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1. Genome-wide association meta-analysis of spontaneous coronary artery dissection identifies risk variants and genes related to artery integrity and tissue-mediated coagulation

Author: Adlam, David, Berrandou, Takiy-Eddine, Georges, Adrien, Nelson, Christopher P, Giannoulatou, Eleni, Henry, Joséphine, Ma, Lijiang, Blencowe, Montgomery, Turley, Tamiel N, Yang, Min-Lee, Chopade, Sandesh, Finan, Chris, Braund, Peter S, Sadeg-Sayoud, Ines, Iismaa, Siiri E, Kosel, Matthew L, Zhou, Xiang, Hamby, Stephen E, Cheng, Jenny, Liu, Lu, Tarr, Ingrid, Muller, David WM, D'Escamard, Valentina, King, Annette, Brunham, Liam R, Baranowska-Clarke, Ania A, Debette, Stéphanie, Amouyel, Philippe, Olin, Jeffrey W, Patil, Snehal, Hesselson, Stephanie E, Junday, Keerat, Kanoni, Stavroula, Aragam, Krishna G, Butterworth, Adam S, CARDIoGRAMPlusC4D, MEGASTROKE, International Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group, Tweet, Marysia S, Gulati, Rajiv, Combaret, Nicolas, DISCO Register, Kadian-Dodov, Daniella, Kalman, Jonathan M, Fatkin, Diane, Hingorani, Aroon D, Saw, Jacqueline, Webb, Tom R, Hayes, Sharonne N, Yang, Xia, Ganesh, Santhi K, Olson, Timothy M, Kovacic, Jason C, Graham, Robert M, Samani, Nilesh J, Bouatia-Naji, Nabila, Adlam, David [0000-0002-0080-9884], Berrandou, Takiy-Eddine [0000-0002-0525-3002], Georges, Adrien [0000-0003-4208-2393], Nelson, Christopher P [0000-0001-8025-2897], Finan, Chris [0000-0002-3319-1937], Braund, Peter S [0000-0001-8540-5709], Iismaa, Siiri E [0000-0003-2409-7356], Zhou, Xiang [0000-0002-4331-7599], Hamby, Stephen E [0000-0002-6215-5791], Muller, David WM [0000-0002-5281-0166], Brunham, Liam R [0000-0002-3686-3807], Debette, Stéphanie [0000-0001-8675-7968], Amouyel, Philippe [0000-0001-9088-234X], Olin, Jeffrey W [0000-0003-3374-616X], Hesselson, Stephanie E [0000-0002-4521-5086], Kanoni, Stavroula [0000-0002-1691-9615], Aragam, Krishna G [0000-0003-3223-9131], Butterworth, Adam S [0000-0002-6915-9015], Combaret, Nicolas [0000-0003-4905-0765], Fatkin, Diane [0000-0002-9010-9856], Hingorani, Aroon D [0000-0001-8365-0081], Saw, Jacqueline [0000-0002-7027-984X], Webb, Tom R [0000-0001-5998-8226], Hayes, Sharonne N [0000-0003-3129-362X], Yang, Xia [0000-0002-3971-038X], Olson, Timothy M [0000-0003-2716-9423], Kovacic, Jason C [0000-0003-4555-769X], Graham, Robert M [0000-0002-1042-2587], Bouatia-Naji, Nabila [0000-0001-5424-2134], and Apollo - University of Cambridge Repository
Subjects: Myocardial Infarction, Humans, Female, Vascular Diseases, Coronary Artery Disease, Genome-Wide Association Study
Abstract: Spontaneous coronary artery dissection (SCAD) is an understudied cause of myocardial infarction primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Here we present a genome-wide association meta-analysis (1,917 cases and 9,292 controls) identifying 16 risk loci for SCAD. Integrative functional annotations prioritized genes that are likely to be regulated in vascular smooth muscle cells and artery fibroblasts and implicated in extracellular matrix biology. One locus containing the tissue factor gene F3, which is involved in blood coagulation cascade initiation, appears to be specific for SCAD risk. Several associated variants have diametrically opposite associations with CAD, suggesting that shared biological processes contribute to both diseases, but through different mechanisms. We also infer a causal role for high blood pressure in SCAD. Our findings provide novel pathophysiological insights involving arterial integrity and tissue-mediated coagulation in SCAD and set the stage for future specific therapeutics and preventions.
Published: 2023

2. Genome-wide association meta-analysis of spontaneous coronary artery dissection identifies risk variants and genes related to artery integrity and tissue-mediated coagulation

Author: Adlam, David, Berrandou, Takiy-Eddine, Georges, Adrien, Nelson, Christopher P., Giannoulatou, Eleni, Henry, Joséphine, Ma, Lijiang, Blencowe, Montgomery, Turley, Tamiel N., Yang, Min-Lee, Chopade, Sandesh, Finan, Chris, Braund, Peter S., Sadeg-Sayoud, Ines, Iismaa, Siiri E., Kosel, Matthew L., Zhou, Xiang, Hamby, Stephen E., Cheng, Jenny, Liu, Lu, Tarr, Ingrid, Muller, David W. M., d’Escamard, Valentina, King, Annette, Brunham, Liam R., Baranowska-Clarke, Ania A., Debette, Stéphanie, Amouyel, Philippe, Olin, Jeffrey W., Patil, Snehal, Hesselson, Stephanie E., Junday, Keerat, Kanoni, Stavroula, Aragam, Krishna G., Butterworth, Adam S., Tweet, Marysia S., Gulati, Rajiv, Combaret, Nicolas, Kadian-Dodov, Daniella, Kalman, Jonathan M., Fatkin, Diane, Hingorani, Aroon D., Saw, Jacqueline, Webb, Tom R., Hayes, Sharonne N., Yang, Xia, Ganesh, Santhi K., Olson, Timothy M., Kovacic, Jason C., Graham, Robert M., Samani, Nilesh J., Bouatia-Naji, Nabila, Adlam, David [0000-0002-0080-9884], Berrandou, Takiy-Eddine [0000-0002-0525-3002], Georges, Adrien [0000-0003-4208-2393], Nelson, Christopher P. [0000-0001-8025-2897], Finan, Chris [0000-0002-3319-1937], Braund, Peter S. [0000-0001-8540-5709], Iismaa, Siiri E. [0000-0003-2409-7356], Zhou, Xiang [0000-0002-4331-7599], Hamby, Stephen E. [0000-0002-6215-5791], Muller, David W. M. [0000-0002-5281-0166], Brunham, Liam R. [0000-0002-3686-3807], Debette, Stéphanie [0000-0001-8675-7968], Amouyel, Philippe [0000-0001-9088-234X], Olin, Jeffrey W. [0000-0003-3374-616X], Hesselson, Stephanie E. [0000-0002-4521-5086], Kanoni, Stavroula [0000-0002-1691-9615], Aragam, Krishna G. [0000-0003-3223-9131], Butterworth, Adam S. [0000-0002-6915-9015], Combaret, Nicolas [0000-0003-4905-0765], Fatkin, Diane [0000-0002-9010-9856], Hingorani, Aroon D. [0000-0001-8365-0081], Saw, Jacqueline [0000-0002-7027-984X], Webb, Tom R. [0000-0001-5998-8226], Hayes, Sharonne N. [0000-0003-3129-362X], Yang, Xia [0000-0002-3971-038X], Olson, Timothy M. [0000-0003-2716-9423], Kovacic, Jason C. [0000-0003-4555-769X], Graham, Robert M. [0000-0002-1042-2587], Bouatia-Naji, Nabila [0000-0001-5424-2134], and Apollo - University of Cambridge Repository
Abstract: Spontaneous coronary artery dissection (SCAD) is an understudied cause of myocardial infarction primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Here we present a genome-wide association meta-analysis (1,917 cases and 9,292 controls) identifying 16 risk loci for SCAD. Integrative functional annotations prioritized genes that are likely to be regulated in vascular smooth muscle cells and artery fibroblasts and implicated in extracellular matrix biology. One locus containing the tissue factor gene F3, which is involved in blood coagulation cascade initiation, appears to be specific for SCAD risk. Several associated variants have diametrically opposite associations with CAD, suggesting that shared biological processes contribute to both diseases, but through different mechanisms. We also infer a causal role for high blood pressure in SCAD. Our findings provide novel pathophysiological insights involving arterial integrity and tissue-mediated coagulation in SCAD and set the stage for future specific therapeutics and preventions.
Published: 2023

3. Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease

Author: Holstege, Henne, Hulsman, Marc, Charbonnier, Camille, Grenier-Boley, Benjamin, Quenez, Olivier, Grozeva, Detelina, van Rooij, Jeroen G. J., Sims, Rebecca, Ahmad, Shahzad, Amin, Najaf, Norsworthy, Penny J., Dols Icardo, Oriol, Hummerich, Holger, Kawalia, Amit, Amouyel, Philippe, Beecham, Gary W., Berr, Claudine, Bis, Joshua C., Boland, Anne, Bossù, Paola, Bouwman, Femke, Bras, Jose, Campion, Dominique, Cochran, J. Nicholas, Daniele, Antonio, Dartigues, Jean-François, Debette, Stéphanie, Deleuze, Jean-François, Denning, Nicola, DeStefano, Anita L., Farrer, Lindsay A., Fernández, Maria Victoria, Fox, Nick C., Galimberti, Daniela, Genin, Emmanuelle, Gille, Johan J. P., Le Guen, Yann, Guerreiro, Rita, Haines, Jonathan L., Holmes, Clive, Ikram, M. Arfan, Ikram, M. Kamran, Jansen, Iris E., Kraaij, Robert, Lathrop, Marc, Lemstra, Afina W., Lleó, Alberto, Luckcuck, Lauren, Mannens, Marcel M. A. M., Marshall, Rachel, Martin, Eden R., Masullo, Carlo, Mayeux, Richard, Mecocci, Patrizia, Meggy, Alun, Mol, Merel O., Morgan, Kevin, Myers, Richard M., Nacmias, Benedetta, Naj, Adam C., Napolioni, Valerio, Pasquier, Florence, Pastor, Pau, Pericak-Vance, Margaret A., Raybould, Rachel, Redon, Richard, Reinders, Marcel J. T., Richard, Anne-Claire, Riedel-Heller, Steffi G., Rivadeneira, Fernando, Rousseau, Stéphane, Ryan, Natalie S., Saad, Salha, Sánchez-Juan, Pascual, Schellenberg, Gerard D., Scheltens, Philip, Schott, Jonathan M., Seripa, Davide, Seshadri, Sudha, Sie, Daoud, Sistermans, Erik A., Sorbi, Sandro, van Spaendonk, Resie, Spalletta, Gianfranco, Tesi, Niccolo, Tijms, Betty, Uitterlinden, André G., van der Lee, Sven J., Visser, Pieter Jelle, Wagner, Michael, Wallon, David, Wang, Li-San, Zarea, Aline, Clarimón, Jordi, van Swieten, John C., Greicius, Michael D., Yokoyama, Jennifer S., Cruchaga, Carlos, Hardy, John, Ramirez, Alfredo, Mead, Simon, van der Flier, Wiesje M., van Duijn, Cornelia M., Williams, Julie, Nicolas, Gaël, Bellenguez, Céline, Lambert, Jean-Charles, Universitat Autònoma de Barcelona, Internal Medicine, Neurology, Epidemiology, Amsterdam Neuroscience - Neurodegeneration, VU University medical center, Human genetics, General practice, Amsterdam Neuroscience - Brain Imaging, APH - Personalized Medicine, APH - Methodology, Complex Trait Genetics, Human Genetics, and ACS - Pulmonary hypertension & thrombosis
Subjects: Adenosine Triphosphatases, rare damaging variants, Membrane Transport Proteins, genetics [Alzheimer Disease], Alzheimer's disease, ATP8B4 protein, human, genetics [Adenosine Triphosphatases], genetics [Exosomes], Settore MED/26 - NEUROLOGIA, SDG 3 - Good Health and Well-being, Alzheimer Disease, Risk Factors, ddc:570, Genetics research, ABCA1 protein, human, Genetics, SORL1 protein, human, Humans, genetics [ATP Binding Cassette Transporter 1], LDL-Receptor Related Proteins, Genome-Wide Association Study, ATP Binding Cassette Transporter 1
Abstract: Alzheimer’s disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals—16,036 AD cases and 16,522 controls. Next to variants in TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD.
Published: 2022
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4. Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease

Author: Holstege, Henne, Hulsman, Marc, Charbonnier, Camille, Grenier-Boley, Benjamin, Quenez, Olivier, Grozeva, Detelina, van Rooij, Jeroen GJ, Sims, Rebecca, Ahmad, Shahzad, Amin, Najaf, Norsworthy, Penny J, Dols-Icardo, Oriol, Hummerich, Holger, Kawalia, Amit, Amouyel, Philippe, Beecham, Gary W, Berr, Claudine, Bis, Joshua C, Boland, Anne, Bossù, Paola, Bouwman, Femke, Bras, Jose, Campion, Dominique, Cochran, J Nicholas, Daniele, Antonio, Dartigues, Jean-François, Debette, Stéphanie, Deleuze, Jean-François, Denning, Nicola, DeStefano, Anita L, Farrer, Lindsay A, Fernández, Maria Victoria, Fox, Nick C, Galimberti, Daniela, Genin, Emmanuelle, Gille, Johan JP, Le Guen, Yann, Guerreiro, Rita, Haines, Jonathan L, Holmes, Clive, Ikram, M Arfan, Ikram, M Kamran, Jansen, Iris E, Kraaij, Robert, Lathrop, Marc, Lemstra, Afina W, Lleó, Alberto, Luckcuck, Lauren, Mannens, Marcel MAM, Marshall, Rachel, Martin, Eden R, Masullo, Carlo, Mayeux, Richard, Mecocci, Patrizia, Meggy, Alun, Mol, Merel O, Morgan, Kevin, Myers, Richard M, Nacmias, Benedetta, Naj, Adam C, Napolioni, Valerio, Pasquier, Florence, Pastor, Pau, Pericak-Vance, Margaret A, Raybould, Rachel, Redon, Richard, Reinders, Marcel JT, Richard, Anne-Claire, Riedel-Heller, Steffi G, Rivadeneira, Fernando, Rousseau, Stéphane, Ryan, Natalie S, Saad, Salha, Sanchez-Juan, Pascual, Schellenberg, Gerard D, Scheltens, Philip, Schott, Jonathan M, Seripa, Davide, Seshadri, Sudha, Sie, Daoud, Sistermans, Erik A, Sorbi, Sandro, van Spaendonk, Resie, Spalletta, Gianfranco, Tesi, Niccolo', Tijms, Betty, Uitterlinden, André G, van der Lee, Sven J, Visser, Pieter Jelle, Wagner, Michael, Wallon, David, Wang, Li-San, Zarea, Aline, Clarimon, Jordi, van Swieten, John C, Greicius, Michael D, Yokoyama, Jennifer S, Cruchaga, Carlos, Hardy, John, and Ramirez, Alfredo
Subjects: Aging, Neurodegenerative, Exosomes, Alzheimer's Disease, Medical and Health Sciences, Alzheimer Disease, Risk Factors, Clinical Research, Acquired Cognitive Impairment, Genetics, Humans, 2.1 Biological and endogenous factors, Aetiology, Adenosine Triphosphatases, Prevention, Human Genome, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Biological Sciences, Brain Disorders, Neurological, Dementia, Genome-Wide Association Study, ATP Binding Cassette Transporter 1, Biotechnology, Developmental Biology
Abstract: Alzheimer's disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals-16,036 AD cases and 16,522 controls. Next to variants in TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD.
Published: 2022

5. Author Correction: Genetic investigation of fibromuscular dysplasia identifies risk loci and shared genetics with common cardiovascular diseases

Author: Georges, Adrien, Yang, Min-Lee, Berrandou, Takiy-Eddine, Bakker, Mark K, Dikilitas, Ozan, Kiando, Soto Romuald, Ma, Lijiang, Satterfield, Benjamin A, Sengupta, Sebanti, Yu, Mengyao, Deleuze, Jean-François, Dupré, Delia, Hunker, Kristina L, Kyryachenko, Sergiy, Liu, Lu, Sayoud-Sadeg, Ines, Amar, Laurence, Brummett, Chad M, Coleman, Dawn M, d'Escamard, Valentina, de Leeuw, Peter, Fendrikova-Mahlay, Natalia, Kadian-Dodov, Daniella, Li, Jun Z, Lorthioir, Aurélien, Pappaccogli, Marco, Prejbisz, Aleksander, Smigielski, Witold, Stanley, James C, Zawistowski, Matthew, Zhou, Xiang, Zöllner, Sebastian, FEIRI investigators, International Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group, MEGASTROKE, Amouyel, Philippe, De Buyzere, Marc L, Debette, Stéphanie, Dobrowolski, Piotr, Drygas, Wojciech, Gornik, Heather L, Olin, Jeffrey W, Piwonski, Jerzy, Rietzschel, Ernst R, Ruigrok, Ynte M, Vikkula, Miikka, Warchol Celinska, Ewa, Januszewicz, Andrzej, Kullo, Iftikhar J, Azizi, Michel, ARCADIA Investigators, Jeunemaitre, Xavier, Persu, Alexandre, Kovacic, Jason C, Ganesh, Santhi K, Bouatia-Naji, Nabila, UCL - SSS/IREC/CARD - Pôle de recherche cardiovasculaire, and UCL - (SLuc) Département cardiovasculaire
Subjects: Multidisciplinary, General Physics and Astronomy, General Chemistry, General Biochemistry, Genetics and Molecular Biology
Abstract: No abstract available
Published: 2022
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6. Stroke Genetics: Discovery, Insight Into Mechanisms, and Clinical Perspectives

Author: Debette, Stéphanie and Markus, Hugh S.
Subjects: Stroke, Physiology, Humans, Genetic Predisposition to Disease, cardiovascular diseases, Cardiology and Cardiovascular Medicine, Genome-Wide Association Study
Abstract: Stroke is the second leading cause of death worldwide and a complex, heterogeneous condition. In this review, we provide an overview of the current knowledge on monogenic and multifactorial forms of stroke, highlighting recent insight into the continuum between these. We describe how, in recent years, large-scale genome-wide association studies have enabled major progress in deciphering the genetic basis for stroke and its subtypes, although more research is needed to interpret these findings. We cover the potential of stroke genetics to reveal novel pathophysiological processes underlying stroke, to accelerate the discovery of new therapeutic approaches, and to identify individuals in the population who are at high risk of stroke and could be targeted for tailored preventative interventions.
Published: 2022
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7. Outcome associated with prescription of cardiac rehabilitation according to predicted risk after acute myocardial infarction: Insights from the FAST-MI registries

Author: Debiec, Hanna, Dossier, Claire, Letouzé, Eric, Gillies, Christopher, Vivarelli, Marina, Putler, Rosemary, Ars, Elisabet, Jacqz-Aigrain, Evelyne, Elie, Valery, Colucci, Manuela, Debette, Stéphanie, Amouyel, Philippe, Elalaoui, Siham, Sefiani, Abdelaziz, Dubois, Valérie, Kretzler, Matthias, Ballarin, Jose, Emma, Francesco, Sampson, Matthew, Deschênes, Georges, Ronco, Pierre, Ederhy, Stephane, Cohen, Ariel, Boccara, Franck, Aissaoui, Nadia, Elbaz, Meyer, Bonnefoy-Cudraz, Eric, Druelles, Philipe, Andrieu, Stéphane, Angoulvant, Denis, Furber, Alain, Cottin, Yves, Puymirat, Etienne, Bonaca, Marc, Iliou, Marie-Christine, Tea, Victoria, Ducrocq, Grégory, Douard, Hervé, Labrunee, Marc, Plastaras, Philoktimon, Chevallereau, Pierre, Taldir, Guillaume, Bataille, Vincent, Ferrières, Jean, Schiele, François, Simon, Tabassome, Danchin, Nicolas, Centre de Ressources Biologiques APHP-SU (PASS-CRB-APHP-SU), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), and Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Time Factors, MESH: Registries, health care facilities, manpower, and services, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Cardiac rehabilitation, 030204 cardiovascular system & hematology, MESH: Risk Assessment, MESH: Aged, 80 and over, 0302 clinical medicine, Risk Factors, MESH: Risk Factors, Medicine, Registries, MESH: Cardiac Rehabilitation, 030212 general & internal medicine, Myocardial infarction, Atherothrombotic risk stratification, Non-ST Elevated Myocardial Infarction, health care economics and organizations, Cancer, MESH: Treatment Outcome, Aged, 80 and over, MESH: Aged, education.field_of_study, MESH: Middle Aged, Framingham Risk Score, Rehabilitation, nephrotic syndrome, MESH: Polymorphism, Single Nucleotide, Hazard ratio, Score, genetic renal disease, General Medicine, Middle Aged, MESH: Recovery of Function, 3. Good health, In-hospital mortality, Treatment Outcome, Stratification risque athérothrombotique, cardiovascular system, Female, France, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, pediatrics, education, Population, Infarctus du myocarde, Acute myocardial infarction, Mortalité, MESH: Phenotype, Risk Assessment, 03 medical and health sciences, Intensive care, Internal medicine, MESH: Spain, Humans, cardiovascular diseases, Mortality, Réadaptation cardiaque, MESH: ST Elevation Myocardial Infarction, Medical prescription, Aged, focal segmental glomerulosclerosis, genome-wide association study, MESH: Humans, business.industry, MESH: Time Factors, MESH: Italy, Recovery of Function, medicine.disease, MESH: Male, MESH: Quantitative Trait Loci, MESH: Steroids, Confidence interval, MESH: France, MESH: Non-ST Elevated Myocardial Infarction, gene expression, Mortalité hospitalière, ST Elevation Myocardial Infarction, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Nephrotic Syndrome, business, MESH: Female
Abstract: Cardiac rehabilitation is strongly recommended in patients after acute myocardial infarction.To assess cardiac rehabilitation prescription after acute myocardial infarction according to predicted risk, and its association with 1-year mortality, using the FAST-MI registries.We used data from three 1-month French nationwide registries, conducted 5 years apart from 2005 to 2015, including 13130 patients with acute myocardial infarction admitted to coronary or intensive care units. Atherothrombotic risk stratification was performed using the Thrombolysis In Myocardial Infarction Risk Score for Secondary Prevention (TRS-2P). Patients were classified into three categories: Group 1 (low risk; no or one risk indicator; score of 0 or 1); Group 2 (intermediate risk; two risk indicators; score of 2); and Group 3 (high risk; at least three risk indicators; score of≥3).Among the 12291 patients, cardiac rehabilitation prescription was 43.6% (49.9% in Group 1; 43.0% in Group 2; 35.2% in Group 3). Using Cox multivariable analysis, cardiac rehabilitation prescription was associated with lower mortality at 1 year in the overall population (3.8% vs. 8.2%; hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.61-0.85; P0.001). Cardiac rehabilitation was associated with improved 1-year mortality, with homogeneous relative risk reductions in low- and intermediate-risk categories (HR 0.70, 95% CI 0.51-0.94) compared with high-risk patients (HR 0.72, 95% CI 0.59-0.88). In absolute terms, however, mortality decrease associated with cardiac rehabilitation was positively correlated with risk level (Group 1, 0.9% vs. 2.4%; Group 2, 3.0% vs. 4.2%; Group 3, 10.5% vs. 17.3%).Cardiac rehabilitation prescription was inversely correlated with patient risk. A positive association between cardiac rehabilitation and 1-year survival after acute myocardial infarction was present whatever the risk level, but the greatest mortality reduction was observed in high-risk patients.
Published: 2019
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8. sj-pdf-1-wso-10.1177_17474930211007288 - Supplemental material for International stroke genetics consortium recommendations for studies of genetics of stroke outcome and recovery

Author: Lindgren, Arne G, Robynne G Braun, Majersik, Jennifer Juhl, Clatworthy, Philip, Mainali, Shraddha, Derdeyn, Colin P, Maguire, Jane, Jern, Christina, Rosand, Jonathan, Cole, John W, Jin-Moo Lee, Khatri, Pooja, Nyquist, Paul, Debette, Stéphanie, Loo Keat Wei, Rundek, Tatjana, Leifer, Dana, Thijs, Vincent, Lemmens, Robin, Heitsch, Laura, Kameshwar Prasad, Conde, Jordi Jimenez, Dichgans, Martin, Rost, Natalia S, Cramer, Steven C, Bernhardt, Julie, Worrall, Bradford B, and Fernandez-Cadenas, Israel
Subjects: FOS: Clinical medicine, Cardiology, Medicine, 110904 Neurology and Neuromuscular Diseases
Abstract: Supplemental material, sj-pdf-1-wso-10.1177_17474930211007288 for International stroke genetics consortium recommendations for studies of genetics of stroke outcome and recovery by Arne G Lindgren, Robynne G Braun, Jennifer Juhl Majersik, Philip Clatworthy, Shraddha Mainali, Colin P Derdeyn, Jane Maguire, Christina Jern, Jonathan Rosand, John W Cole, Jin-Moo Lee, Pooja Khatri, Paul Nyquist, Stéphanie Debette, Loo Keat Wei, Tatjana Rundek, Dana Leifer, Vincent Thijs, Robin Lemmens, Laura Heitsch, Kameshwar Prasad, Jordi Jimenez Conde, Martin Dichgans, Natalia S Rost, Steven C Cramer, Julie Bernhardt, Bradford B Worrall, Israel Fernandez-Cadenas and International Stroke Genetics Consortium in International Journal of Stroke
Published: 2021
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9. sj-pdf-1-wso-10.1177_17474930211007288 - Supplemental material for International stroke genetics consortium recommendations for studies of genetics of stroke outcome and recovery

Author: Lindgren, Arne G, Robynne G Braun, Majersik, Jennifer Juhl, Clatworthy, Philip, Mainali, Shraddha, Derdeyn, Colin P, Maguire, Jane, Jern, Christina, Rosand, Jonathan, Cole, John W, Jin-Moo Lee, Khatri, Pooja, Nyquist, Paul, Debette, Stéphanie, Loo Keat Wei, Rundek, Tatjana, Leifer, Dana, Thijs, Vincent, Lemmens, Robin, Heitsch, Laura, Kameshwar Prasad, Conde, Jordi Jimenez, Dichgans, Martin, Rost, Natalia S, Cramer, Steven C, Bernhardt, Julie, Worrall, Bradford B, and Fernandez-Cadenas, Israel
Subjects: FOS: Clinical medicine, Cardiology, Medicine, 110904 Neurology and Neuromuscular Diseases
Abstract: Supplemental material, sj-pdf-1-wso-10.1177_17474930211007288 for International stroke genetics consortium recommendations for studies of genetics of stroke outcome and recovery by Arne G Lindgren, Robynne G Braun, Jennifer Juhl Majersik, Philip Clatworthy, Shraddha Mainali, Colin P Derdeyn, Jane Maguire, Christina Jern, Jonathan Rosand, John W Cole, Jin-Moo Lee, Pooja Khatri, Paul Nyquist, Stéphanie Debette, Loo Keat Wei, Tatjana Rundek, Dana Leifer, Vincent Thijs, Robin Lemmens, Laura Heitsch, Kameshwar Prasad, Jordi Jimenez Conde, Martin Dichgans, Natalia S Rost, Steven C Cramer, Julie Bernhardt, Bradford B Worrall, Israel Fernandez-Cadenas and International Stroke Genetics Consortium in International Journal of Stroke
Published: 2021
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10. sj-pdf-3-wso-10.1177_17474930211007288 - Supplemental material for International stroke genetics consortium recommendations for studies of genetics of stroke outcome and recovery

Author: Lindgren, Arne G, Robynne G Braun, Majersik, Jennifer Juhl, Clatworthy, Philip, Mainali, Shraddha, Derdeyn, Colin P, Maguire, Jane, Jern, Christina, Rosand, Jonathan, Cole, John W, Jin-Moo Lee, Khatri, Pooja, Nyquist, Paul, Debette, Stéphanie, Loo Keat Wei, Rundek, Tatjana, Leifer, Dana, Thijs, Vincent, Lemmens, Robin, Heitsch, Laura, Kameshwar Prasad, Conde, Jordi Jimenez, Dichgans, Martin, Rost, Natalia S, Cramer, Steven C, Bernhardt, Julie, Worrall, Bradford B, and Fernandez-Cadenas, Israel
Subjects: FOS: Clinical medicine, Cardiology, Medicine, 110904 Neurology and Neuromuscular Diseases
Abstract: Supplemental material, sj-pdf-3-wso-10.1177_17474930211007288 for International stroke genetics consortium recommendations for studies of genetics of stroke outcome and recovery by Arne G Lindgren, Robynne G Braun, Jennifer Juhl Majersik, Philip Clatworthy, Shraddha Mainali, Colin P Derdeyn, Jane Maguire, Christina Jern, Jonathan Rosand, John W Cole, Jin-Moo Lee, Pooja Khatri, Paul Nyquist, Stéphanie Debette, Loo Keat Wei, Tatjana Rundek, Dana Leifer, Vincent Thijs, Robin Lemmens, Laura Heitsch, Kameshwar Prasad, Jordi Jimenez Conde, Martin Dichgans, Natalia S Rost, Steven C Cramer, Julie Bernhardt, Bradford B Worrall, Israel Fernandez-Cadenas and International Stroke Genetics Consortium in International Journal of Stroke
Published: 2021
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11. sj-pdf-3-wso-10.1177_17474930211007288 - Supplemental material for International stroke genetics consortium recommendations for studies of genetics of stroke outcome and recovery

Author: Lindgren, Arne G, Robynne G Braun, Majersik, Jennifer Juhl, Clatworthy, Philip, Mainali, Shraddha, Derdeyn, Colin P, Maguire, Jane, Jern, Christina, Rosand, Jonathan, Cole, John W, Jin-Moo Lee, Khatri, Pooja, Nyquist, Paul, Debette, Stéphanie, Loo Keat Wei, Rundek, Tatjana, Leifer, Dana, Thijs, Vincent, Lemmens, Robin, Heitsch, Laura, Kameshwar Prasad, Conde, Jordi Jimenez, Dichgans, Martin, Rost, Natalia S, Cramer, Steven C, Bernhardt, Julie, Worrall, Bradford B, and Fernandez-Cadenas, Israel
Subjects: FOS: Clinical medicine, Cardiology, Medicine, 110904 Neurology and Neuromuscular Diseases
Abstract: Supplemental material, sj-pdf-3-wso-10.1177_17474930211007288 for International stroke genetics consortium recommendations for studies of genetics of stroke outcome and recovery by Arne G Lindgren, Robynne G Braun, Jennifer Juhl Majersik, Philip Clatworthy, Shraddha Mainali, Colin P Derdeyn, Jane Maguire, Christina Jern, Jonathan Rosand, John W Cole, Jin-Moo Lee, Pooja Khatri, Paul Nyquist, Stéphanie Debette, Loo Keat Wei, Tatjana Rundek, Dana Leifer, Vincent Thijs, Robin Lemmens, Laura Heitsch, Kameshwar Prasad, Jordi Jimenez Conde, Martin Dichgans, Natalia S Rost, Steven C Cramer, Julie Bernhardt, Bradford B Worrall, Israel Fernandez-Cadenas and International Stroke Genetics Consortium in International Journal of Stroke
Published: 2021
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12. Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors

Author: Bakker, Mark K, van der Spek, Rick AA, van Rheenen, Wouter, Morel, Sandrine, Bourcier, Romain, Hostettler, Isabel C, Alg, Varinder S, van Eijk, Kristel R, Koido, Masaru, Akiyama, Masato, Terao, Chikashi, Matsuda, Koichi, Walters, Robin G, Lin, Kuang, Li, Liming, Millwood, Iona Y, Chen, Zhengming, Rouleau, Guy A, Zhou, Sirui, Rannikmäe, Kristiina, Sudlow, Cathie LM, Houlden, Henry, van den Berg, Leonard H, Dina, Christian, Naggara, Olivier, Gentric, Jean-Christophe, Shotar, Eimad, Eugène, François, Desal, Hubert, Winsvold, Bendik S, Børte, Sigrid, Johnsen, Marianne Bakke, Brumpton, Ben M, Sandvei, Marie Søfteland, Willer, Cristen J, Hveem, Kristian, Zwart, John-Anker, Verschuren, WM Monique, Friedrich, Christoph M, Hirsch, Sven, Schilling, Sabine, Dauvillier, Jérôme, Martin, Olivier, HUNT All-In Stroke, China Kadoorie Biobank Collaborative Group, BioBank Japan Project Consortium, ICAN Study Group, CADISP Group, Genetics and Observational Subarachnoid Haemorrhage (GOSH) Study investigators, International Stroke Genetics Consortium (ISGC), Jones, Gregory T, Bown, Matthew J, Ko, Nerissa U, Kim, Helen, Coleman, Jonathan RI, Breen, Gerome, Zaroff, Jonathan G, Klijn, Catharina JM, Malik, Rainer, Dichgans, Martin, Sargurupremraj, Muralidharan, Tatlisumak, Turgut, Amouyel, Philippe, Debette, Stéphanie, Rinkel, Gabriel JE, Worrall, Bradford B, Pera, Joanna, Slowik, Agnieszka, Gaál-Paavola, Emília I, Niemelä, Mika, Jääskeläinen, Juha E, von Und Zu Fraunberg, Mikael, Lindgren, Antti, Broderick, Joseph P, Werring, David J, Woo, Daniel, Redon, Richard, Bijlenga, Philippe, Kamatani, Yoichiro, Veldink, Jan H, and Ruigrok, Ynte M
Subjects: BioBank Japan Project Consortium, Blood Pressure, Cardiovascular, Medical and Health Sciences, International Stroke Genetics Consortium, White People, Asian People, Risk Factors, Clinical Research, Genetics, ICAN Study Group, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Polymorphism, Aetiology, China Kadoorie Biobank Collaborative Group, CADISP Group, Prevention, Smoking, Human Genome, Neurosciences, Endothelial Cells, Intracranial Aneurysm, Single Nucleotide, Subarachnoid Hemorrhage, Biological Sciences, Brain Disorders, Stroke, Case-Control Studies, Hypertension, HUNT All-In Stroke, Genetics and Observational Subarachnoid Haemorrhage (GOSH) Study investigators, Genome-Wide Association Study, Developmental Biology
Abstract: Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits.
Published: 2020

13. Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as novel risk factors for Alzheimer’s Disease

Author: Holstege, Henne, Hulsman, Marc, Charbonnier, Camille, Grenier-Boley, Benjamin, Quenez, Olivier, Grozeva, Detelina, van Rooij, Jeroen G.J., Sims, Rebecca, Ahmad, Shahzad, Amin, Najaf, Norsworthy, Penny J., Dols-Icardo, Oriol, Hummerich, Holger, Kawalia, Amit, Amouyel, Philippe, Beecham, Gary W., Berr, Claudine, Bis, Joshua C., Boland, Anne, Bossù, Paola, Bouwman, Femke, Bras, Jose, Campion, Dominique, Cochran, J. Nicholas, Daniele, Antonio, Dartigues, Jean-François, Debette, Stéphanie, Deleuze, Jean-François, Denning, Nicola, DeStefano, Anita L, Farrer, Lindsay A., Fernandez, Maria Victoria, Fox, Nick C., Galimberti, Daniela, Genin, Emmanuelle, Gille, Hans, Guen, Yann Le, Guerreiro, Rita, Haines, Jonathan L., Holmes, Clive, Ikram, M. Arfan, Ikram, M. Kamran, Jansen, Iris E., Kraaij, Robert, Lathrop, Marc, Lemstra, Afina W., Lleó, Alberto, Luckcuck, Lauren, Mannens, Marcel M. A. M., Marshall, Rachel, Martin, Eden R, Masullo, Carlo, Mayeux, Richard, Mecocci, Patrizia, Meggy, Alun, Mol, Merel O., Morgan, Kevin, Myers, Richard M., Nacmias, Benedetta, Naj, Adam C, Napolioni, Valerio, Pasquier, Florence, Pastor, Pau, Pericak-Vance, Margaret A., Raybould, Rachel, Redon, Richard, Reinders, Marcel J.T., Richard, Anne-Claire, Riedel-Heller, Steffi G, Rivadeneira, Fernando, Rousseau, Stéphane, Ryan, Natalie S., Saad, Salha, Sanchez-Juan, Pascual, Schellenberg, Gerard D., Scheltens, Philip, Schott, Jonathan M., Seripa, Davide, Seshadri, Sudha, Sie, Daoud, Sistermans, Erik, Sorbi, Sandro, van Spaendonk, Resie, Spalletta, Gianfranco, Tesi, Niccólo, Tijms, Betty, Uitterlinden, André G, van der Lee, Sven J., de Visser, Pieter Jelle, Wagner, Michael, Wallon, David, Wang, Li-San, Zarea, Aline, Clarimon, Jordi, van Swieten, John C., Greicius, Michael D., Yokoyama, Jennifer S., Cruchaga, Carlos, Hardy, John, Ramirez, Alfredo, Mead, Simon, van der Flier, Wiesje M., van Duijn, Cornelia M, Williams, Julie, Nicolas, Gaël, Bellenguez, Céline, and Lambert, Jean-Charles
Subjects: Genetics, symbols.namesake, TREM2, SORL1, Mendelian inheritance, symbols, Disease, Allele, Biology, Genome, Gene, Exome sequencing
Abstract: Background With the development of next-generation sequencing technologies, it is possible to identify rare genetic variants that influence the risk of complex disorders. To date, whole exome sequencing (WES) strategies have shown that specific clusters of damaging rare variants in the TREM2, SORL1 and ABCA7 genes are associated with an increased risk of developing Alzheimer’s Disease (AD), reaching odds ratios comparable with the APOE-e4 allele, the main common AD genetic risk factor. Here, we set out to identify additional AD-associated genes by an exome-wide investigation of the burden of rare damaging variants in the genomes of AD cases and cognitively healthy controls. Method We integrated the data from 25,982 samples from the European ADES consortium and the American ADSP consortium. We developed new techniques to homogenize and analyze these data. Carriers of pathogenic variants in genes associated with Mendelian inheritance of dementia were excluded. After quality control, we used 12,652 AD cases and 8,693 controls for analysis. Genes were analyzed using a burden analysis, including both non-synonymous and loss-of-function rare variants, the impact of which was prioritized using REVEL. Result We confirmed that carrying rare protein-damaging genetic variants in TREM2, SORL1 or ABCA7 is associated with increased AD-risk. Moreover, we found that carrying rare damaging variants in the microglial ATP8B4 gene was significantly associated with AD, and we found suggestive evidence that rare variants in ADAM10, ABCA1, ORC6, B3GNT4 and SRC genes associated with increased AD risk. High-impact variants in these genes were mostly extremely rare and enriched in AD patients with earlier ages at onset. Additionally, we identified two suggestive protective associations in CBX3 and PRSS3. We are currently replicating these associations in independent datasets. Conclusion With our newly developed homogenization methods, we identified novel genetic determinants of AD which provide further evidence for a pivotal role of APP processing, lipid metabolism, and microglia and neuroinflammatory processes in AD pathophysiology.
Published: 2020
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14. Cerebral small vessel disease genomics and its implications across the lifespan

Author: Sargurupremraj, Muralidharan, Suzuki, Hideaki, Jian, Xueqiu, Sarnowski, Chloé, Evans, Tavia E., Bis, Joshua C., Eiriksdóttir, Gudny, Sakaue, Saori, Terzikhan, Natalie, Habes, Mohamad, Zhao, Wei, Armstrong, Nicola J., Hofer, Edith, Yanek, Lisa R., Hagenaars, Saskia P., Kumar, Rajan B., van den Akker, Erik B., McWhirter, Rebekah E., Trompet, Stella, Mishra, Aniket, Saba, Yasaman, Satizabal, Claudia L., Beaudet, Gregory, Petit, Laurent, Tsuchida, Ami, Zago, Laure, Schilling, Sabrina, Sigurdsson, Sigurdur, Gottesman, Rebecca F., Lewis, Cora E., Aggarwal, Neelum T, Lopez, Oscar L., Smith, Jennifer A., Hernández, Maria C. Valdés, van der Grond, Jeroen, Wright, Margaret J., Knol, Maria J., Dörr, Marcus, Thomson, Russell J., Bordes, Constance, Le Grand, Quentin, Duperron, Marie-Gabrielle, Smith, Albert V., Knopman, David S., Winsvold, Bendik K S, Pedersen, Linda Margareth, Stubhaug, Audun, Nielsen, Christopher Sivert, Zwart, John-Anker, and Debette, Stéphanie
Subjects: mental disorders, behavioral disciplines and activities
Abstract: White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.
Published: 2020
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15. Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis

Author: Rhodes, Christopher J, Batai, Ken, Bleda, Marta, Haimel, Matthias, Southgate, Laura, Germain, Marine, Pauciulo, Michael W, Hadinnapola, Charaka, Aman, Jurjan, Girerd, Barbara, Arora, Amit, Knight, Jo, Hanscombe, Ken B, Karnes, Jason H, Kaakinen, Marika, Gall, Henning, Ulrich, Anna, Harbaum, Lars, Cebola, Inês, Ferrer, Jorge, Lutz, Katie, Swietlik, Emilia M, Ahmad, Ferhaan, Amouyel, Philippe, Archer, Stephen L, Argula, Rahul, Austin, Eric D, Badesch, David, Bakshi, Sahil, Barnett, Christopher, Benza, Raymond, Bhatt, Nitin, Bogaard, Harm J, Burger, Charles D, Chakinala, Murali, Church, Colin, Coghlan, John G, Condliffe, Robin, Corris, Paul A, Danesino, Cesare, Debette, Stéphanie, Elliott, C Gregory, Elwing, Jean, Eyries, Melanie, Fortin, Terry, Franke, Andre, Frantz, Robert P, Frost, Adaani, Garcia, Joe GN, Ghio, Stefano, Ghofrani, Hossein-Ardeschir, Gibbs, J Simon R, Harley, John, He, Hua, Hill, Nicholas S, Hirsch, Russel, Houweling, Arjan C, Howard, Luke S, Ivy, Dunbar, Kiely, David G, Klinger, James, Kovacs, Gabor, Lahm, Tim, Laudes, Matthias, Machado, Rajiv D, MacKenzie Ross, Robert V, Marsolo, Keith, Martin, Lisa J, Moledina, Shahin, Montani, David, Nathan, Steven D, Newnham, Michael, Olschewski, Andrea, Olschewski, Horst, Oudiz, Ronald J, Ouwehand, Willem H, Peacock, Andrew J, Pepke-Zaba, Joanna, Rehman, Zia, Robbins, Ivan, Roden, Dan M, Rosenzweig, Erika B, Saydain, Ghulam, Scelsi, Laura, Schilz, Robert, Seeger, Werner, Shaffer, Christian M, Simms, Robert W, Simon, Marc, Sitbon, Olivier, Suntharalingam, Jay, Tang, Haiyang, Tchourbanov, Alexander Y, Thenappan, Thenappan, Torres, Fernando, Toshner, Mark R, Treacy, Carmen M, Vonk Noordegraaf, Anton, Waisfisz, Quinten, and Walsworth, Anna K
Subjects: Male, US PAH Biobank Consortium, Genotyping Techniques, Clinical Sciences, UK PAH Cohort Study Consortium, HLA-DP alpha-Chains, Cardiovascular, Risk Assessment, UK NIHR BioResource Rare Diseases Consortium, SOXF Transcription Factors, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Polymorphism, Aetiology, Lung, HLA-DP beta-Chains, Pulmonary Arterial Hypertension, Other Medical and Health Sciences, Human Genome, Genetic Variation, Single Nucleotide, Middle Aged, Survival Analysis, Public Health and Health Services, Female, Signal Transduction, Genome-Wide Association Study
Abstract: BackgroundRare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes.MethodsWe did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses.FindingsA locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55-2·08], p=5·13 × 10-15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42-1·71], p=7·65 × 10-20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25-1·48], p=1·69 × 10-12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02-8·05]), despite similar baseline disease severity.InterpretationThis is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials.FundingUK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR.
Published: 2019

16. Clinical Significance of Magnetic Resonance Imaging Markers of Vascular Brain Injury

Author: Debette, Stéphanie, Schilling, Sabrina, Duperron, Marie-Gabrielle, Larsson, Susanna C., and Markus, Hugh S.
Published: 2019
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17. Fibromuscular Dysplasia and Its Neurologic Manifestations

Author: Touzé, Emmanuel, Southerland, Andrew M., Boulanger, Marion, Labeyrie, Paul-Emile, Azizi, Michel, Bouatia-Naji, Nabila, Debette, Stéphanie, Gornik, Heather L., Hussain, Shazam M., Jeunemaitre, Xavier, Joux, Julien, Kirton, Adam, Le Hello, Claire, Majersik, Jennifer J., Mocco, J., Persu, Alexandre, Sharma, Aditya, Worrall, Bradford B., Olin, Jeffrey W., and Plouin, Pierre-François
Published: 2019
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18. Author Correction: Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors

Author: Bakker, Mark K, van der Spek, Rick A A, Terao, Chikashi, Bulters, Diederik, Kitchen, Neil, Brown, Martin, Grieve, Joan, Matsuda, Koichi, Walters, Robin G, Lin, Kuang, Li, Liming, Millwood, Iona Y, Chen, Zhengming, Rouleau, Guy A, Zhou, Sirui, Rannikmäe, Kristiina, van Rheenen, Wouter, Sudlow, Cathie L M, Houlden, Henry, van den Berg, Leonard H, Dina, Christian, Naggara, Olivier, Gentric, Jean-Christophe, Shotar, Eimad, Eugène, François, Desal, Hubert, Winsvold, Bendik S, Morel, Sandrine, Børte, Sigrid, Johnsen, Marianne Bakke, Brumpton, Ben M, Sandvei, Marie Søfteland, Willer, Cristen J, Hveem, Kristian, Zwart, John-Anker, Verschuren, W M Monique, Friedrich, Christoph M, Hirsch, Sven, Bourcier, Romain, Schilling, Sabine, Dauvillier, Jérôme, Martin, Olivier, Stroke, HUNT All-In, Group, China Kadoorie Biobank Collaborative, Consortium, BioBank Japan Project, Group, ICAN Study, Group, CADISP, Genetics, Haemorrhage, Observational Subarachnoid, Hostettler, Isabel C, Consortium, International Stroke Genetics, Jones, Gregory T, Bown, Matthew J, Ko, Nerissa U, Kim, Helen, Coleman, Jonathan R I, Breen, Gerome, Zaroff, Jonathan G, Klijn, Catharina J M, Malik, Rainer, Alg, Varinder S, Dichgans, Martin, Sargurupremraj, Muralidharan, Tatlisumak, Turgut, Amouyel, Philippe, Debette, Stéphanie, Rinkel, Gabriel J E, Worrall, Bradford B, Pera, Joanna, Slowik, Agnieszka, Gaál-Paavola, Emília I, van Eijk, Kristel R, Niemelä, Mika, Jääskeläinen, Juha E, von Und Zu Fraunberg, Mikael, Lindgren, Antti, Broderick, Joseph P, Werring, David J, Woo, Daniel, Redon, Richard, Bijlenga, Philippe, Kamatani, Yoichiro, Koido, Masaru, Veldink, Jan H, Ruigrok, Ynte M, Bian, Zheng, Chen, Junshi, Chen, Yiping, Clarke, Robert, Collins, Rory, Guo, Yu, Han, Xiao, Hill, Michael, Akiyama, Masato, Liu, Depei, Lv, Jun, Millwood, Iona, Peto, Richard, Sansome, Sam, Walters, Robin, Yang, Xiaoming, Yu, Canqing, Bonner, Stephen, and Walsh, Daniel
Subjects: 572: Biochemie, ddc:570, Medizin, Genetics, MEDLINE, Genome-wide association study, Computational biology, Biology, Clinical risk factor, 616: Innere Medizin und Krankheiten
Abstract: In the version of this article initially published, the following statement was missing from the Acknowledgements: “We are grateful to the GenoBiRD core facility (Biogenouest), the Clinical Investigation Center (INSERM CIC1413) and the Center of Biological Resources in Nantes (BB-0033-00040; CHU Nantes, France) for their assistance in managing and genotyping the ICAN and PREGO biobanks. R.R. was supported by the French Regional Council of Pays-de-la-Loire (VaCaRMe program) and the Agence Nationale de la Recherche (ANR-15-CE17-0008-01 to G.L). H.D. and R.B. were supported by the French Ministry of Health (clinical trial NCT02848495 to H.D.), the Genavie Foundation, the Société Française de Radiologie and the Société Française de Neuroradiologie.” The error has been corrected in the HTML and PDF versions of the article. *Lists of authors and their affiliations appear online. Korrektur zu 10.1038/s41588-020-00725-7
Published: 2020
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19. Genetic determinants of risk and survival in pulmonary arterial hypertension

Author: Rhodes, Christopher J., Batai, Ken, Bleda, Marta, Haimel, Matthias, Southgate, Laura, Germain, Marine, Pauciulo, Michael W., Hadinnapola, Charaka, Aman, Jurjan, Girerd, Barbara, Arora, Amit, Knight, Jo, Hanscombe, Ken B., Karnes, Jason H., Kaakinen, Marika, Gall, Henning, Ulrich, Anna, Harbaum, Lars, Cebola, Inês, Ferrer, Jorge, Ahmad, Ferhaan, Amouyel, Philippe, Stephen L., Archer, Argula, Rahul, Eric D., Austin, Badesch, David, Bakshi, Sahil, Barnett, Christopher F., Benza, Raymond, Bhatt, Nitin, Bogaard, Harm J., Burger, Charles D., Chakinala, Murali M., Church, Colin, Coghlan, John G., Condliffe, Robin, Corris, Paul A., Danesino, Cesare, Debette, Stéphanie, Elliott, C. Gregory, Elwing, Jean, Eyries, Melanie, Fortin, Terry, Franke, Andre, Frantz, Robert P., Frost, Adaani, Garcia, Joe G.N., Ghio, Stefano, Ghofrani, Hossein-Ardeschir, Simon, J., Gibbs, R., Harley, John B., He, Hua, Hill, Nicholas S., Hirsch, Russel, Houweling, Arjan C., Howard, Luke S., Ivy, Dunbar, Kiely, David G., Klinger, James, Kovacs, Gabor, Lahm, Tim, Laudes, Matthias, Lutz, Katie, Machado, Rajiv D., MacKenzie Ross, Robert V., Marsolo, Keith, Martin, Lisa J., Moledina, Shahin, Montani, David, Nathan, Steven D., Newnham, Michael, Olschewski, Andrea, Olschewski, Horst, Oudiz, Ronald J., Ouwehand, Willem H., Peacock, Andrew J., Pepke-Zaba, Joanna, Rehman, Zia, Robbins, Ivan M., Roden, Dan M., Rosenzweig, Erika B., Saydain, Ghulam, Scelsi, Laura, Schilz, Robert, Seeger, Werner, Shaffer, Christian M., Simms, Robert W., Simon, Marc, Sitbon, Olivier, Suntharalingam, Jay, Swietlik, Emilia, Tang, Haiyang, Tchourbanov, Alexander Y., Thenappan, Thenappan, Torres, Fernando, Toshner, Mark R., Treacy, Carmen M., Noordegraaf, Anton Vonk, Waisfisz, Quinten, Walsworth, Anna K., Walter, Robert E, Wharton, John, White, R. James, Wilt, Jeffrey, Wort, Stephen J., Yung, Delphine, Lawrie, Allan, Humbert, Marc, Soubrier, Florent, Trégouët, David-Alexandre, Prokopenko, Inga, Kittles, Richard, Gräf, Stefan, Nichols, William C., Trembath, Richard C., Desai, Ankit A., Morrell, Nicholas W., and Wilkins, Martin R.
Subjects: 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, 030204 cardiovascular system & hematology, 3. Good health, 030304 developmental biology
Abstract: BackgroundPulmonary arterial hypertension (PAH) is a rare disorder leading to premature death. Rare genetic variants contribute to disease etiology but the contribution of common genetic variation to disease risk and outcome remains poorly characterized.MethodsWe performed two separate genome-wide association studies of PAH using data across 11,744 European-ancestry individuals (including 2,085 patients), one with genotypes from 5,895 whole genome sequences and another with genotyping array data from 5,849 further samples. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. We functionally annotated associated variants and tested associations with duration of survival.FindingsA locus atHLA-DPA1/DPB1within the class II major histocompatibility (MHC) region and a second nearSOX17were significantly associated with PAH. TheSOX17locus contained two independent signals associated with PAH. Functional and epigenomic data indicate that the risk variants nearSOX17alter gene regulation via an enhancer active in endothelial cells. PAH risk variants determined haplotype-specific enhancer activity and CRISPR-inhibition of the enhancer reducedSOX17expression. Analysis of median survival showed that PAH patients with two copies of theHLA-DPA1/DPB1risk variant had a two-fold difference (>16 years versus 8 years), compared to patients homozygous for the alternative allele.InterpretationWe have found that common genetic variation at loci inHLA-DPA1/DPB1and an enhancer nearSOX17are associated with PAH. Impairment of Sox17 function may be more common in PAH than suggested by rare mutations inSOX17. Allelic variation atHLA-DPB1stratifies PAH patients for survival following diagnosis, with implications for future therapeutic trial design.FundingUK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, Inserm, Université Paris-Sud, and French ANR.
Published: 2018
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20. Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure

Author: Wain, Louise V, Verwoert, Germaine C, O'Reilly, Paul F, Shi, Gang, Johnson, Toby, Johnson, Andrew D, Bochud, Murielle, Rice, Kenneth M, Henneman, Peter, Smith, Albert V, Ehret, Georg B, Amin, Najaf, Larson, Martin G, Mooser, Vincent, Hadley, David, Dörr, Marcus, Bis, Joshua C, Aspelund, Thor, Esko, Tõnu, Janssens, A Cecile JW, Zhao, Jing Hua, Heath, Simon, Laan, Maris, Fu, Jingyuan, Pistis, Giorgio, Luan, Jian'an, Arora, Pankaj, Lucas, Gavin, Pirastu, Nicola, Pichler, Irene, Jackson, Anne U, Webster, Rebecca J, Zhang, Feng, Peden, John F, Schmidt, Helena, Tanaka, Toshiko, Campbell, Harry, Igl, Wilmar, Milaneschi, Yuri, Hottenga, Jouke-Jan, Vitart, Veronique, Chasman, Daniel I, Trompet, Stella, Bragg-Gresham, Jennifer L, Alizadeh, Behrooz Z, Chambers, John C, Guo, Xiuqing, Lehtimäki, Terho, Kühnel, Brigitte, Lopez, Lorna M, Polašek, Ozren, Boban, Mladen, Nelson, Christopher P, Morrison, Alanna C, Pihur, Vasyl, Ganesh, Santhi K, Hofman, Albert, Kundu, Suman, Mattace-Raso, Francesco US, Rivadeneira, Fernando, Sijbrands, Eric JG, Uitterlinden, Andre G, Hwang, Shih-Jen, Vasan, Ramachandran S, Wang, Thomas J, Bergmann, Sven, Vollenweider, Peter, Waeber, Gérard, Laitinen, Jaana, Pouta, Anneli, Zitting, Paavo, McArdle, Wendy L, Kroemer, Heyo K, Völker, Uwe, Völzke, Henry, Glazer, Nicole L, Taylor, Kent D, Harris, Tamara B, Alavere, Helene, Haller, Toomas, Keis, Aime, Tammesoo, Mari-Liis, Aulchenko, Yurii, Barroso, Inês, Khaw, Kay-Tee, Galan, Pilar, Hercberg, Serge, Lathrop, Mark, Eyheramendy, Susana, Org, Elin, Sõber, Siim, Lu, Xiaowen, Nolte, Ilja M, Penninx, Brenda W, Corre, Tanguy, Masciullo, Corrado, Sala, Cinzia, Groop, Leif, Voight, Benjamin F, Melander, Olle, O'Donnell, Christopher J, Salomaa, Veikko, D'Adamo, Adamo Pio, Fabretto, Antonella, Faletra, Flavio, Ulivi, Sheila, Del Greco, Fabiola M, Facheris, Maurizio, Collins, Francis S, Bergman, Richard N, Beilby, John P, Hung, Joseph, Musk, A William, Mangino, Massimo, Shin, So-Youn, Soranzo, Nicole, Watkins, Hugh, Goel, Anuj, Hamsten, Anders, Gider, Pierre, Loitfelder, Marisa, Zeginigg, Marion, Hernandez, Dena, Najjar, Samer S, Navarro, Pau, Wild, Sarah H, Corsi, Anna Maria, Singleton, Andrew, De Geus, Eco JC, Willemsen, Gonneke, Parker, Alex N, Rose, Lynda M, Buckley, Brendan, Stott, David, Orru, Marco, Uda, Manuela, LifeLines Cohort Study, Van Der Klauw, Melanie M, Zhang, Weihua, Li, Xinzhong, Scott, James, Chen, Yii-Der Ida, Burke, Gregory L, Kähönen, Mika, Viikari, Jorma, Döring, Angela, Meitinger, Thomas, Davies, Gail, Starr, John M, Emilsson, Valur, Plump, Andrew, Lindeman, Jan H, Hoen, Peter AC 'T, König, Inke R, EchoGen Consortium, Felix, Janine F, Clarke, Robert, Hopewell, Jemma C, Ongen, Halit, Breteler, Monique, Debette, Stéphanie, Destefano, Anita L, Fornage, Myriam, AortaGen Consortium, Mitchell, Gary F, CHARGE Consortium Heart Failure Working Group, Smith, Nicholas L, KidneyGen Consortium, Holm, Hilma, Stefansson, Kari, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, CKDGen Consortium, Cardiogenics Consortium, CardioGram, Samani, Nilesh J, Preuss, Michael, Rudan, Igor, Hayward, Caroline, Deary, Ian J, Wichmann, H-Erich, Raitakari, Olli T, Palmas, Walter, Kooner, Jaspal S, Stolk, Ronald P, Jukema, J Wouter, Wright, Alan F, Boomsma, Dorret I, Bandinelli, Stefania, Gyllensten, Ulf B, Wilson, James F, Ferrucci, Luigi, Schmidt, Reinhold, Farrall, Martin, Spector, Tim D, Palmer, Lyle J, Tuomilehto, Jaakko, Pfeufer, Arne, Gasparini, Paolo, Siscovick, David, Altshuler, David, Loos, Ruth JF, Toniolo, Daniela, Snieder, Harold, Gieger, Christian, Meneton, Pierre, Wareham, Nicholas J, Oostra, Ben A, Metspalu, Andres, Launer, Lenore, Rettig, Rainer, Strachan, David P, Beckmann, Jacques S, Witteman, Jacqueline CM, Erdmann, Jeanette, Van Dijk, Ko Willems, Boerwinkle, Eric, Boehnke, Michael, Ridker, Paul M, Jarvelin, Marjo-Riitta, Chakravarti, Aravinda, Abecasis, Goncalo R, Gudnason, Vilmundur, Newton-Cheh, Christopher, Levy, Daniel, Munroe, Patricia B, Psaty, Bruce M, Caulfield, Mark J, Rao, Dabeeru C, Tobin, Martin D, Elliott, Paul, and Van Duijn, Cornelia M
Subjects: Genetic Loci, Case-Control Studies, Hypertension, Humans, Blood Pressure, cardiovascular diseases, Arteries, Polymorphism, Single Nucleotide, Linkage Disequilibrium, circulatory and respiratory physiology, Follow-Up Studies, Genome-Wide Association Study
Abstract: Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.
Published: 2018
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21. Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI

Author: Verhaaren, Benjamin FJ, Debette, Stéphanie, Bis, Joshua C, Smith, Jennifer A, Ikram, M Kamran, Adams, Hieab H, Beecham, Ashley H, Rajan, Kumar B, Lopez, Lorna M, Barral, Sandra, van Buchem, Mark A, van der Grond, Jeroen, Smith, Albert V, Hegenscheid, Katrin, Aggarwal, Neelum T, de Andrade, Mariza, Atkinson, Elizabeth J, Beekman, Marian, Beiser, Alexa S, Blanton, Susan H, Boerwinkle, Eric, Brickman, Adam M, Bryan, R Nick, Chauhan, Ganesh, Chen, Christopher PLH, Chouraki, Vincent, de Craen, Anton JM, Crivello, Fabrice, Deary, Ian J, Deelen, Joris, De Jager, Philip L, Dufouil, Carole, Elkind, Mitchell SV, Evans, Denis A, Freudenberger, Paul, Gottesman, Rebecca F, Guðnason, Vilmundur, Habes, Mohamad, Heckbert, Susan R, Heiss, Gerardo, Hilal, Saima, Hofer, Edith, Hofman, Albert, Ibrahim-Verbaas, Carla A, Knopman, David S, Lewis, Cora E, Liao, Jiemin, Liewald, David CM, Luciano, Michelle, van der Lugt, Aad, Martinez, Oliver O, Mayeux, Richard, Mazoyer, Bernard, Nalls, Mike, Nauck, Matthias, Niessen, Wiro J, Oostra, Ben A, Psaty, Bruce M, Rice, Kenneth M, Rotter, Jerome I, von Sarnowski, Bettina, Schmidt, Helena, Schreiner, Pamela J, Schuur, Maaike, Sidney, Stephen S, Sigurdsson, Sigurdur, Slagboom, P Eline, Stott, David JM, van Swieten, John C, Teumer, Alexander, Töglhofer, Anna Maria, Traylor, Matthew, Trompet, Stella, Turner, Stephen T, Tzourio, Christophe, Uh, Hae-Won, Uitterlinden, André G, Vernooij, Meike W, Wang, Jing J, Wong, Tien Y, Wardlaw, Joanna M, Windham, B Gwen, Wittfeld, Katharina, Wolf, Christiane, Wright, Clinton B, Yang, Qiong, Zhao, Wei, Zijdenbos, Alex, Jukema, J Wouter, Sacco, Ralph L, Kardia, Sharon LR, Amouyel, Philippe, Mosley, Thomas H, Longstreth, WT, DeCarli, Charles C, van Duijn, Cornelia M, Schmidt, Reinhold, Launer, Lenore J, Grabe, Hans J, and Seshadri, Sudha S
Subjects: Male, single nucleotide, Aging, hypertension, Medical Biotechnology, and over, Neurodegenerative, Cardiorespiratory Medicine and Haematology, Alzheimer's Disease, Chromosomes, leukoencephalopathies, Genetic, Meta-Analysis as Topic, Models, Clinical Research, 80 and over, Genetics, Acquired Cognitive Impairment, Humans, 2.1 Biological and endogenous factors, Alzheimer's Disease including Alzheimer's Disease Related Dementias, Aetiology, Aged, genome-wide association study, Continental Population Groups, Prevention, Racial Groups, Human Genome, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), cerebrovascular disorders, Middle Aged, White Matter, Brain Disorders, Stroke, Cardiovascular System & Hematology, Genetic Loci, Female, Dementia, cerebral small vessel diseases, polymorphisms, Human, Biotechnology
Abstract: BackgroundThe burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies.Methods and resultsWe included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10(-19)) and identified novel loci on chr10q24 (P=1.6×10(-9)) and chr2p21 (P=4.4×10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10(-8)) and chr2p16 (P=1.5×10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16).ConclusionsWe identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.
Published: 2015

22. Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection

Author: Debette, Stéphanie, Kamatani, Yoichiro, Wolf, Christiane, Agabiti Rosei, Enrico, Lanfranconi, Silvia, Ferrarese, Carlo, Susani, Emanuela, Bicocca, Milano, Giacalone, Giacomo, Paolucci, Stefano, Palmirotta, Raffaele, Paciaroni, Maurizio, Ballabio, Elena, Dittrich, Ralf, Parati, Eugenio A, Ciusani, Emilio, Fluri, Felix, Hatz, Florian, Gisler, Dominique, Amort, Margareth, Bevan, Steve, James, Tom, Olsson, Sandra, Holmegaard, Lukas, Touzé, Emmanuel, Altintas, Ayse, Martin, Juan José, Kittner, Steven, MItchell, Braxton, Stine, Colin, O'Connell, Jeff, Dueker, Nicole, Koudstaal, Peter J, de Lau, Lonneke M L, Hofman, Albert, Southerland, Andrew M, Verhaaren, Benjamin F, Uitterlinden, Andre G, Montaner, Joan, Mendioroz, Maite, Yadav, Sunaina, Khan, Muhammad Saleem, Wilder, Michael, van Dijk, Ewoud, Maaijwee, Noortje, Rutten-Jacobs, Loes, Samson, Yves, Kramer, Jamie, Malik, Shaneela, Brott, Thomas G, Brown, Robert D, Singleton, Andrew, Hardy, John, Rich, Stephen S, Tanislav, Christian, Jungehülsing, Jan, Abboud, Shérine, Béjot, Yannick, Caso, Valeria, Bersano, Anna, Gschwendtner, Andreas, Metso, Tiina M, Sessa, Maria, Cole, John, Lamy, Chantal, Medeiros, Elisabeth, Beretta, Simone, Bonati, Leo H, Grau, Armin J, Michel, Patrik, Majersik, Jennifer J, Sharma, Pankaj, Kloss, Manja, Kalashnikova, Ludmila, Nazarova, Maria, Dobrynina, Larisa, Bartels, Eva, Guillon, Benoit, van den Herik, Evita G, Fernandez-Cadenas, Israel, Jood, Katarina, Nalls, Michael A, De Leeuw, Frank-Erik, Chauhan, Ganesh, Jern, Christina, Cheng, Yu-Ching, Werner, Inge, Metso, Antti J, Lichy, Christoph, Lyrer, Philippe A, Brandt, Tobias, Boncoraglio, Giorgio B, Wichmann, Heinz-Erich, Gieger, Christian, Engelter, Stefan T, Johnson, Andrew D, Böttcher, Thomas, Castellano, Maurizio, Arveiler, Dominique, Ikram, M Arfan, Breteler, Monique M B, Padovani, Alessandro, Meschia, James F, Kuhlenbäumer, Gregor, Rolfs, Arndt, Pezzini, Alessandro, Worrall, Bradford B, Consortium, International Stroke Genetics, Ringelstein, Erich-Bernd, Zelenika, Diana, Tatlisumak, Turgut, Lathrop, Mark, Leys, Didier, Amouyel, Philippe, Dallongeville, Jean, Group, CADISP, Thijs, Vincent, Lemmens, Robin, Pandolfo, Massimo, Bodenant, Marie, Louillet, Fabien, Mas, Jean-Louis, Deltour, Sandrine, Leder, Sara, Léger, Anne, Canaple, Sandrine, Godefroy, Olivier, Markus, Hugh S, Giroud, Maurice, Jacquin, Agnès, Moulin, Thierry, Vullier, Fabrice, Tzourio, Christophe, Dos Santos, Michael, Malik, Rainer, Hausser, Ingrid, Thomas-Feles, Constanze, Weber, Ralf, Dichgans, Martin, Grond-Ginsbach, Caspar, Hacke, Werner, Giossi, Alessia, Volonghi, Irene, Costa, Paolo, del Zotto, Elisabetta, Morotti, Andrea, Poli, Loris, Lorenza Muiesan, Maria, Salvetti, Massimo, Epidémiologie des maladies chroniques: impact des intéractions gène environnement sur la santé des populations, 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, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Epidemiologie-Biostatistique [Bordeaux], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux Ségalen [Bordeaux 2], Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Helsinki University Central Hospital [Finland] (HUCH), Heidelberg University Hospital [Heidelberg], University Hospital Basel [Basel], Università degli Studi di Brescia = University of Brescia (UniBs), University Hospitals Leuven [Leuven], Leuven Center for Cancer Biology (VIB-KU-CCB), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven)-Vlaams Instituut voor Biotechnologie [Ghent, Belgique] (VIB), University of Cambridge [UK] (CAM), Institute for Stroke and Dementia Research (ISD), Klinikum der Universität [München]-Ludwig Maximilian University [Munich] (LMU), Ludwig-Maximilians-Universität München (LMU), University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neurologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), University of Virginia, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Neurochirurgie Expérimentale [Brussels] (ULB 257), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Università degli Studi di Perugia = University of Perugia (UNIPG), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Munich Cluster for systems neurology [Munich] (SyNergy), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Ludwig-Maximilians-Universität München (LMU), Ospedale San Raffaele, University of Maryland School of Medicine, University of Maryland System, Service de neurologie [Amiens], CHU Amiens-Picardie, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), Klinikum Ludwigshafen [Germany], Service of Neurology [CHUV, Lausanne, Switzerland], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), University of Utah School of Medicine [Salt Lake City], Institute of Cardiovascular Research (ICR2UL), Royal Holloway [University of London] (RHUL), Ashford and St Peter's hospitals NHS foundation trust, Russian Academy of Sciences [Moscow] (RAS), Centre for Cognition and Decision Making [HSE, Moscow], Institut of Cognitive Neuroscience [HSE, Moscow] (ICN), Vysšaja škola èkonomiki = National Research University Higher School of Economics [Moscow] (HSE)-Vysšaja škola èkonomiki = National Research University Higher School of Economics [Moscow] (HSE), Zentrum für neurologische Gefäßdiagnostik - Center for Neurological Vascular Diagnostics [Munich, Germany], Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Department of Neurology [Erasmus MC, Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Hospital Universitario Mutua de Terrassa, Vall d'Hebron University Hospital [Barcelona], Insitute of Neuroscience and Physiology, University of Gothenburg (GU), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Donders Institute for Brain, Cognition and Behaviour, Radboud University [Nijmegen], Schmieder Klinik [Heidelberg, Germany], Helmholtz Zentrum München = German Research Center for Environmental Health, Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), University Hospital Rostock, Progression tumorale et microenvironnement. Approches translationnelles et épidémiologie, Université de Strasbourg (UNISTRA)-CHU Strasbourg-Les Hôpitaux Universitaires de Strasbourg (HUS)-Institut Régional du Cancer-Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC), Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), University of Brescia, Mayo Clinic [Jacksonville], Institute of Experimental Medicine - Institut für Experimentelle Medizin [Kiel, Germany] (IEM), Christian-Albrechts-Universität zu Kiel (CAU), Westfälische Wilhelms-Universität Münster = University of Münster (WWU), 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, McGill University and Genome Quebec Innovation Centre, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, Pharmacologie de la mort neuronale et de la plasticité cérébrale, IFR114-Université de Lille, Droit et Santé, Réseau International des Instituts Pasteur (RIIP), Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, 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, Droit et Santé, The CADISP study has been supported by INSERM, Lille 2 University, Institut Pasteur de Lille and Lille University Hospital and received funding from the European Regional Development Fund (FEDER funds) and Région Nord-Pas-de-Calais in the framework of Contrat de Projets Etat-Region 2007–2013 Région Nord-Pas-de-Calais (grant 09120030), Centre National de Génotypage, the Emil Aaltonen Foundation, the Paavo Ilmari Ahvenainen Foundation, the Helsinki University Central Hospital Research Fund, the Helsinki University Medical Foundation, the Päivikki and Sakari Sohlberg Foundation, the Aarne Koskelo Foundation, the Maire Taponen Foundation, the Aarne and Aili Turunen Foundation, the Lilly Foundation, the Alfred Kordelin Foundation, the Finnish Medical Foundation, the Orion Farmos Research Foundation, the Maud Kuistila Foundation, the Finnish Brain Foundation, the Biomedicum Helsinki Foundation, Projet Hospitalier de Recherche Clinique Régional, Fondation de France, Génopôle de Lille, Adrinord, the Basel Stroke Funds, the Käthe-Zingg-Schwichtenberg-Fonds of the Swiss Academy of Medical Sciences and the Swiss Heart Foundation.L.H.B., S.T.E. and P.A.L. were supported, in part, by a grant from the Swiss National Science Foundation (33CM30-124119). S.D. is supported by a Chair of Excellence from the French National Research Agency (ANR). S.D. and M.D. are supported by a grant from the Leducq Foundation. M.D. is supported by the Vascular Dementia Research Foundation. I.F.-C. is supported by the Miguel Servet programme (CP12/03298) from the Spanish Ministry of Health (Instituto de Salud Carlos III). G.K. is a member of the Deutsche Forschungsgemeinschaft Cluster of Excellence 'Inflammation at Interfaces'. P.S. is supported by a Department of Health (UK) senior fellowship. A.M.S. is supported by the American Heart Association/American Stroke Association National Clinical Research Program (AHA 3CRP14140001). V.T. is supported by Fonds Wetenschappelijk Onderzoek Flanders., CADISP Group, RIKEN Center for Integrative Medical Science, Università degli Studi di Brescia [Brescia], University of Virginia [Charlottesville], Service des Urgences Cérébro-Vasculaires [CHU Pitié-Salpêtrière]], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Laboratoire de Neurologie Expérimentale [ULB, Brussels, Belgium] (ULB 257), Université Libre de Bruxelles [Bruxelles] (ULB)-Hôpital Erasme (Bruxelles), Università degli Studi di Perugia (UNIPG), Technische Universität München [München] (TUM)-Ludwig-Maximilians-Universität München (LMU), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Università degli Studi di Milano-Bicocca [Milano] (UNIMIB), National Research University Higher School of Economics [Moscow] (HSE)-National Research University Higher School of Economics [Moscow] (HSE), Radboud university [Nijmegen], Helmholtz-Zentrum München (HZM), Westfälische Wilhelms-Universität Münster (WWU), The authors thank the staff and participants of all CADISP centers for their important contributions., Service des Urgences Cérébro-Vasculaires [CHU Pitié-Salpétriêre], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Fondation Jean Dausset-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Erasmus MC other, Epidemiology, Debette, S, Kamatani, Y, Metso, T, Kloss, M, Chauhan, G, Engelter, S, Pezzini, A, Thijs, V, Markus, H, Dichgans, M, Wolf, C, Dittrich, R, Touzé, E, Southerland, A, Samson, Y, Abboud, S, Béjot, Y, Caso, V, Bersano, A, Gschwendtner, A, Sessa, M, Cole, J, Lamy, C, Medeiros, E, Beretta, S, Bonati, L, Grau, A, Michel, P, Majersik, J, Sharma, P, Kalashnikova, L, Nazarova, M, Dobrynina, L, Bartels, E, Guillon, B, Van Den Herik, E, Fernandez Cadenas, I, Jood, K, Nalls, M, De Leeuw, F, Jern, C, Cheng, Y, Werner, I, Metso, A, Lichy, C, Lyrer, P, Brandt, T, Boncoraglio, G, Wichmann, H, Gieger, C, Johnson, A, Böttcher, T, Castellano, M, Arveiler, D, Ikram, M, Breteler, M, Padovani, A, Meschia, J, Kuhlenbäumer, G, Rolfs, A, Worrall, B, Ringelstein, E, Zelenika, D, Tatlisumak, T, Lathrop, M, Leys, D, Amouyel, P, Dallongeville, J, Lemmens R, P, and Ferrarese, C
Subjects: Male, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Myocardial Infarction, Genome-wide association study, Carotid Artery, Internal, Dissection, Gastroenterology, epidemiology [Carotid Artery, Internal, Dissection], Brain Ischemia, 0302 clinical medicine, Migraine Disorder, Odds Ratio, Finland, Vertebral Artery Dissection, 0303 health sciences, education.field_of_study, epidemiology [Hypercholesterolemia], MESH: Middle Aged, MESH: Polymorphism, Single Nucleotide, Phactr-1 protein, human, MESH: Brain Ischemia, MESH: Follow-Up Studies, 3. Good health, MESH: Myocardial Infarction, Human, medicine.medical_specialty, Migraine Disorders, Hypercholesterolemia, MESH: Vertebral Artery Dissection, Lower risk, genetics [Brain Ischemia], Article, Follow-Up Studie, MESH: Carotid Artery, Internal, Dissection, 03 medical and health sciences, Genetic, SDG 3 - Good Health and Well-being, genetics [Carotid Artery, Internal, Dissection], Genetics, Genetic predisposition, epidemiology [Brain Ischemia], Humans, epidemiology [Vertebral Artery Dissection], Polymorphism, education, Alleles, MESH: Humans, genetics [Vertebral Artery Dissection], MESH: Adult, Odds ratio, Microfilament Protein, medicine.disease, Adult, Female, Follow-Up Studies, Genetic Pleiotropy, Genetic Predisposition to Disease, Genome-Wide Association Study, Hypertension, Microfilament Proteins, Middle Aged, Obesity, Risk Factors, Polymorphism, Single Nucleotide, MESH: Genome-Wide Association Study, Carotid Artery, MESH: Female, 030217 neurology & neurosurgery, epidemiology [Finland], Cervical Artery, Vertebral artery dissection, epidemiology [Hypertension], MESH: Hypertension, MESH: Risk Factors, MESH: Obesity, Stroke, Allele, Dissection, MESH: Finland, MESH: Genetic Predisposition to Disease, MESH: Hypercholesterolemia, Single Nucleotide, MESH: Migraine Disorders, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], epidemiology [Myocardial Infarction], [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, Population, MESH: Genetic Pleiotropy, physiology [Microfilament Proteins], Biology, MESH: Microfilament Proteins, Internal medicine, ddc:570, medicine, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, 030304 developmental biology, epidemiology [Obesity], Risk Factor, MESH: Alleles, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Internal, MESH: Odds Ratio, MESH: Male, epidemiology [Migraine Disorders], genetics [Microfilament Proteins]
Abstract: Item does not contain fulltext Cervical artery dissection (CeAD), a mural hematoma in a carotid or vertebral artery, is a major cause of ischemic stroke in young adults although relatively uncommon in the general population (incidence of 2.6/100,000 per year). Minor cervical traumas, infection, migraine and hypertension are putative risk factors, and inverse associations with obesity and hypercholesterolemia are described. No confirmed genetic susceptibility factors have been identified using candidate gene approaches. We performed genome-wide association studies (GWAS) in 1,393 CeAD cases and 14,416 controls. The rs9349379[G] allele (PHACTR1) was associated with lower CeAD risk (odds ratio (OR) = 0.75, 95% confidence interval (CI) = 0.69-0.82; P = 4.46 x 10(-10)), with confirmation in independent follow-up samples (659 CeAD cases and 2,648 controls; P = 3.91 x 10(-3); combined P = 1.00 x 10(-11)). The rs9349379[G] allele was previously shown to be associated with lower risk of migraine and increased risk of myocardial infarction. Deciphering the mechanisms underlying this pleiotropy might provide important information on the biological underpinnings of these disabling conditions.
Published: 2015
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23. Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure

Author: Wain, Louise V, Verwoert, Germaine C, O'Reilly, Paul F, Shi, Gang, Johnson, Toby, Johnson, Andrew D, Bochud, Murielle, Rice, Kenneth M, Henneman, Peter, Smith, Albert V, Ehret, Georg B, Amin, Najaf, Larson, Martin G, Mooser, Vincent, Hadley, David, Dörr, Marcus, Bis, Joshua C, Aspelund, Thor, Esko, Tõnu, Janssens, A Cecile JW, Zhao, Jing Hua, Heath, Simon, Laan, Maris, Fu, Jingyuan, Pistis, Giorgio, Luan, Jian'an, Arora, Pankaj, Lucas, Gavin, Pirastu, Nicola, Pichler, Irene, Jackson, Anne U, Webster, Rebecca J, Zhang, Feng, Peden, John F, Schmidt, Helena, Tanaka, Toshiko, Campbell, Harry, Igl, Wilmar, Milaneschi, Yuri, Hottenga, Jouke-Jan, Vitart, Veronique, Chasman, Daniel I, Trompet, Stella, Bragg-Gresham, Jennifer L, Alizadeh, Behrooz Z, Chambers, John C, Guo, Xiuqing, Lehtimäki, Terho, Kühnel, Brigitte, Lopez, Lorna M, Polašek, Ozren, Boban, Mladen, Nelson, Christopher P, Morrison, Alanna C, Pihur, Vasyl, Ganesh, Santhi K, Hofman, Albert, Kundu, Suman, Mattace-Raso, Francesco US, Rivadeneira, Fernando, Sijbrands, Eric JG, Uitterlinden, Andre G, Hwang, Shih-Jen, Vasan, Ramachandran S, Wang, Thomas J, Bergmann, Sven, Vollenweider, Peter, Waeber, Gérard, Laitinen, Jaana, Pouta, Anneli, Zitting, Paavo, McArdle, Wendy L, Kroemer, Heyo K, Völker, Uwe, Völzke, Henry, Glazer, Nicole L, Taylor, Kent D, Harris, Tamara B, Alavere, Helene, Haller, Toomas, Keis, Aime, Tammesoo, Mari-Liis, Aulchenko, Yurii, Barroso, Inês, Khaw, Kay-Tee, Galan, Pilar, Hercberg, Serge, Lathrop, Mark, Eyheramendy, Susana, Org, Elin, Sõber, Siim, Lu, Xiaowen, Nolte, Ilja M, Penninx, Brenda W, Corre, Tanguy, Masciullo, Corrado, Sala, Cinzia, Groop, Leif, Voight, Benjamin F, Melander, Olle, O'Donnell, Christopher J, Salomaa, Veikko, d'Adamo, Adamo Pio, Fabretto, Antonella, Faletra, Flavio, Ulivi, Sheila, Del Greco, Fabiola M, Facheris, Maurizio, Collins, Francis S, Bergman, Richard N, Beilby, John P, Hung, Joseph, Musk, A William, Mangino, Massimo, Shin, So-Youn, Soranzo, Nicole, Watkins, Hugh, Goel, Anuj, Hamsten, Anders, Gider, Pierre, Loitfelder, Marisa, Zeginigg, Marion, Hernandez, Dena, Najjar, Samer S, Navarro, Pau, Wild, Sarah H, Corsi, Anna Maria, Singleton, Andrew, de Geus, Eco JC, Willemsen, Gonneke, Parker, Alex N, Rose, Lynda M, Buckley, Brendan, Stott, David, Orru, Marco, Uda, Manuela, LifeLines Cohort Study, van der Klauw, Melanie M, Zhang, Weihua, Li, Xinzhong, Scott, James, Chen, Yii-Der Ida, Burke, Gregory L, Kähönen, Mika, Viikari, Jorma, Döring, Angela, Meitinger, Thomas, Davies, Gail, Starr, John M, Emilsson, Valur, Plump, Andrew, Lindeman, Jan H, Hoen, Peter AC 't, König, Inke R, EchoGen consortium, Felix, Janine F, Clarke, Robert, Hopewell, Jemma C, Ongen, Halit, Breteler, Monique, Debette, Stéphanie, Destefano, Anita L, Fornage, Myriam, AortaGen Consortium, Mitchell, Gary F, CHARGE Consortium Heart Failure Working Group, Smith, Nicholas L, KidneyGen consortium, Holm, Hilma, Stefansson, Kari, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, CKDGen consortium, Cardiogenics consortium, CardioGram, Samani, Nilesh J, Preuss, Michael, Rudan, Igor, Hayward, Caroline, Deary, Ian J, Wichmann, H-Erich, Raitakari, Olli T, Palmas, Walter, Kooner, Jaspal S, Stolk, Ronald P, Jukema, J Wouter, Wright, Alan F, Boomsma, Dorret I, Bandinelli, Stefania, Gyllensten, Ulf B, Wilson, James F, Ferrucci, Luigi, Schmidt, Reinhold, Farrall, Martin, Spector, Tim D, Palmer, Lyle J, Tuomilehto, Jaakko, Pfeufer, Arne, Gasparini, Paolo, Siscovick, David, Altshuler, David, Loos, Ruth JF, Toniolo, Daniela, Snieder, Harold, Gieger, Christian, Meneton, Pierre, Wareham, Nicholas J, Oostra, Ben A, Metspalu, Andres, Launer, Lenore, Rettig, Rainer, Strachan, David P, Beckmann, Jacques S, Witteman, Jacqueline CM, Erdmann, Jeanette, van Dijk, Ko Willems, Boerwinkle, Eric, Boehnke, Michael, Ridker, Paul M, Jarvelin, Marjo-Riitta, Chakravarti, Aravinda, Abecasis, Goncalo R, Gudnason, Vilmundur, Newton-Cheh, Christopher, Levy, Daniel, Munroe, Patricia B, Psaty, Bruce M, Caulfield, Mark J, Rao, Dabeeru C, Tobin, Martin D, Elliott, Paul, van Duijn, Cornelia M, Zhao, Jing Hua [0000-0003-4930-3582], Luan, Jian'an [0000-0003-3137-6337], Barroso, Ines [0000-0001-5800-4520], Khaw, Kay-Tee [0000-0002-8802-2903], Soranzo, Nicole [0000-0003-1095-3852], Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository
Subjects: Genetic Loci, Case-Control Studies, Hypertension, Humans, Blood Pressure, cardiovascular diseases, Arteries, Polymorphism, Single Nucleotide, Linkage Disequilibrium, circulatory and respiratory physiology, Follow-Up Studies, Genome-Wide Association Study
Abstract: Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.
Published: 2011

24. GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

Author: Franceschini, Nora, Giambartolomei, Claudia, De Vries, Paul S, Finan, Chris, Bis, Joshua C, Huntley, Rachael P, Lovering, Ruth C, Tajuddin, Salman M, Winkler, Thomas W, Graff, Misa, Kavousi, Maryam, Dale, Caroline, Smith, Albert V, Hofer, Edith, Van Leeuwen, Elisabeth M, Nolte, Ilja M, Lu, Lingyi, Scholz, Markus, Sargurupremraj, Muralidharan, Pitkänen, Niina, Franzén, Oscar, Joshi, Peter K, Noordam, Raymond, Marioni, Riccardo E, Hwang, Shih-Jen, Musani, Solomon K, Schminke, Ulf, Palmas, Walter, Isaacs, Aaron, Correa, Adolfo, Zonderman, Alan B, Hofman, Albert, Teumer, Alexander, Cox, Amanda J, Uitterlinden, André G, Wong, Andrew, Smit, Andries J, Newman, Anne B, Britton, Annie, Ruusalepp, Arno, Sennblad, Bengt, Hedblad, Bo, Pasaniuc, Bogdan, Penninx, Brenda W, Langefeld, Carl D, Wassel, Christina L, Tzourio, Christophe, Fava, Cristiano, Baldassarre, Damiano, O'Leary, Daniel H, Teupser, Daniel, Kuh, Diana, Tremoli, Elena, Mannarino, Elmo, Grossi, Enzo, Boerwinkle, Eric, Schadt, Eric E, Ingelsson, Erik, Veglia, Fabrizio, Rivadeneira, Fernando, Beutner, Frank, Chauhan, Ganesh, Heiss, Gerardo, Snieder, Harold, Campbell, Harry, Völzke, Henry, Markus, Hugh S, Deary, Ian J, Jukema, J Wouter, De Graaf, Jacqueline, Price, Jacqueline, Pott, Janne, Hopewell, Jemma C, Liang, Jingjing, Thiery, Joachim, Engmann, Jorgen, Gertow, Karl, Rice, Kenneth, Taylor, Kent D, Dhana, Klodian, Kiemeney, Lambertus ALM, Lind, Lars, Raffield, Laura M, Launer, Lenore J, Holdt, Lesca M, Dörr, Marcus, Dichgans, Martin, Traylor, Matthew, Sitzer, Matthias, Kumari, Meena, Kivimaki, Mika, Nalls, Mike A, Melander, Olle, Raitakari, Olli, Franco, Oscar H, Rueda-Ochoa, Oscar L, Roussos, Panos, Whincup, Peter H, Amouyel, Philippe, Giral, Philippe, Anugu, Pramod, Wong, Quenna, Malik, Rainer, Rauramaa, Rainer, Burkhardt, Ralph, Hardy, Rebecca, Schmidt, Reinhold, De Mutsert, Renée, Morris, Richard W, Strawbridge, Rona J, Wannamethee, S Goya, Hägg, Sara, Shah, Sonia, McLachlan, Stela, Trompet, Stella, Seshadri, Sudha, Kurl, Sudhir, Heckbert, Susan R, Ring, Susan, Harris, Tamara B, Lehtimäki, Terho, Galesloot, Tessel E, Shah, Tina, De Faire, Ulf, Plagnol, Vincent, Rosamond, Wayne D, Post, Wendy, Zhu, Xiaofeng, Zhang, Xiaoling, Guo, Xiuqing, Saba, Yasaman, MEGASTROKE Consortium, Dehghan, Abbas, Seldenrijk, Adrie, Morrison, Alanna C, Hamsten, Anders, Psaty, Bruce M, Van Duijn, Cornelia M, Lawlor, Deborah A, Mook-Kanamori, Dennis O, Bowden, Donald W, Schmidt, Helena, Wilson, James F, Wilson, James G, Rotter, Jerome I, Wardlaw, Joanna M, Deanfield, John, Halcox, Julian, Lyytikäinen, Leo-Pekka, Loeffler, Markus, Evans, Michele K, Debette, Stéphanie, Humphries, Steve E, Völker, Uwe, Gudnason, Vilmundur, Hingorani, Aroon D, Björkegren, Johan LM, Casas, Juan P, and O'Donnell, Christopher J
Subjects: Quantitative Trait Loci, ADAMTS9 Protein, Coronary Disease, Carotid Intima-Media Thickness, Polymorphism, Single Nucleotide, Plaque, Atherosclerotic, 3. Good health, Protein-Lysine 6-Oxidase, Risk Factors, cardiovascular system, Humans, Genetic Predisposition to Disease, cardiovascular diseases, Amino Acid Oxidoreductases, Lod Score, Genome-Wide Association Study
Abstract: Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

25. Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke

Author: Cole, John W, Xu, Huichun, Ryan, Kathleen, Jaworek, Thomas, Dueker, Nicole, McArdle, Patrick, Gaynor, Brady, Cheng, Yu-Ching, O'Connell, Jeffrey, Bevan, Steve, Malik, Rainer, Ahmed, Naveed Uddin, Amouyel, Philippe, Anjum, Sheraz, Bis, Joshua C, Crosslin, David, Danesh, John, Engelter, Stefan T, Fornage, Myriam, Frossard, Philippe, Gieger, Christian, Giese, Anne-Katrin, Grond-Ginsbach, Caspar, Ho, Weang Kee, Holliday, Elizabeth, Hopewell, Jemma, Hussain, M, Iqbal, W, Jabeen, S, Jannes, Jim, Kamal, Ayeesha, Kamatani, Yoichiro, Kanse, Sandip, Kloss, Manja, Lathrop, Mark, Leys, Didier, Lindgren, Arne, Longstreth, WT, Mahmood, Khalid, Meisinger, Christa, Metso, Tiina M, Mosley, Thomas, Müller-Nurasyid, Martina, Norrving, Bo, Parati, Eugenio, Peters, Annette, Pezzini, Alessandro, Quereshi, I, Rasheed, Asif, Rauf, A, Salam, T, Shen, Jess, Słowik, Agnieszka, Stanne, Tara, Strauch, Konstantin, Tatlisumak, Turgut, Thijs, Vincent N, Tiedt, Steffen, Traylor, Matthew, Waldenberger, Melanie, Walters, Matthew, Zhao, Wei, Boncoraglio, Giorgio, Debette, Stéphanie, Jern, Christina, Levi, Christopher, Markus, Hugh, Meschia, James, Rolfs, Arndt, Rothwell, Peter, Saleheen, Danish, Seshadri, Sudha, Sharma, Pankaj, Sudlow, Cathie, Worrall, Bradford, METASTROKE Consortium Of The ISGC, WTCCC-2 Consortium, Stine, O Colin, Kittner, Steven J, and Mitchell, Braxton D
Subjects: Adult, Male, Adolescent, Thrombomodulin, Endothelial Protein C Receptor, Middle Aged, Polymorphism, Single Nucleotide, White People, 3. Good health, Brain Ischemia, Black or African American, Stroke, Young Adult, Case-Control Studies, Humans, Female, Genetic Predisposition to Disease, Age of Onset, Genetic Association Studies
Abstract: BACKGROUND AND PURPOSE: Polymorphisms in coagulation genes have been associated with early-onset ischemic stroke. Here we pursue an a priori hypothesis that genetic variation in the endothelial-based receptors of the thrombomodulin-protein C system (THBD and PROCR) may similarly be associated with early-onset ischemic stroke. We explored this hypothesis utilizing a multi-stage design of discovery and replication. METHODS: Discovery was performed in the Genetics-of-Early-Onset Stroke (GEOS) Study, a biracial population-based case-control study of ischemic stroke among men and women aged 15-49 including 829 cases of first ischemic stroke (42.2% African-American) and 850 age-comparable stroke-free controls (38.1% African-American). Twenty-four single-nucleotide-polymorphisms (SNPs) in THBD and 22 SNPs in PROCR were evaluated. Following LD pruning (r2≥0.8), we advanced uncorrelated SNPs forward for association analyses. Associated SNPs were evaluated for replication in an early-onset ischemic stroke population (onset-age

26. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Author: Davies, Gail, Lam, Max, Harris, Sarah E, Trampush, Joey W, Luciano, Michelle, Hill, W David, Hagenaars, Saskia P, Ritchie, Stuart J, Marioni, Riccardo E, Fawns-Ritchie, Chloe, Liewald, David CM, Okely, Judith A, Ahola-Olli, Ari V, Barnes, Catriona LK, Bertram, Lars, Bis, Joshua C, Burdick, Katherine E, Christoforou, Andrea, DeRosse, Pamela, Djurovic, Srdjan, Espeseth, Thomas, Giakoumaki, Stella, Giddaluru, Sudheer, Gustavson, Daniel E, Hayward, Caroline, Hofer, Edith, Ikram, M Arfan, Karlsson, Robert, Knowles, Emma, Lahti, Jari, Leber, Markus, Li, Shuo, Mather, Karen A, Melle, Ingrid, Morris, Derek, Oldmeadow, Christopher, Palviainen, Teemu, Payton, Antony, Pazoki, Raha, Petrovic, Katja, Reynolds, Chandra A, Sargurupremraj, Muralidharan, Scholz, Markus, Smith, Jennifer A, Smith, Albert V, Terzikhan, Natalie, Thalamuthu, Anbupalam, Trompet, Stella, Van Der Lee, Sven J, Ware, Erin B, Windham, B Gwen, Wright, Margaret J, Yang, Jingyun, Yu, Jin, Ames, David, Amin, Najaf, Amouyel, Philippe, Andreassen, Ole A, Armstrong, Nicola J, Assareh, Amelia A, Attia, John R, Attix, Deborah, Avramopoulos, Dimitrios, Bennett, David A, Böhmer, Anne C, Boyle, Patricia A, Brodaty, Henry, Campbell, Harry, Cannon, Tyrone D, Cirulli, Elizabeth T, Congdon, Eliza, Conley, Emily Drabant, Corley, Janie, Cox, Simon R, Dale, Anders M, Dehghan, Abbas, Dick, Danielle, Dickinson, Dwight, Eriksson, Johan G, Evangelou, Evangelos, Faul, Jessica D, Ford, Ian, Freimer, Nelson A, Gao, He, Giegling, Ina, Gillespie, Nathan A, Gordon, Scott D, Gottesman, Rebecca F, Griswold, Michael E, Gudnason, Vilmundur, Harris, Tamara B, Hartmann, Annette M, Hatzimanolis, Alex, Heiss, Gerardo, Holliday, Elizabeth G, Joshi, Peter K, Kähönen, Mika, Kardia, Sharon LR, Karlsson, Ida, Kleineidam, Luca, Knopman, David S, Kochan, Nicole A, Konte, Bettina, Kwok, John B, Le Hellard, Stephanie, Lee, Teresa, Lehtimäki, Terho, Li, Shu-Chen, Liu, Tian, Koini, Marisa, London, Edythe, Longstreth, Will T, Lopez, Oscar L, Loukola, Anu, Luck, Tobias, Lundervold, Astri J, Lundquist, Anders, Lyytikäinen, Leo-Pekka, Martin, Nicholas G, Montgomery, Grant W, Murray, Alison D, Need, Anna C, Noordam, Raymond, Nyberg, Lars, Ollier, William, Papenberg, Goran, Pattie, Alison, Polasek, Ozren, Poldrack, Russell A, Psaty, Bruce M, Reppermund, Simone, Riedel-Heller, Steffi G, Rose, Richard J, Rotter, Jerome I, Roussos, Panos, Rovio, Suvi P, Saba, Yasaman, Sabb, Fred W, Sachdev, Perminder S, Satizabal, Claudia L, Schmid, Matthias, Scott, Rodney J, Scult, Matthew A, Simino, Jeannette, Slagboom, P Eline, Smyrnis, Nikolaos, Soumaré, Aïcha, Stefanis, Nikos C, Stott, David J, Straub, Richard E, Sundet, Kjetil, Taylor, Adele M, Taylor, Kent D, Tzoulaki, Ioanna, Tzourio, Christophe, Uitterlinden, André, Vitart, Veronique, Voineskos, Aristotle N, Kaprio, Jaakko, Wagner, Michael, Wagner, Holger, Weinhold, Leonie, Wen, K Hoyan, Widen, Elisabeth, Yang, Qiong, Zhao, Wei, Adams, Hieab HH, Arking, Dan E, Bilder, Robert M, Bitsios, Panos, Boerwinkle, Eric, Chiba-Falek, Ornit, Corvin, Aiden, De Jager, Philip L, Debette, Stéphanie, Donohoe, Gary, Elliott, Paul, Fitzpatrick, Annette L, Gill, Michael, Glahn, David C, Hägg, Sara, Hansell, Narelle K, Hariri, Ahmad R, Ikram, M Kamran, Jukema, J Wouter, Vuoksimaa, Eero, Keller, Matthew C, Kremen, William S, Launer, Lenore, Lindenberger, Ulman, Palotie, Aarno, Pedersen, Nancy L, Pendleton, Neil, Porteous, David J, Räikkönen, Katri, Raitakari, Olli T, Ramirez, Alfredo, Reinvang, Ivar, Rudan, Igor, Rujescu, Dan, Schmidt, Reinhold, Schmidt, Helena, Schofield, Peter W, Schofield, Peter R, Starr, John M, Steen, Vidar M, Trollor, Julian N, Turner, Steven T, Van Duijn, Cornelia M, Villringer, Arno, Weinberger, Daniel R, Weir, David R, Wilson, James F, Malhotra, Anil, McIntosh, Andrew M, Gale, Catharine R, Seshadri, Sudha, Mosley, Thomas H, Bressler, Jan, Lencz, Todd, and Deary, Ian J
Subjects: quantitative trait, cognitive neuroscience, genetics of the nervous system, genome-wide association studies, 3. Good health
Abstract: General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

27. Association of anthropometry and weight change with risk of dementia and its major subtypes: A meta-analysis consisting 2.8 million adults with 57 294 cases of dementia

Author: Lee, Crystal ManYing, Woodward, Mark, Batty, G David, Beiser, Alexa S, Bell, Steven, Berr, Claudine, Bjertness, Espen, Chalmers, John, Clarke, Robert, Dartigues, Jean-Francois, Davis-Plourde, Kendra, Debette, Stéphanie, Di Angelantonio, Emanuele, Feart, Catherine, Frikke-Schmidt, Ruth, Gregson, John, Haan, Mary N, Hassing, Linda B, Hayden, Kathleen M, Hoevenaar-Blom, Marieke P, Kaprio, Jaakko, Kivimaki, Mika, Lappas, Georgios, Larson, Eric B, LeBlanc, Erin S, Lee, Anne, Lui, Li-Yung, Moll Van Charante, Eric P, Ninomiya, Toshiharu, Nordestgaard, Liv Tybjaerg, Ohara, Tomoyuki, Ohkuma, Toshiaki, Palviainen, Teemu, Peres, Karine, Peters, Ruth, Qizilbash, Nawab, Richard, Edo, Rosengren, Annika, Seshadri, Sudha, Shipley, Martin, Singh-Manoux, Archana, Strand, Bjorn Heine, Van Gool, Willem A, Vuoksimaa, Eero, Yaffe, Kristine, and Huxley, Rachel R
Subjects: 2. Zero hunger, Adult, Male, Anthropometry, Dementia, Vascular, Body Weight, Middle Aged, Weight Gain, 3. Good health, Body Mass Index, Thinness, Risk Factors, mental disorders, Weight Loss, Body Size, Humans, Dementia, Female, Obesity, Waist Circumference, Aged
Abstract: Uncertainty exists regarding the relation of body size and weight change with dementia risk. As populations continue to age and the global obesity epidemic shows no sign of waning, reliable quantification of such associations is important. We examined the relationship of body mass index, waist circumference, and annual percent weight change with risk of dementia and its subtypes by pooling data from 19 prospective cohort studies and four clinical trials using meta-analysis. Compared with body mass index-defined lower-normal weight (18.5-22.4 kg/m2 ), the risk of all-cause dementia was higher among underweight individuals but lower among those with upper-normal (22.5-24.9 kg/m2 ) levels. Obesity was associated with higher risk in vascular dementia. Similarly, relative to the lowest fifth of waist circumference, those in the highest fifth had nonsignificant higher vascular dementia risk. Weight loss was associated with higher all-cause dementia risk relative to weight maintenance. Weight gain was weakly associated with higher vascular dementia risk. The relationship between body size, weight change, and dementia is complex and exhibits non-linear associations depending on dementia subtype under scrutiny. Weight loss was associated with an elevated risk most likely due to reverse causality and/or pathophysiological changes in the brain, although the latter remains speculative.

28. Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis

Author: Rhodes, Christopher J, Batai, Ken, Bleda, Marta, Haimel, Matthias, Southgate, Laura, Germain, Marine, Pauciulo, Michael W, Hadinnapola, Charaka, Aman, Jurjan, Girerd, Barbara, Arora, Amit, Knight, Jo, Hanscombe, Ken B, Karnes, Jason H, Kaakinen, Marika, Gall, Henning, Ulrich, Anna, Harbaum, Lars, Cebola, Inês, Ferrer, Jorge, Lutz, Katie, Swietlik, Emilia M, Ahmad, Ferhaan, Amouyel, Philippe, Archer, Stephen L, Argula, Rahul, Austin, Eric D, Badesch, David, Bakshi, Sahil, Barnett, Christopher, Benza, Raymond, Bhatt, Nitin, Bogaard, Harm J, Burger, Charles D, Chakinala, Murali, Church, Colin, Coghlan, John G, Condliffe, Robin, Corris, Paul A, Danesino, Cesare, Debette, Stéphanie, Elliott, C Gregory, Elwing, Jean, Eyries, Melanie, Fortin, Terry, Franke, Andre, Frantz, Robert P, Frost, Adaani, Garcia, Joe GN, Ghio, Stefano, Ghofrani, Hossein-Ardeschir, Gibbs, J Simon R, Harley, John, He, Hua, Hill, Nicholas S, Hirsch, Russel, Houweling, Arjan C, Howard, Luke S, Ivy, Dunbar, Kiely, David G, Klinger, James, Kovacs, Gabor, Lahm, Tim, Laudes, Matthias, Machado, Rajiv D, MacKenzie Ross, Robert V, Marsolo, Keith, Martin, Lisa J, Moledina, Shahin, Montani, David, Nathan, Steven D, Newnham, Michael, Olschewski, Andrea, Olschewski, Horst, Oudiz, Ronald J, Ouwehand, Willem H, Peacock, Andrew J, Pepke-Zaba, Joanna, Rehman, Zia, Robbins, Ivan, Roden, Dan M, Rosenzweig, Erika B, Saydain, Ghulam, Scelsi, Laura, Schilz, Robert, Seeger, Werner, Shaffer, Christian M, Simms, Robert W, Simon, Marc, Sitbon, Olivier, Suntharalingam, Jay, Tang, Haiyang, Tchourbanov, Alexander Y, Thenappan, Thenappan, Torres, Fernando, Toshner, Mark R, Treacy, Carmen M, Vonk Noordegraaf, Anton, Waisfisz, Quinten, Walsworth, Anna K, Walter, Robert E, Wharton, John, White, R James, Wilt, Jeffrey, Wort, Stephen J, Yung, Delphine, Lawrie, Allan, Humbert, Marc, Soubrier, Florent, Trégouët, David-Alexandre, Prokopenko, Inga, Kittles, Richard, Gräf, Stefan, Nichols, William C, Trembath, Richard C, Desai, Ankit A, Morrell, Nicholas W, Wilkins, Martin R, UK NIHR BioResource Rare Diseases Consortium, UK PAH Cohort Study Consortium, and US PAH Biobank Consortium
Subjects: Male, Pulmonary Arterial Hypertension, Genotyping Techniques, Genetic Variation, HLA-DP alpha-Chains, Middle Aged, Polymorphism, Single Nucleotide, Risk Assessment, Survival Analysis, 3. Good health, SOXF Transcription Factors, Humans, Female, Genetic Predisposition to Disease, HLA-DP beta-Chains, Genome-Wide Association Study, Signal Transduction
Abstract: BACKGROUND: Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. METHODS: We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. FINDINGS: A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55-2·08], p=5·13 × 10-15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42-1·71], p=7·65 × 10-20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25-1·48], p=1·69 × 10-12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02-8·05]), despite similar baseline disease severity. INTERPRETATION: This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials. FUNDING: UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR.

29. Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting

Author: Chauhan, Ganesh, Adams, Hieab HH, Satizabal, Claudia L, Bis, Joshua C, Teumer, Alexander, Sargurupremraj, Muralidharan, Hofer, Edith, Trompet, Stella, Hilal, Saima, Smith, Albert Vernon, Jian, Xueqiu, Malik, Rainer, Traylor, Matthew, Pulit, Sara L, Amouyel, Philippe, Mazoyer, Bernard, Zhu, Yi-Cheng, Kaffashian, Sara, Schilling, Sabrina, Beecham, Gary W, Montine, Thomas J, Schellenberg, Gerard D, Kjartansson, Olafur, Guðnason, Vilmundur, Knopman, David S, Griswold, Michael E, Windham, B Gwen, Gottesman, Rebecca F, Mosley, Thomas H, Schmidt, Reinhold, Saba, Yasaman, Schmidt, Helena, Takeuchi, Fumihiko, Yamaguchi, Shuhei, Nabika, Toru, Kato, Norihiro, Rajan, Kumar B, Aggarwal, Neelum T, De Jager, Philip L, Evans, Denis A, Psaty, Bruce M, Rotter, Jerome I, Rice, Kenneth, Lopez, Oscar L, Liao, Jiemin, Chen, Christopher, Cheng, Ching-Yu, Wong, Tien Y, Ikram, Mohammad K, Van Der Lee, Sven J, Amin, Najaf, Chouraki, Vincent, DeStefano, Anita L, Aparicio, Hugo J, Romero, Jose R, Maillard, Pauline, DeCarli, Charles, Wardlaw, Joanna M, Hernández, Maria Del C Valdés, Luciano, Michelle, Liewald, David, Deary, Ian J, Starr, John M, Bastin, Mark E, Muñoz Maniega, Susana, Slagboom, P Eline, Beekman, Marian, Deelen, Joris, Uh, Hae-Won, Lemmens, Robin, Brodaty, Henry, Wright, Margaret J, Ames, David, Boncoraglio, Giorgio B, Hopewell, Jemma C, Beecham, Ashley H, Blanton, Susan H, Wright, Clinton B, Sacco, Ralph L, Wen, Wei, Thalamuthu, Anbupalam, Armstrong, Nicola J, Chong, Elizabeth, Schofield, Peter R, Kwok, John B, Van Der Grond, Jeroen, Stott, David J, Ford, Ian, Jukema, J Wouter, Vernooij, Meike W, Hofman, Albert, Uitterlinden, André G, Van Der Lugt, Aad, Wittfeld, Katharina, Grabe, Hans J, Hosten, Norbert, Von Sarnowski, Bettina, Völker, Uwe, Levi, Christopher, Jimenez-Conde, Jordi, Sharma, Pankaj, Sudlow, Cathie LM, Rosand, Jonathan, Woo, Daniel, Cole, John W, Meschia, James F, Slowik, Agnieszka, Thijs, Vincent, Lindgren, Arne, Melander, Olle, Grewal, Raji P, Rundek, Tatjana, Rexrode, Kathy, Rothwell, Peter M, Arnett, Donna K, Jern, Christina, Johnson, Julie A, Benavente, Oscar R, Wasssertheil-Smoller, Sylvia, Lee, Jin-Moo, Wong, Quenna, Mitchell, Braxton D, Rich, Stephen S, McArdle, Patrick F, Geerlings, Mirjam I, Van Der Graaf, Yolanda, De Bakker, Paul IW, Asselbergs, Folkert W, Srikanth, Velandai, Thomson, Russell, McWhirter, Rebekah, Moran, Chris, Callisaya, Michele, Phan, Thanh, Rutten-Jacobs, Loes CA, Bevan, Steve, Tzourio, Christophe, Mather, Karen A, Sachdev, Perminder S, Van Duijn, Cornelia M, Worrall, Bradford B, Dichgans, Martin, Kittner, Steven J, Markus, Hugh S, Ikram, Mohammad A, Fornage, Myriam, Launer, Lenore J, Seshadri, Sudha, Longstreth, WT, Debette, Stéphanie, and Stroke Genetics Network (SiGN), The International Stroke Genetics Consortium (ISGC), METASTROKE, Alzheimer's Disease Genetics Consortium (ADGC), And The Neurology Working Group Of The Cohorts For Heart And Aging Research In Genomic Epidemiology (CHARGE) Consortium
Subjects: 2. Zero hunger, Stroke Genetics Network (SiGN), the International Stroke Genetics Consortium (ISGC), METASTROKE, Alzheimer's Disease Genetics Consortium (ADGC), and the Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, 3. Good health
Abstract: OBJECTIVE: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. METHODS: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. RESULTS: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10-8; and LINC00539/ZDHHC20, p = 5.82 × 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p [BI] = 9.38 × 10-25; p [SSBI] = 5.23 × 10-14 for hypertension), smoking (p [BI] = 4.4 × 10-10; p [SSBI] = 1.2 × 10-4), diabetes (p [BI] = 1.7 × 10-8; p [SSBI] = 2.8 × 10-3), previous cardiovascular disease (p [BI] = 1.0 × 10-18; p [SSBI] = 2.3 × 10-7), stroke (p [BI] = 3.9 × 10-69; p [SSBI] = 3.2 × 10-24), and MRI-defined white matter hyperintensity burden (p [BI] = 1.43 × 10-157; p [SSBI] = 3.16 × 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy. CONCLUSION: In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.

30. Trans-ethnic association study of blood pressure determinants in over 750,000 individuals

Author: Giri, Ayush, Hellwege, Jacklyn N, Keaton, Jacob M, Park, Jihwan, Qiu, Chengxiang, Warren, Helen R, Torstenson, Eric S, Kovesdy, Csaba P, Sun, Yan V, Wilson, Otis D, Robinson-Cohen, Cassianne, Roumie, Christianne L, Chung, Cecilia P, Birdwell, Kelly A, Damrauer, Scott M, DuVall, Scott L, Klarin, Derek, Cho, Kelly, Wang, Yu, Evangelou, Evangelos, Cabrera, Claudia P, Wain, Louise V, Shrestha, Rojesh, Mautz, Brian S, Akwo, Elvis A, Sargurupremraj, Muralidharan, Debette, Stéphanie, Boehnke, Michael, Scott, Laura J, Luan, Jian'an, Zhao, Jing-Hua, Willems, Sara M, Thériault, Sébastien, Shah, Nabi, Oldmeadow, Christopher, Almgren, Peter, Li-Gao, Ruifang, Verweij, Niek, Boutin, Thibaud S, Mangino, Massimo, Ntalla, Ioanna, Feofanova, Elena, Surendran, Praveen, Cook, James P, Karthikeyan, Savita, Lahrouchi, Najim, Liu, Chunyu, Sepúlveda, Nuno, Richardson, Tom G, Kraja, Aldi, Amouyel, Philippe, Farrall, Martin, Poulter, Neil R, Understanding Society Scientific Group, International Consortium For Blood Pressure, Blood Pressure-International Consortium Of Exome Chip Studies, Laakso, Markku, Zeggini, Eleftheria, Sever, Peter, Scott, Robert A, Langenberg, Claudia, Wareham, Nicholas J, Conen, David, Palmer, Colin Neil Alexander, Attia, John, Chasman, Daniel I, Ridker, Paul M, Melander, Olle, Mook-Kanamori, Dennis Owen, Harst, Pim Van Der, Cucca, Francesco, Schlessinger, David, Hayward, Caroline, Spector, Tim D, Jarvelin, Marjo-Riitta, Hennig, Branwen J, Timpson, Nicholas J, Wei, Wei-Qi, Smith, Joshua C, Xu, Yaomin, Matheny, Michael E, Siew, Edward E, Lindgren, Cecilia, Herzig, Karl-Heinz, Dedoussis, George, Denny, Joshua C, Psaty, Bruce M, Howson, Joanna MM, Munroe, Patricia B, Newton-Cheh, Christopher, Caulfield, Mark J, Elliott, Paul, Gaziano, J Michael, Concato, John, Wilson, Peter WF, Tsao, Philip S, Velez Edwards, Digna R, Susztak, Katalin, Million Veteran Program, O'Donnell, Christopher J, Hung, Adriana M, and Edwards, Todd L
Subjects: Male, Adolescent, Gene Expression, Blood Pressure, Middle Aged, Polymorphism, Single Nucleotide, 3. Good health, Up-Regulation, Mice, Kidney Tubules, Ethnicity, Animals, Humans, Female, Transcriptome, Genome-Wide Association Study
Abstract: In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.

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30 results on '"Debette, Stéphanie"'

1. Genome-wide association meta-analysis of spontaneous coronary artery dissection identifies risk variants and genes related to artery integrity and tissue-mediated coagulation

2. Genome-wide association meta-analysis of spontaneous coronary artery dissection identifies risk variants and genes related to artery integrity and tissue-mediated coagulation

3. Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease

4. Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease

5. Author Correction: Genetic investigation of fibromuscular dysplasia identifies risk loci and shared genetics with common cardiovascular diseases

6. Stroke Genetics: Discovery, Insight Into Mechanisms, and Clinical Perspectives

7. Outcome associated with prescription of cardiac rehabilitation according to predicted risk after acute myocardial infarction: Insights from the FAST-MI registries

8. sj-pdf-1-wso-10.1177_17474930211007288 - Supplemental material for International stroke genetics consortium recommendations for studies of genetics of stroke outcome and recovery

9. sj-pdf-1-wso-10.1177_17474930211007288 - Supplemental material for International stroke genetics consortium recommendations for studies of genetics of stroke outcome and recovery

10. sj-pdf-3-wso-10.1177_17474930211007288 - Supplemental material for International stroke genetics consortium recommendations for studies of genetics of stroke outcome and recovery

11. sj-pdf-3-wso-10.1177_17474930211007288 - Supplemental material for International stroke genetics consortium recommendations for studies of genetics of stroke outcome and recovery

12. Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors

13. Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as novel risk factors for Alzheimer’s Disease

14. Cerebral small vessel disease genomics and its implications across the lifespan

15. Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis

16. Clinical Significance of Magnetic Resonance Imaging Markers of Vascular Brain Injury

17. Fibromuscular Dysplasia and Its Neurologic Manifestations

18. Author Correction: Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors

19. Genetic determinants of risk and survival in pulmonary arterial hypertension

20. Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure

21. Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI

22. Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection

23. Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure

24. GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

25. Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke

26. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

27. Association of anthropometry and weight change with risk of dementia and its major subtypes: A meta-analysis consisting 2.8 million adults with 57 294 cases of dementia

28. Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis

29. Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting

30. Trans-ethnic association study of blood pressure determinants in over 750,000 individuals

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