); dos marcadores que se habían asociado de forma independiente con el riesgo de sufrir TV. Asimismo, hemos observado una evidencia indicativa de asociación entre hsa-miR-370-3p (p = 0,019), hsa-miR-27b-3p (p = 0,016) y hsa-miR-222-3p (p = 0,049) y la recidiva de TV; los resultados los dos últimos miARN confirman los hallazgos recientes de Wang et al. (Clin Epigenetics, 2019). Además, al efectuar estudios de asociación del genoma completo sobre los niveles de miARN y al metaanalizar nuestros resultados con otros disponibles públicamente, hemos identificado 21 asociaciones nuevas de polimorfismos de un solo nucleótido (PSN) con niveles de miARN plasmático con un umbral de significación estadística de p

Published
2019

18. A Genome Wide Association Study on plasma FV levels identified PLXDC2 as a new modifier of the coagulation process

Author

Jean-François Deleuze, Pierre-Emmanuel Morange, Florian Thibord, Manal Ibrahim-Kosta, Per Eriksson, Lise M Hardy, Noémie Saut, Mete Civelek, Anne-Sophie Pulcrano-Nicolas, Louisa Goumidi, David-Alexandre Trégouët, Wilfried Le Goff, Sorbonne Université (SU), Université de Bordeaux (UB), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Timone [CHU - APHM] (TIMONE), Aix Marseille Université (AMU), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Virginia, Karolinska Institutet [Stockholm], University Hospital, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Fondation Jean Dausset, Assistance Publique - Hôpitaux de Marseille (APHM), ANR-10-LABX-0013, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Adult, Male, Cell type, In silico, Receptors, Cell Surface, Locus (genetics), Genome-wide association study, 030204 cardiovascular system & hematology, Polymorphism, Single Nucleotide, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, computational biology, Cell Line, Tumor, Genetic variation, Gene expression, Humans, genetics, coagulation factor, Blood Coagulation, Aged, Genetics, factor V, biology, Factor V, biomarkers, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Middle Aged, 3. Good health, Phenotype, Gene Expression Regulation, Factor X, Hepatocytes, biology.protein, Female, Prothrombin, Genome-Wide Association Study
Abstract

International audience; Background Factor V (FV) is a circulating protein primarily synthesized in the liver, and mainly present in plasma. It is a major component of the coagulation process. Objective To detect novel genetic loci participating to the regulation of FV plasma levels. Methods We conducted the first Genome Wide Association Study on FV plasma levels in a sample of 510 individuals and replicated the main findings in an independent sample of 1156 individuals. Results In addition to genetic variations at the F5 locus, we identified novel associations at the PLXDC2 locus, with the lead PLXDC2 rs927826 polymorphism explaining ~3.7% (P = 7.5 × 10−15 in the combined discovery and replication samples) of the variability of FV plasma levels. In silico transcriptomic analyses in various cell types confirmed that PLXDC2 expression is positively correlated to F5 expression. SiRNA experiments in human hepatocellular carcinoma cell line confirmed the role of PLXDC2 in modulating factor F5 gene expression, and revealed further influences on F2 and F10 expressions. Conclusion Our study identified PLXDC2 as a new molecular player of the coagulation process.

Published
2019

19. Minor allele of the factor V K858R variant protects from venous thrombosis only in non-carriers of factor V Leiden mutation

Author

Céline Derbois, Noémie Saut, Philippe Amouyel, Stéphanie Debette, Louisa Goumidi, Elisabetta Castoldi, Manal Ibrahim-Kosta, David M. Smadja, Marine Germain, P. van Doorn, Pierre Morange, Etienne Patin, Marie-Christine Alessi, Pierre Suchon, Robert Olaso, David A. Tregouet, Francis Couturaud, Jean-François Deleuze, Florian Thibord, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'hématologie biologique [Hôpital de la Timone - Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Département de Médecine Interne et Pneumologie [Brest] (DMIP - Brest), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Innovations thérapeutiques en hémostase (IThEM - U1140), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hématologie biologique [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre National de Recherche en Génomique Humaine (CNRGH), Maastricht University [Maastricht], Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Génétique Evolutive Humaine - Human Evolutionary Genetics, The authors would like to thank three research programs managed by the National Research Agency (ANR) as part of the French Investment for the Future initiative genetic investigations: the GENMED Laboratory of Excellence on Medical Genomics (ANR-10-LABX-0013), the French Clinical Research Infrastructure Network on Venous Thrombo-Embolism (F-CRIN INNOVTE) and the ICAN Institute for Cardiometabolism and Nutrition (ANR-10-IAHU-05) who partially supported performing genetic investigations in the MARTHA GWAS, MARTHA12, EDITH and FARIVE studies. TF was financially supported by a PhD grant from the GENMED Laboratory of Excellence on Medical Genomics (ANR-10-LABX-0013). vDP was supported by grant nr. 2014-1 from the Dutch Thrombosis Foundation. The present project was supported by a grant from CSL Behring., ANR-10-LABX-0013,GENMED,Medical Genomics(2010), ANR-10-INBS-0003,F-CRIN,Plateforme Nationale d'Infrastructures de Recherche Clinique(2010), ANR-10-IAHU-0005,ICAN,Institut de Cardiologie-Métabolisme-Nutrition(2010), Biochemie, RS: CARIM - R1 - Thrombosis and haemostasis, RS: CARIM - R1.01 - Blood proteins & engineering, RS: Carim - B01 Blood proteins & engineering, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre recherche en CardioVasculaire et Nutrition (C2VN), Université de Brest (UBO), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), ANR: PREFI-10-LABX-13/10-LABX-0013,GENMED,Medical Genomics(2010), ANR-10-INBS-03-01/10-INBS-0003,F-CRIN,Plateforme Nationale d'Infrastructures de Recherche Clinique(2010), ANR-10-IAHU-0005/10-IAHU-0005,ICAN,ICAN(2010), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)

Subjects
0301 basic medicine, Male, lcsh:Medicine, Genome-wide association study, polymorphisme, PATHWAY, 0302 clinical medicine, COAGULATION-FACTOR-V, lcsh:Science, Venous Thrombosis, RISK, Multidisciplinary, biology, Factor V, DEFECTS, Venous thrombosis, Female, France, medicine.drug, medicine.medical_specialty, Heterozygote, B-DOMAIN, Médecine humaine et pathologie, Article, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, medicine, Factor V Leiden, Humans, Allele, GENOME-WIDE ASSOCIATION, coagulation, facteur viii, Alleles, Genetic Association Studies, business.industry, lcsh:R, allèle, medicine.disease, GENE, Minor allele frequency, 030104 developmental biology, Endocrinology, Amino Acid Substitution, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Case-Control Studies, biology.protein, lcsh:Q, Human health and pathology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Activated protein C resistance, business, 030217 neurology & neurosurgery, Protein C, RESISTANCE, thrombose veineuse
Abstract

Factor V serves an important role in the regulation of blood coagulation. The rs6025 (R534Q) and rs4524 (K858R) polymorphisms in the F5 gene, are known to influence the risk of venous thrombosis. While the rare Q534 (factor V Leiden) allele is associated with an increased risk of venous thrombosis, the minor R858 allele is associated with a lower risk of disease. However, no study has deeply examined the cumulative impact of these two variations on venous thrombosis risk. We study the association of these polymorphisms with the risk of venous thrombosis in 4 French case-control populations comprising 3719 patients and 4086 controls. We demonstrate that the Q534 allele has a dominant effect over R858. Besides, we show that in individuals not carrying the Q534 allele, the protective effect of the R858 allele acts in a dominant mode. Thrombin generation-based normalized activated protein C sensitivity ratio was lower in the 858R/R homozygotes than in the 858K/K homozygotes (1.92 ± 1.61 vs 2.81 ± 1.57, p = 0.025). We demonstrate that the R858 allele of the F5 rs4524 variant protects from venous thrombosis only in non-carriers of the Q534 allele of the F5 rs6025. Its protective effect is mediated by reduced factor VIII levels and reduced activated protein C resistance.

Published
2019

20. Unification of miRNA and isomiR research: the mirGFF3 format and the mirtop API

Author

Ernesto Aparicio-Puerta, Isidore Rigoutsos, Roderic Espín, Marc K. Halushka, Marc R. Friedländer, Victor Barrera, Phillipe Loher, Xavier Bofill-De Ros, Bastian Fromm, Aristeidis G. Telonis, Michael Hackenberg, Thomas Desvignes, Lorena Pantano, Gianvito Urgese, Florian Thibord, Jeffery Ma, Jason Sydes, Karen Eilbeck, John H. Postlethwait, Eric Londin, Ioannis S. Vlachos, and Elisa Ficarra

Subjects
Statistics and Probability, Small RNA, miRNA, isomiR, isomiR-SEA, miRNA-seq, small RNA, mirGFF3, Computer science, Computational biology, Biochemistry, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, IsomiR, microRNA, Nucleotide, Molecular Biology, 030304 developmental biology, computer.programming_language, chemistry.chemical_classification, Regulation of gene expression, 0303 health sciences, Sequence Analysis, RNA, High-Throughput Nucleotide Sequencing, Python (programming language), File format, Original Papers, Data science, Pipeline (software), miRNA, isomiR, isomiR-SEA, miRNA-seq, small RNA, mirGFF3, Computer Science Applications, Computational Mathematics, MicroRNAs, Computational Theory and Mathematics, chemistry, Gene Expression Regulation, 030220 oncology & carcinogenesis, computer
Abstract

Motivation MicroRNAs (miRNAs) are small RNA molecules (∼22 nucleotide long) involved in post-transcriptional gene regulation. Advances in high-throughput sequencing technologies led to the discovery of isomiRs, which are miRNA sequence variants. While many miRNA-seq analysis tools exist, the diversity of output formats hinders accurate comparisons between tools and precludes data sharing and the development of common downstream analysis methods. Results To overcome this situation, we present here a community-based project, miRNA Transcriptomic Open Project (miRTOP) working towards the optimization of miRNA analyses. The aim of miRTOP is to promote the development of downstream isomiR analysis tools that are compatible with existing detection and quantification tools. Based on the existing GFF3 format, we first created a new standard format, mirGFF3, for the output of miRNA/isomiR detection and quantification results from small RNA-seq data. Additionally, we developed a command line Python tool, mirtop, to create and manage the mirGFF3 format. Currently, mirtop can convert into mirGFF3 the outputs of commonly used pipelines, such as seqbuster, isomiR-SEA, sRNAbench, Prost! as well as BAM files. Some tools have also incorporated the mirGFF3 format directly into their code, such as, miRge2.0, IsoMIRmap and OptimiR. Its open architecture enables any tool or pipeline to output or convert results into mirGFF3. Collectively, this isomiR categorization system, along with the accompanying mirGFF3 and mirtop API, provide a comprehensive solution for the standardization of miRNA and isomiR annotation, enabling data sharing, reporting, comparative analyses and benchmarking, while promoting the development of common miRNA methods focusing on downstream steps of miRNA detection, annotation and quantification. Availability and implementation https://github.com/miRTop/mirGFF3/ and https://github.com/miRTop/mirtop. Supplementary information Supplementary data are available at Bioinformatics online.

Published
2018
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21. Whole-Blood miRNA Sequencing Profiling for Vasospasm in Patients With Aneurysmal Subarachnoid Hemorrhage

Author

Florian Thibord, Louis Puybasset, Alice Jacquens, Maguelonne Roux, Carole Proust, Anne-Sophie Pulcrano-Nicolas, Frédéric Clarençon, David-Alexandre Trégouët, Eimad Shotar, Claire Perret, Sophie Garnier, Vincent Degos, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), BIOSFAST [CHU Pitié-Salpêtrière] (GRC 14), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Garnier, Sophie, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de neurosciences translationnelles de Paris (NeurATRIS - IHU-A-ICM), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Subarachnoid hemorrhage, [SDV]Life Sciences [q-bio], Risk Assessment, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, biomarkers Word count: 2345, Humans, Vasospasm, Intracranial, In patient, Prospective Studies, Prospective cohort study, miRNA, Whole blood, Advanced and Specialized Nursing, Sequence Analysis, RNA, business.industry, Mirna sequencing, High-Throughput Nucleotide Sequencing, Vasospasm, Middle Aged, Subarachnoid Hemorrhage, medicine.disease, 3. Good health, body regions, [SDV] Life Sciences [q-bio], MicroRNAs, 030104 developmental biology, cerebral vasospasm, Cardiology, Biomarker (medicine), Female, Neurology (clinical), Cardiology and Cardiovascular Medicine, business, Complication, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Biomarkers, 030217 neurology & neurosurgery
Abstract

Background and Purpose— Arterial vasospasm is a well-known delayed complication of aneurysmal subarachnoid hemorrhage (aSAH). However, no validated biomarker exists to help clinicians discriminating patients with aSAH who will develop vasospasm (VSP + ) and identifying those who then deserve aggressive preventive therapy. We hypothesized that whole-blood miRNAs could be a source of candidate biomarkers for vasospasm. Methods— Using a next-generation sequencing approach, we performed whole-blood miRNA profiling between VSP + patients with aSAH and patients who did not develop vasospasm (VSP − ) in a prospective cohort of 32 patients. Profiling was performed on the admission day and 3 days before vasospasm. Results— Four hundred forty-two miRNAs were highly expressed in whole blood of patients with aSAH. Among them, hsa-miR-3177-3p demonstrated significant ( P =5.9×10 −5 ; P Bonferroni corrected =0.03) lower levels in VSP − compared with VSP + patients. Looking for whole-blood mRNA correlates of hsa-miR-3177-3p, we observed some evidence that the decrease in hsa-miR-3177-3p levels after aSAH was associated with an increase in LDHA mRNA levels in VSP − ( P –3 ) but not in VSP + ( P =0.66) patients. Conclusions— Whole-blood miRNA levels of hsa-miR-3177-3p could serve as a biomarker for vasospasm. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT01779713.

Published
2018

22. MACARON: a python framework to identify and re-annotate multi-base affected codons in whole genome/exome sequence data

Author

Waqasuddin Khan, Tania Cuppens, Thomas Ludwig, David-Alexandre Trégouët, Emmanuelle Génin, Florian Thibord, Jean-François Deleuze, Ganapathi Varma Saripella, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre National de Recherche en Génomique Humaine (CNRGH), FREX Consortium, GENMED Consortium, ANR-10-LABX-0013,GENMED,Medical Genomics(2010), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Brestois Santé Agro Matière (IBSAM), and Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Statistics and Probability, Computer science, Computational biology, Biochemistry, Genome, 03 medical and health sciences, 0302 clinical medicine, Data sequences, Humans, Nucleotide, Exome, Codon, Molecular Biology, computer.programming_language, chemistry.chemical_classification, Genome, Human, Computational Biology, High-Throughput Nucleotide Sequencing, Molecular Sequence Annotation, Python (programming language), Computer Science Applications, Computational Mathematics, 030104 developmental biology, Computational Theory and Mathematics, chemistry, Programming Languages, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], computer, 030217 neurology & neurosurgery, Software
Abstract

Summary Predicted deleteriousness of coding variants is a frequently used criterion to filter out variants detected in next-generation sequencing projects and to select candidates impacting on the risk of human diseases. Most available dedicated tools implement a base-to-base annotation approach that could be biased in presence of several variants in the same genetic codon. We here proposed the MACARON program that, from a standard VCF file, identifies, re-annotates and predicts the amino acid change resulting from multiple single nucleotide variants (SNVs) within the same genetic codon. Applied to the whole exome dataset of 573 individuals, MACARON identifies 114 situations where multiple SNVs within a genetic codon induce an amino acid change that is different from those predicted by standard single SNV annotation tool. Such events are not uncommon and deserve to be studied in sequencing projects with inconclusive findings. Availability and implementation MACARON is written in python with codes available on the GENMED website (www.genmed.fr). Supplementary information Supplementary data are available at Bioinformatics online.

Published
2018

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