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1. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

Author

Malik, Rainer, Chauhan, Ganesh, Traylor, Matthew, Sargurupremraj, Muralidharan, Okada, Yukinori, Mishra, Aniket, Rutten-Jacobs, Loes, Giese, Anne-Katrin, van der Laan, Sander W, Gretarsdottir, Solveig, Anderson, Christopher D, Chong, Michael, Adams, Hieab HH, Ago, Tetsuro, Almgren, Peter, Amouyel, Philippe, Ay, Hakan, Bartz, Traci M, Benavente, Oscar R, Bevan, Steve, Boncoraglio, Giorgio B, Brown, Robert D, Butterworth, Adam S, Carrera, Caty, Carty, Cara L, Chasman, Daniel I, Chen, Wei-Min, Cole, John W, Correa, Adolfo, Cotlarciuc, Ioana, Cruchaga, Carlos, Danesh, John, de Bakker, Paul IW, DeStefano, Anita L, den Hoed, Marcel, Duan, Qing, Engelter, Stefan T, Falcone, Guido J, Gottesman, Rebecca F, Grewal, Raji P, Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeffrey, Harris, Tamara B, Hassan, Ahamad, Havulinna, Aki S, Heckbert, Susan R, Holliday, Elizabeth G, Howard, George, Hsu, Fang-Chi, Hyacinth, Hyacinth I, Ikram, M Arfan, Ingelsson, Erik, Irvin, Marguerite R, Jian, Xueqiu, Jiménez-Conde, Jordi, Johnson, Julie A, Jukema, J Wouter, Kanai, Masahiro, Keene, Keith L, Kissela, Brett M, Kleindorfer, Dawn O, Kooperberg, Charles, Kubo, Michiaki, Lange, Leslie A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lee, Jin-Moo, Lemmens, Robin, Leys, Didier, Lewis, Cathryn M, Lin, Wei-Yu, Lindgren, Arne G, Lorentzen, Erik, Magnusson, Patrik K, Maguire, Jane, Manichaikul, Ani, McArdle, Patrick F, Meschia, James F, Mitchell, Braxton D, Mosley, Thomas H, Nalls, Michael A, Ninomiya, Toshiharu, O’Donnell, Martin J, Psaty, Bruce M, Pulit, Sara L, Rannikmäe, Kristiina, Reiner, Alexander P, Rexrode, Kathryn M, Rice, Kenneth, Rich, Stephen S, Ridker, Paul M, Rost, Natalia S, Rothwell, Peter M, Rotter, Jerome I, Rundek, Tatjana, Sacco, Ralph L, Sakaue, Saori, and Sale, Michele M

Subjects
Biological Sciences, Genetics, Human Genome, Stroke, Clinical Research, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Cardiovascular, Computational Biology, Databases, Genetic, Epigenesis, Genetic, Female, Gene Regulatory Networks, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, INDEL Mutation, Linkage Disequilibrium, Male, Models, Genetic, Polymorphism, Single Nucleotide, Risk Factors, AFGen Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, International Genomics of Blood Pressure (iGEN-BP) Consortium, INVENT Consortium, STARNET, BioBank Japan Cooperative Hospital Group, COMPASS Consortium, EPIC-CVD Consortium, EPIC-InterAct Consortium, International Stroke Genetics Consortium, METASTROKE Consortium, Neurology Working Group of the CHARGE Consortium, NINDS Stroke Genetics Network, UK Young Lacunar DNA Study, MEGASTROKE Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

Published
2018

2. Association of Apolipoprotein e with Intracerebral Hemorrhage Risk by Race/Ethnicity : A Meta-analysis

Author

Marini, Sandro, Crawford, Katherine, Morotti, Andrea, Lee, Myung J, Pezzini, Alessandro, Moomaw, Charles J, Flaherty, Matthew L, Montaner, Joan, Roquer, Jaume, Jimenez-Conde, Jordi, Giralt-Steinhauer, Eva, Elosua, Roberto, Cuadrado-Godia, Elisa, Soriano-Tarraga, Carolina, Slowik, Agnieszka, Jagiella, Jeremiasz M, Pera, Joanna, Urbanik, Andrzej, Pichler, Alexander, Hansen, Bjorn M, McCauley, Jacob L, Tirschwell, David L, Selim, Magdy, Brown, Devin L, Silliman, Scott L, Worrall, Bradford B, Meschia, James F, Kidwell, Chelsea S, Testai, Fernando D, Kittner, Steven J, Schmidt, Helena, Enzinger, Christian, Deary, Lan J, Rannikmae, Kristiina, Samarasekera, Neshika, Salman, Rustam Al-Shahi, Sudlow, Catherine L, Klijn, Catharina JM, van Nieuwenhuizen, Koen M, Fernandez-Cadenas, Israel, Delgado, Pilar, Nonving, Bo, Lindgren, Ame, Goldstein, Joshua N, Viswanathan, Anand, Greenberg, Steven M, Falcone, Guido J, Biffi, Alessandro, Langefeld, Carl D, Woo, Daniel, Rosand, Jonathan, Anderson, Christopher D, Smoller, Sylvia, Sorkin, John, Wang, Xingwu, Pikula, Aleksandra, Wolf, Philip, Debette, Stephanie, Seshadri, Sudha, de Bakker, Paul, Chasman, Daniel, Rexrode, Kathryn, Chen, Ida, Rotter, Jerome, Luke, May, Sale, Michelle, Lee, Tsong-Hai, Chang, Ku-Chou, Elkind, Mitchell, Goldstein, Larry, James, Michael Luke, Breteler, Monique, O'Donnell, Chris, Leys, Didier, Carty, Cara, Kidwell, Chelsea, Olesen, Jes, Sharma, Pankaj, Rich, Stephen, Tatlisumak, Turgot, Happola, Olli, Bijlenga, Philippe, Soriano, Carolina, Giralt, Eva, Cotlarcius, Loana, Hardy, John, Korostynski, Michal, Boncoraglio, Giorgio, Ballabio, Elena, Parati, Eugenio, Mateusz, Adamski, Dziedzic, Tomasz, Jagiella, Jeremiasz, Gasowski, Jerzy, Wnuk, Marcin, Olszanecki, Rafaf, Juchniewicz, Karol Jozef, Levi, Christopher, Nyquist, Paul, Cendes, Iscia, Cabral, Norberto, Franca, Paulo, Goncalves, Anderson, Keller, Lina, Crisby, Milita, Kostulas, Konstantinos, Lennnnens, Robin, Ahmadi, Kourosh, Opherk, Christian, Duering, Marco, Dichgans, Martin, Malik, Rainer, Gonik, Mariya, Staals, Julie, Melander, Olle, Burri, Philippe, Sadr-Nabavi, Ariane, Romero, Javier, Anderson, Chris, Falcone, Guido, Brouwers, Bart, Rost, Natalia, Du, Rose, Kourkoulis, Christina, Battey, Thomas, Lubitz, Steven, Mueller-Myhsok, Bertram, Meschia, James, Brott, Thomas, Pare, Guillaume, Schmidt, Reinhold, Seiler, Stephan, Blanton, Susan, Yamada, Yoshiji, Bersano, Anna, Rundek, Tatiana, Sacco, Ralph, Chan, Yu-Feng Yvonne, Gschwendtner, Andreas, Deng, Zhen, Barr, Taura, Gwinn, Katrina, Corriveau, Roderick, Singleton, Andrew, Waddy, Salina, Launer, Lenore, Chen, Christopher, Le, Kim En, Lee, Wei Ling, Tan, Eng King, Olugbodi, Akintomi, Rothwell, Peter, Schilling, Sabrina, Mok, Vincent, Lebedeva, Elena, Jem, Christina, Jood, Katarina, Olsson, Sandra, Kim, Helen, Lee, Chaeyoung, Kilarski, Laura, Markus, Hugh, Peycke, Jennifer, Bevan, Steve, Sheu, Wayne, Chiou, Hung Yi, Chern, Joseph, Giraldo, Elias, Taqi, Muhammad, Jain, Vivek, Lam, Olivia, Howard, George, Kittner, Steven, Mitchell, Braxton, Cole, John, O'Connell, Jeff, Milewicz, Dianna, Illoh, Kachikwu, Worrall, Bradford, Stine, Colin, Karaszewski, Bartosz, Werring, David, Sofat, Reecha, Smalley, June, Lindgren, Arne, Hansen, Bjorn, Norrving, Bo, Smith, Gustav, Martin, Juan Jose, Thijs, Vincent, Klijn, Karin, van't Hof, Femke, Algra, Ale, Macleod, Mary, Perry, Rodney, Arnett, Donna, Padovani, Alessandro, Cramer, Steve, Fisher, Marl, Saleheen, Danish, Broderick, Joseph, Kissela, Brett, Doney, Alex, Sudlow, Cathie, Silliman, Scott, McDonough, Caitrin, Walters, Matthew, Pedersen, Annie, Nakagawa, Kazuma, Chang, Christy, Dobbins, Mark, McArdle, Patrick, Chang, Yu-Ching, Brown, Robert, Brown, Devin, Holliday, Elizabeth, Kalaria, Raj, Maguire, Jane, Hunter, John, Attia, John, Farrall, Martin, Giese, Anne-Katrin, Fomage, Myriam, Majersik, Jennifer, Cushman, Maly, Keene, Keith, Bennett, Siiri, Tirschwell, David, Psaty, Bruce, Reiner, Alex, Longstreth, Will, Spence, David, Langefeld, Carl, Bushnell, Cheryl, Heitsch, Laura, Lee, Jin-Moo, Sheth, Kevin, Consortium, Int Genetics, Neurologian yksikkö, Department of Neurosciences, Clinicum, Doctoral Programme in Clinical Research, HUS Neurocenter, RS: Carim - B05 Cerebral small vessel disease, RS: CARIM - R3.03 - Cerebral small vessel disease, and Epidemiology

Subjects
Male, Race ethnicity, Hemorràgia cerebral, 3124 Neurology and psychiatry, 0302 clinical medicine, Risk Factors, WHITES, BLACKS, 030212 general & internal medicine, Biological sciences, Original Investigation, ALZHEIMER-DISEASE, African Americans, Aged, 80 and over, GENETIC-VARIATION, Hispanic or Latino, Middle Aged, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Medical research, University hospital, 3. Good health, ETHNICITY, ALLELE, Research centre, Hypertension, lipids (amino acids, peptides, and proteins), Female, Apolipoprotein E, Core laboratory, Hispanic Americans, medicine.medical_specialty, COA REDUCTASE INHIBITORS, European Continental Ancestry Group, Clinical Neurology, Raça, APOE EPSILON-4, White People, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Apolipoproteins E, Political science, medicine, Journal Article, Online First, Humans, Genetic Predisposition to Disease, cardiovascular diseases, General hospital, Aged, Cerebral Hemorrhage, Research, LOBAR, 3112 Neurosciences, E GENOTYPE, United States, nervous system diseases, Black or African American, Cognitive epidemiology, Family medicine, Case-Control Studies, Neurology (clinical), 030217 neurology & neurosurgery
Abstract

Key Points Question Is history of hypertension and apolipoprotein E (APOE) associated with intracerebral hemorrhage risk in participants stratified by self-reported race/ethnicity? Findings In this case-control study of 13 124 adults, having a copy of APOE ε4 alleles increased the risk for lobar intracerebral hemorrhage only in white individuals, but after propensity score matching for hypertension burden, Hispanic individuals showed the same risk of APOE ε4. Meaning APOE ε4 appears to be confirmed as a risk factor for lobar intracerebral hemorrhage in nonwhite populations but is masked by differential hypertension burden in Hispanic individuals; further studies are needed to explore the interactions between APOE alleles and environmental exposures., Importance Genetic studies of intracerebral hemorrhage (ICH) have focused mainly on white participants, but genetic risk may vary or could be concealed by differing nongenetic coexposures in nonwhite populations. Transethnic analysis of risk may clarify the role of genetics in ICH risk across populations. Objective To evaluate associations between established differences in ICH risk by race/ethnicity and the variability in the risks of apolipoprotein E (APOE) ε4 alleles, the most potent genetic risk factor for ICH. Design, Setting, and Participants This case-control study of primary ICH meta-analyzed the association of APOE allele status on ICH risk, applying a 2-stage clustering approach based on race/ethnicity and stratified by a contributing study. A propensity score analysis was used to model the association of APOE with the burden of hypertension across race/ethnic groups. Primary ICH cases and controls were collected from 3 hospital- and population-based studies in the United States and 8 in European sites in the International Stroke Genetic Consortium. Participants were enrolled from January 1, 1999, to December 31, 2017. Participants with secondary causes of ICH were excluded from enrollment. Controls were regionally matched within each participating study. Main Outcomes and Measures Clinical variables were systematically obtained from structured interviews within each site. APOE genotype was centrally determined for all studies. Results In total, 13 124 participants (7153 [54.5%] male with a median [interquartile range] age of 66 [56-76] years) were included. In white participants, APOE ε2 (odds ratio [OR], 1.49; 95% CI, 1.24-1.80; P, This case-control study examines whether the risk for intracerebral hemorrhage presented by apolipoprotein E ε4 and ε2 alleles varies by race/ethnicity.

Published
2019

3. Association of MTHFR C677T Genotype With Ischemic Stroke Is Confined to Cerebral Small Vessel Disease Subtype

Author

Rutten-Jacobs, Loes C. A., Traylor, Matthew, Adib-Samii, Poneh, Thijs, Vincent, Sudlow, Cathie, Rothwell, Peter M., Boncoraglio, Giorgio, Dichgans, Martin, Meschia, James, Maguire, Jane, Levi, Christopher, Rost, Natalia S., Rosand, Jonathan, Hassan, Ahamad, Bevan, Steve, Markus, Hugh S., Jacobs, Loes [0000-0003-3223-885X], Traylor, Matthew [0000-0001-6624-8621], Markus, Hugh [0000-0002-9794-5996], and Apollo - University of Cambridge Repository

Subjects
Male, hypertension, genetic association, Genotype, Original Contributions, Clinical Sciences, Brain Ischemia, Cohort Studies, Risk Factors, Humans, cardiovascular diseases, C440 Molecular Genetics, Genetic Association Studies, Methylenetetrahydrofolate Reductase (NADPH2), Neurology & Neurosurgery, cerebral small vessel disease, lacunar stroke, homocysteine, C420 Human Genetics, C431 Medical Genetics, Cerebral Small Vessel Diseases, C400 Genetics, MTHFR, Stroke, Lacunar, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Female
Abstract

Supplemental Digital Content is available in the text., Background and Purpose— Elevated plasma homocysteine levels are associated with stroke. However, this might be a reflection of bias or confounding because trials have failed to demonstrate an effect from homocysteine lowering in stroke patients, although a possible benefit has been suggested in lacunar stroke. Genetic studies could potentially overcome these issues because genetic variants are inherited randomly and are fixed at conception. Therefore, we tested the homocysteine levels–associated genetic variant MTHFR C677T for association with magnetic resonance imaging–confirmed lacunar stroke and compared this with associations with large artery and cardioembolic stroke subtypes. Methods— We included 1359 magnetic resonance imaging–confirmed lacunar stroke cases, 1824 large artery stroke cases, 1970 cardioembolic stroke cases, and 14 448 controls, all of European ancestry. Furthermore, we studied 3670 ischemic stroke patients in whom white matter hyperintensities volume was measured. We tested MTHFR C677T for association with stroke subtypes and white matter hyperintensities volume. Because of the established association of homocysteine with hypertension, we additionally stratified for hypertension status. Results— MTHFR C677T was associated with lacunar stroke (P=0.0003) and white matter hyperintensity volume (P=0.04), but not with the other stroke subtypes. Stratifying the lacunar stroke cases for hypertension status confirmed this association in hypertensive individuals (P=0.0002), but not in normotensive individuals (P=0.30). Conclusions— MTHFR C677T was associated with magnetic resonance imaging–confirmed lacunar stroke, but not large artery or cardioembolic stroke. The association may act through increased susceptibility to, or interaction with, high blood pressure. This heterogeneity of association might explain the lack of effect of lowering homocysteine in secondary prevention trials which included all strokes.

Published
2016

4. Genetic associations with white matter hyperintensities confer risk of lacunar stroke

Author

Traylor, Matthew, Rutten-Jacobs, Loes CA, Thijs, Vincent, Holliday, Elizabeth G, Levi, Chris, Bevan, Steve, Malik, Rainer, Boncoraglio, Giorgio, Sudlow, Cathie, Rothwell, Peter M, Dichgans, Martin, Markus, Hugh S, Traylor, Matthew [0000-0001-6624-8621], Jacobs, Loes [0000-0003-3223-885X], Markus, Hugh [0000-0002-9794-5996], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, Risk, genetic association studies, Original Contributions, Clinical Sciences, Polymorphism, Single Nucleotide, behavioral disciplines and activities, leukoencephalopathies, mental disorders, Humans, genetics, Genetic Predisposition to Disease, Registries, cardiovascular diseases, Aged, Aged, 80 and over, Leukoaraiosis, stroke, lacunar, Middle Aged, Magnetic Resonance Imaging, C400 Genetics, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Female, cerebral small vessel diseases
Abstract

Supplemental Digital Content is available in the text., Background and Purpose— White matter hyperintensities (WMH) are increased in patients with lacunar stroke. Whether this is because of shared pathogenesis remains unknown. Using genetic data, we evaluated whether WMH-associated genetic susceptibility factors confer risk of lacunar stroke, and therefore whether they share pathogenesis. Methods— We used a genetic risk score approach to test whether single nucleotide polymorphisms associated with WMH in community populations were associated with magnetic resonance imaging–confirmed lacunar stroke (n=1,373), as well as cardioembolic (n=1,331) and large vessel (n=1,472) Trial of Org 10172 in Acute Stroke Treatment subtypes, against 9,053 controls. Second, we separated lacunar strokes into those with WMH (n=568) and those without (n=787) and tested for association with the risk score in these 2 groups. In addition, we evaluated whether WMH-associated single nucleotide polymorphisms are associated with lacunar stroke, or in the 2 groups. Results— The WMH genetic risk score was associated with lacunar stroke (odds ratio [OR; 95% confidence interval [CI]]=1.14 [1.06–1.22]; P=0.0003), in patients both with and without WMH (WMH: OR [95% CI]=1.15 [1.05–1.26]; P=0.003 and no WMH: OR [95% CI]=1.11 [1.02–1.21]; P=0.019). Conversely, the risk score was not associated with cardioembolic stroke (OR [95% CI]=1.03 [0.97–1.09]; P=0.63) or large vessel stroke (OR [95% CI]=0.99 [0.93,1.04]; P=0.39). However, none of the WMH-associated single nucleotide polymorphisms passed Bonferroni-corrected significance for association with lacunar stroke. Conclusions— Genetic variants that influence WMH are associated with an increased risk of lacunar stroke but not cardioembolic or large vessel stroke. Some genetic susceptibility factors seem to be shared across different radiological manifestations of small vessel disease.

Published
2018

5. Common NOTCH3 Variants and Cerebral Small-Vessel Disease

Author

Rutten-Jacobs, Loes CA, Traylor, Matthew, Adib-Samii, Poneh, Thijs, Vincent, Sudlow, Cathie, Rothwell, Peter M, Boncoraglio, Giorgio, Dichgans, Martin, Bevan, Steve, Meschia, James, Levi, Christopher, Rost, Natalia S, Rosand, Jonathan, Hassan, Ahamad, Markus, Hugh S, Jacobs, Loes [0000-0003-3223-885X], Traylor, Matthew [0000-0001-6624-8621], Markus, Hugh [0000-0002-9794-5996], and Apollo - University of Cambridge Repository

Subjects
Male, Receptors, Notch, genetic association studies, Original Contributions, Clinical Sciences, CADASIL, stroke, lacunar, Middle Aged, Polymorphism, Single Nucleotide, Gene Frequency, Hypertension, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Humans, Female, cerebral small vessel diseases, Receptor, Notch3, Alleles, Genome-Wide Association Study
Abstract

Supplemental Digital Content is available in the text., Background and Purpose— The most common monogenic cause of cerebral small-vessel disease is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, caused by NOTCH3 gene mutations. It has been hypothesized that more common variants in NOTCH3 may also contribute to the risk of sporadic small-vessel disease. Previously, 4 common variants (rs10404382, rs1043994, rs10423702, and rs1043997) were found to be associated with the presence of white matter hyperintensity in hypertensive community-dwelling elderly. Methods— We investigated the association of common single nucleotide polymorphisms (SNPs) in NOTCH3 in 1350 patients with MRI-confirmed lacunar stroke and 7397 controls, by meta-analysis of genome-wide association study data sets. In addition, we investigated the association of common SNPs in NOTCH3 with MRI white matter hyperintensity volumes in 3670 white patients with ischemic stroke. In each analysis, we considered all SNPs within the NOTCH3 gene, and within 50-kb upstream and downstream of the coding region. A total of 381 SNPs from the 1000 genome population with a mean allele frequency >0.01 were included in the analysis. A significance level of P

Published
2015

6. Oxidative phosphorylation and lacunar stroke: Genome-wide enrichment analysis of common variants

Author

Traylor, Matthew, Anderson, Christopher D., Hurford, Robert, Bevan, Steve, Markus, Hugh S., Traylor, Matthew [0000-0001-6624-8621], Markus, Hugh [0000-0002-9794-5996], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, Leukoaraiosis, Genetic Variation, Cerebral Infarction, Middle Aged, Magnetic Resonance Imaging, Oxidative Phosphorylation, nervous system diseases, body regions, Young Adult, Risk Factors, C400 Genetics, Stroke, Lacunar, Humans, Female, cardiovascular diseases, Aged, Genome-Wide Association Study
Abstract

OBJECTIVE We investigated whether oxidative phosphorylation (OXPHOS) abnormalities were associated with lacunar stroke, hypothesizing that these would be more strongly associated in patients with multiple lacunar infarcts and leukoaraiosis (LA). METHODS In 1,012 MRI-confirmed lacunar stroke cases and 964 age-matched controls recruited from general practice surgeries, we investigated associations between common genetic variants within the OXPHOS pathway and lacunar stroke using a permutation-based enrichment approach. Cases were phenotyped using MRI into those with multiple infarcts or LA (MLI/LA) and those with isolated lacunar infarcts (ILI) based on the number of subcortical infarcts and degree of LA, using the Fazekas grading. Using gene-level association statistics, we tested for enrichment of genes in the OXPHOS pathway with all lacunar stroke and the 2 subtypes. RESULTS There was a specific association with strong evidence of enrichment in the top 1% of genes in the MLI/LA (subtype p = 0.0017) but not in the ILI subtype (p = 1). Genes in the top percentile for the all lacunar stroke analysis were not significantly enriched (p = 0.07). CONCLUSIONS Our results implicate the OXPHOS pathway in the pathogenesis of lacunar stroke, and show the association is specific to patients with the MLI/LA subtype. They show that MRI-based subtyping of lacunar stroke can provide insights into disease pathophysiology, and imply that different radiologic subtypes of lacunar stroke subtypes have distinct underlying pathophysiologic processes.

Published
2016

7. Prognostic significance of pulsatile tinnitus in cervical artery dissection

Author

Kellert, L., Kloss, M., Pezzini, Alessandro, Debette, S., Leys, D., Caso, V., Thijs, V. N., Bersano, A., Touzé, E., Tatlisumak, T., Traenka, C., Lyrer, P. A., Engelter, S. T., Metso, T. M., Grond Ginsbach, C., Pandolfo, Massimo, Bodenant, Marie, Louillet, Fabien, Mas, Jean Louis, Deltour, Sandrine, Léger, Anne, Canaple, Sandrine, Godefroy, Olivier, Béjot, Yannick, Moulin, Thierry, Vuillier, Fabrice, Dos Santos, Michael, Malik, Rainer, Hausser, Ingrid, Brandt, Tobias, Thomas Feles, Constanze, Weber, Ralf, Costa, Paolo, Poli, Loris, Morotti, Andrea, Padovani, Alessandro, Lanfranconi, Silvia, Baron, Pierluigi, Ferrarese, Carlo, Giacolone, Giacomo, Paolucci, Stefano, Fluri, Felix, Hatz, Florian, Gisler, Dominique, Amort, Margareth, Bevan, Steve, Altintas, Ayse, Heidelberg University Hospital [Heidelberg], Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Università degli Studi di Perugia = University of Perugia (UNIPG), University Hospitals Leuven [Leuven], Physiopathologie et imagerie des troubles neurologiques (PhIND), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), CHU Amiens-Picardie, Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) study group, Kellert, L, Kloss, M, Pezzini, A, Debette, S, Leys, D, Caso, V, Thijs, V, Bersano, A, Touzé, E, Tatlisumak, T, Traenka, C, Lyrer, P, Engelter, S, Metso, T, Grond Ginsbach, C, Pandolfo, M, Bodenant, M, Louillet, F, Mas, J, Deltour, S, Léger, A, Canaple, S, Godefroy, O, Béjot, Y, Moulin, T, Vuillier, F, Dos Santos, M, Malik, R, Hausser, I, Brandt, T, Thomas Feles, C, Weber, R, Costa, P, Poli, L, Morotti, A, Padovani, A, Lanfranconi, S, Baron, P, Ferrarese, C, Giacolone, G, Paolucci, S, Fluri, F, Hatz, F, Gisler, D, Amort, M, Bevan, S, and Altintas, A

Subjects
Adult, Male, medicine.medical_specialty, Cervical Artery, Vertebral artery dissection, acute ischaemic stroke, cervical artery dissection, outcome, pulsatile tinnitus, Neurology (clinical), Neurology, Dissection (medical), 030204 cardiovascular system & hematology, Brain Ischemia, Tinnitus, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, Modified Rankin Scale, medicine.artery, Internal medicine, medicine, Humans, Stroke, Vertebral Artery Dissection, business.industry, Odds ratio, Middle Aged, Prognosis, medicine.disease, Confidence interval, Surgery, Cardiology, Female, Internal carotid artery, business, pulsatile tinnitu, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background and purpose Our aim was to investigate whether pulsatile tinnitus (PT) in cervical artery dissection (CeAD) has prognostic significance. Methods All CeAD patients from the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) study with documentation of PT were analysed. The presence of PT was systematically assessed using a standardized questionnaire. Stroke severity at admission was defined according to the National Institutes of Health Stroke Scale (NIHSS). Excellent outcome after 3 months was defined as a modified Rankin Scale of 0–1. Results Sixty-three of 778 patients (8.1%) reported PT. PT+ patients presented less often with ischaemic stroke (41.3% vs. 63.9%, P < 0.001), more often with dissection in the internal carotid artery (85.7% vs. 64.2%, P = 0.001), less often with vessel occlusion (19.0% vs. 34.1%, P = 0.017) and more often with excellent outcome at 3 months (92.1% vs. 75.4%, P = 0.002). Logistic regression analysis identified PT as an independent predictor of excellent outcome after 3 months [odds ratio (OR) 3.96, 95% confidence interval (CI) 1.22–12.87] adjusted to significant outcome predictors NIHSS on admission (OR 0.82, 95% CI 0.79–0.86), Horner syndrome (OR 1.95, 95% CI 1.16–3.29) and vessel occlusion (OR 0.62, 95% CI 0.40–0.94) and to non-significant predictors age, sex, pain and location of CeAD. Conclusion The presence of PT in CeAD is associated with a benign clinical course and predicts a favourable outcome.

Published
2016

8. No additional prognostic value of genetic information in the prediction of vascular events after cerebral ischemia of arterial origin : The PROMISe study

Author

Achterberg, Sefanja, Kappelle, L. Jaap, De Bakker, Paul I W, Traylor, Matthew, Algra, Ale, Van Der Graaf, Y., Grobbee, D. E., Rutten, G. E H M, Visseren, F. L J, Moll, F. L., Mali, W. P T M, Doevendans, P. A., Martin, Farrall, Holliday, Elizabeth G., Sudlow, Cathie, Hopewell, Jemma C., Cheng, Yu Ching, Fornage, Myriam, Ikram, M. Arfan, Malik, Rainer, Bevan, Steve, Thorsteinsdottir, Unnur, DeStefano, Anita L., Worrall, Bradford B., Reiner, Alex P., Mitchell, Braxton D., Clarke, Robert, Levi, Christopher, Seshadri, Sudha, Boncoraglio, Giorgio B., Sharma, Pankaj, Bis, Joshua C., Gretarsdottir, Solveig, Psaty, Bruce M., Rothwell, Peter M., Rosand, Jonathan, Meschia, James F., Stefansson, Kari, Dichgans, Martin, and Markus, Hugh S.

Subjects
Male, medicine.medical_specialty, Genotype, Ischemia, lcsh:Medicine, Single-nucleotide polymorphism, Genome-wide association study, Biochemistry, Polymorphism, Single Nucleotide, Brain Ischemia, Risk Factors, Internal medicine, medicine, Genetic predisposition, Humans, Myocardial infarction, Vascular Diseases, lcsh:Science, Aged, Medicine(all), Multidisciplinary, Receiver operating characteristic, Agricultural and Biological Sciences(all), business.industry, Biochemistry, Genetics and Molecular Biology(all), Incidence, lcsh:R, Arteries, Cerebral Infarction, Middle Aged, medicine.disease, Prognosis, Human genetics, Confidence interval, 3. Good health, Surgery, Stroke, ROC Curve, Area Under Curve, Cardiology, Female, lcsh:Q, business, Genetics and Molecular Biology(all), Research Article, Genome-Wide Association Study
Abstract

Background: Patients who have suffered from cerebral ischemia have a high risk of recurrent vascular events. Predictive models based on classical risk factors typically have limited prognostic value. Given that cerebral ischemia has a heritable component, genetic information might improve performance of these risk models. Our aim was to develop and compare two models: one containing traditional vascular risk factors, the other also including genetic information. Methods and Results: We studied 1020 patients with cerebral ischemia and genotyped them with the Illumina Immunochip. Median follow-up time was 6.5 years; the annual incidence of new ischemic events (primary outcome, n=198) was 3.0%. The prognostic model based on classical vascular risk factors had an area under the receiver operating characteristics curve (AUC-ROC) of 0.65 (95% confidence interval 0.61-0.69). When we added a genetic risk score based on prioritized SNPs from a genome-wide association study of ischemic stroke (using summary statistics from the METASTROKE study which included 12389 cases and 62004 controls), the AUC-ROC remained the same. Similar results were found for the secondary outcome ischemic stroke. Conclusions: We found no additional value of genetic information in a prognostic model for the risk of ischemic events in patients with cerebral ischemia of arterial origin. This is consistent with a complex, polygenic architecture, where many genes of weak effect likely act in concert to influence the heritable risk of an individual to develop (recurrent) vascular events. At present, genetic information cannot help clinicians to distinguish patients at high risk for recurrent vascular events.

Published
2015

9. 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

10. A novel MMP12 locus Is associated with large artery atherosclerotic stroke Using a genome-wide age-at-onset informed approach

Author

Traylor, Matthew, Mäkelä, Kari-Matti, Kilarski, Laura L, Holliday, Elizabeth G, Devan, William J, Nalls, Mike A, Wiggins, Kerri L, Zhao, Wei, Cheng, Yu-Ching, Achterberg, Sefanja, Malik, Rainer, Sudlow, Cathie, Bevan, Steve, Raitoharju, Emma, METASTROKE, International Stroke Genetics Consortium, Wellcome Trust Case Consortium 2 (WTCCC2), Oksala, Niku, Thijs, Vincent, Lemmens, Robin, Lindgren, Arne, Slowik, Agnieszka, Maguire, Jane M, Walters, Matthew, Algra, Ale, Sharma, Pankaj, Attia, John R, Boncoraglio, Giorgio B, Rothwell, Peter M, De Bakker, Paul IW, Bis, Joshua C, Saleheen, Danish, Kittner, Steven J, Mitchell, Braxton D, Rosand, Jonathan, Meschia, James F, Levi, Christopher, Dichgans, Martin, Lehtimäki, Terho, Lewis, Cathryn M, Markus, Hugh S, Traylor, Matthew [0000-0001-6624-8621], Markus, Hugh [0000-0002-9794-5996], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, lcsh:QH426-470, Myocardial Infarction, Arteries, Coronary Artery Disease, Middle Aged, Polymorphism, Single Nucleotide, lcsh:Genetics, C431 Medical Genetics, Matrix Metalloproteinase 12, Humans, Female, Age of Onset, Aged, Genome-Wide Association Study, Glycosaminoglycans
Abstract

Genome-wide association studies (GWAS) have begun to identify the common genetic component to ischaemic stroke (IS). However, IS has considerable phenotypic heterogeneity. Where clinical covariates explain a large fraction of disease risk, covariate informed designs can increase power to detect associations. As prevalence rates in IS are markedly affected by age, and younger onset cases may have higher genetic predisposition, we investigated whether an age-at-onset informed approach could detect novel associations with IS and its subtypes; cardioembolic (CE), large artery atherosclerosis (LAA) and small vessel disease (SVD) in 6,778 cases of European ancestry and 12,095 ancestry-matched controls. Regression analysis to identify SNP associations was performed on posterior liabilities after conditioning on age-at-onset and affection status. We sought further evidence of an association with LAA in 1,881 cases and 50,817 controls, and examined mRNA expression levels of the nearby genes in atherosclerotic carotid artery plaques. Secondly, we performed permutation analyses to evaluate the extent to which age-at-onset informed analysis improves significance for novel loci. We identified a novel association with an MMP12 locus in LAA (rs660599; p = 2.5×10⁻⁷), with independent replication in a second population (p = 0.0048, OR(95% CI) = 1.18(1.05-1.32); meta-analysis p = 2.6×10⁻⁸). The nearby gene, MMP12, was significantly overexpressed in carotid plaques compared to atherosclerosis-free control arteries (p = 1.2×10⁻¹⁵; fold change = 335.6). Permutation analyses demonstrated improved significance for associations when accounting for age-at-onset in all four stroke phenotypes (p

Published
2014

11. 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

12. Differences in Common Genetic Predisposition to Ischemic Stroke by Age and Sex

Author

Traylor, Matthew, Rutten-Jacobs, Loes C. A., Holliday, Elizabeth G., Malik, Rainer, Sudlow, Cathie, Rothwell, Peter M., Maguire, Jane M., Koblar, Simon A., Bevan, Steve, Giorgio Battista Boncoraglio, Dichgans, Martin, Levi, Chris, Lewis, Cathryn M., Markus, Hugh S., Traylor, Matthew [0000-0001-6624-8621], Jacobs, Loes [0000-0003-3223-885X], Markus, Hugh [0000-0002-9794-5996], and Apollo - University of Cambridge Repository

Subjects
Adult, Aged, 80 and over, Male, Aging, Sex Characteristics, Neurology & Neurosurgery, genome-wide association study, Original Contributions, Clinical Sciences, Middle Aged, stroke, Brain Ischemia, Stroke, Cohort Studies, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, epidemiologic studies, sex, Humans, genetics, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Aged
Abstract

Supplemental Digital Content is available in the text., Background and Purpose— Evidence from epidemiological studies points to differences in factors predisposing to stroke by age and sex. Whether these arise because of different genetic influences remained untested. Here, we use data from 4 genome-wide association data sets to study the relationship between genetic influence on stroke with both age and sex. Methods— Using genomic-relatedness-matrix restricted maximum likelihood methods, we performed 4 analyses: (1) we calculated the genetic correlation between groups divided by age and (2) by sex, (3) we calculated the heritability of age-at-stroke-onset, and (4) we evaluated the evidence that heritability of stroke is greater in women than in men. Results— We found that genetic factors influence age at stroke onset (h2 [SE]=18.0 [6.8]; P=0.0038), with a trend toward a stronger influence in women (women: h2 [SE]=21.6 [3.5]; Men: h2 [SE]=13.9 [2.8]). Although a moderate proportion of genetic factors was shared between sexes (rG [SE]=0.68 [0.16]) and between younger and older cases (rG [SE]=0.70 [0.17]), there was evidence to suggest that there are genetic susceptibility factors that are specific to sex (P=0.037) and to younger or older groups (P=0.056), particularly for women (P=0.0068). Finally, we found a trend toward higher heritability of stroke in women although this was not significantly greater than in men (P=0.084). Conclusions— Our results indicate that there are genetic factors that are either unique to or have a different effect between younger and older age groups and between women and men. Performing large, well-powered genome-wide association study analyses in these groups is likely to uncover further associations.

13. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

Author

Malik, Rainer, Chauhan, Ganesh, Traylor, Matthew, Sargurupremraj, Muralidharan, Okada, Yukinori, Mishra, Aniket, Rutten-Jacobs, Loes, Giese, Anne-Katrin, Van Der Laan, Sander W, Gretarsdottir, Solveig, Anderson, Christopher D, Chong, Michael, Adams, Hieab HH, Ago, Tetsuro, Almgren, Peter, Amouyel, Philippe, Ay, Hakan, Bartz, Traci M, Benavente, Oscar R, Bevan, Steve, Boncoraglio, Giorgio B, Brown, Robert D, Butterworth, Adam S, Carrera, Caty, Carty, Cara L, Chasman, Daniel I, Chen, Wei-Min, Cole, John W, Correa, Adolfo, Cotlarciuc, Ioana, Cruchaga, Carlos, Danesh, John, De Bakker, Paul IW, DeStefano, Anita L, Den Hoed, Marcel, Duan, Qing, Engelter, Stefan T, Falcone, Guido J, Gottesman, Rebecca F, Grewal, Raji P, Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeffrey, Harris, Tamara B, Hassan, Ahamad, Havulinna, Aki S, Heckbert, Susan R, Holliday, Elizabeth G, Howard, George, Hsu, Fang-Chi, Hyacinth, Hyacinth I, Ikram, M Arfan, Ingelsson, Erik, Irvin, Marguerite R, Jian, Xueqiu, Jiménez-Conde, Jordi, Johnson, Julie A, Jukema, J Wouter, Kanai, Masahiro, Keene, Keith L, Kissela, Brett M, Kleindorfer, Dawn O, Kooperberg, Charles, Kubo, Michiaki, Lange, Leslie A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lee, Jin-Moo, Lemmens, Robin, Leys, Didier, Lewis, Cathryn M, Lin, Wei-Yu, Lindgren, Arne G, Lorentzen, Erik, Magnusson, Patrik K, Maguire, Jane, Manichaikul, Ani, McArdle, Patrick F, Meschia, James F, Mitchell, Braxton D, Mosley, Thomas H, Nalls, Michael A, Ninomiya, Toshiharu, O'Donnell, Martin J, Psaty, Bruce M, Pulit, Sara L, Rannikmäe, Kristiina, Reiner, Alexander P, Rexrode, Kathryn M, Rice, Kenneth, Rich, Stephen S, Ridker, Paul M, Rost, Natalia S, Rothwell, Peter M, Rotter, Jerome I, Rundek, Tatjana, Sacco, Ralph L, Sakaue, Saori, Sale, Michele M, Salomaa, Veikko, Sapkota, Bishwa R, Schmidt, Reinhold, Schmidt, Carsten O, Schminke, Ulf, Sharma, Pankaj, Slowik, Agnieszka, Sudlow, Cathie LM, Tanislav, Christian, Tatlisumak, Turgut, Taylor, Kent D, Thijs, Vincent NS, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tiedt, Steffen, Trompet, Stella, Tzourio, Christophe, Van Duijn, Cornelia M, Walters, Matthew, Wareham, Nicholas J, Wassertheil-Smoller, Sylvia, Wilson, James G, Wiggins, Kerri L, Yang, Qiong, Yusuf, Salim, AFGen Consortium, Cohorts For Heart And Aging Research In Genomic Epidemiology (CHARGE) Consortium, International Genomics Of Blood Pressure (IGEN-BP) Consortium, INVENT Consortium, STARNET, Bis, Joshua C, Pastinen, Tomi, Ruusalepp, Arno, Schadt, Eric E, Koplev, Simon, Björkegren, Johan LM, Codoni, Veronica, Civelek, Mete, Smith, Nicholas L, Trégouët, David A, Christophersen, Ingrid E, Roselli, Carolina, Lubitz, Steven A, Ellinor, Patrick T, Tai, E Shyong, Kooner, Jaspal S, Kato, Norihiro, He, Jiang, Van Der Harst, Pim, Elliott, Paul, Chambers, John C, Takeuchi, Fumihiko, Johnson, Andrew D, BioBank Japan Cooperative Hospital Group, COMPASS Consortium, EPIC-CVD Consortium, EPIC-InterAct Consortium, International Stroke Genetics Consortium (ISGC), METASTROKE Consortium, Neurology Working Group Of The CHARGE Consortium, NINDS Stroke Genetics Network (SiGN), UK Young Lacunar DNA Study, MEGASTROKE Consortium, Sanghera, Dharambir K, Melander, Olle, Jern, Christina, Strbian, Daniel, Fernandez-Cadenas, Israel, Longstreth, WT, Rolfs, Arndt, Hata, Jun, Woo, Daniel, Rosand, Jonathan, Pare, Guillaume, Hopewell, Jemma C, Saleheen, Danish, Stefansson, Kari, Worrall, Bradford B, Kittner, Steven J, Seshadri, Sudha, Fornage, Myriam, Markus, Hugh S, Howson, Joanna MM, Kamatani, Yoichiro, Debette, Stephanie, and Dichgans, Martin

Subjects
Male, Models, Genetic, Computational Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, 3. Good health, Epigenesis, Genetic, Stroke, INDEL Mutation, Genetic Loci, Risk Factors, Databases, Genetic, Humans, Female, Gene Regulatory Networks, Genetic Predisposition to Disease, Genome-Wide Association Study
Abstract

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

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