Meta-analysis of Genome-wide Association Studies Identifies 1q22 as a Susceptibility Locus for Intracerebral Hemorrhage
Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologi...
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| Published in | American journal of human genetics Vol. 94; no. 4; pp. 511 - 521 |
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| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Elsevier Inc
03.04.2014
Cell Press Elsevier |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0002-9297 1537-6605 1537-6605 |
| DOI | 10.1016/j.ajhg.2014.02.012 |
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| Abstract | Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10−6 was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10−8); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10−8). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10−4; meta-analysis p = 2.2 × 10−10) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10−5). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly. |
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| AbstractList | Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 x ... was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 x ...); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 x ...). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 x ...; meta-analysis p = 2.2 x ...) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 x ...). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly. (ProQuest: ... denotes formulae/symbols omitted.) Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10(-6) was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10(-8)); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10(-8)). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10(-4); meta-analysis p = 2.2 × 10(-10)) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10(-5)). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly. Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10−6 was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10−8); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10−8). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10−4; meta-analysis p = 2.2 × 10−10) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10−5). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly. Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10(-6) was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10(-8)); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10(-8)). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10(-4); meta-analysis p = 2.2 × 10(-10)) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10(-5)). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly.Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10(-6) was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10(-8)); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10(-8)). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10(-4); meta-analysis p = 2.2 × 10(-10)) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10(-5)). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly. Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10 −6 was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10 −8 ); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10 −8 ). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10 −4 ; meta-analysis p = 2.2 × 10 −10 ) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10 −5 ). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly. Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 10 super(-6) was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 10 super(-8)); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 10 super(-8)). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 10 super(-4); meta-analysis p = 2.2 10 super(-10)) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 10 super(-5)). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly. |
| Author | Slowik, Agnieszka Roquer, Jaume Goldstein, Joshua N. Brouwers, H. Bart Falcone, Guido J. Meschia, James F. Pera, Joanna Urbanik, Andrzej Elosua, Roberto Enzinger, Christian Flaherty, Matthew L. Moomaw, Charles J. Rost, Natalia S. Deka, Ranjan Broderick, Joseph P. Raffeld, Miriam R. Fernandez-Cadenas, Israel Martin, Lisa J. Rothwell, Peter M. McCauley, Jacob L. Rosand, Jonathan Jagiella, Jeremiasz M. Delgado, Pilar Selim, Magdy Giralt-Steinhauer, Eva Devan, William J. Kissela, Brett Kraft, Peter Tirschwell, David L. Schmidt, Helena Biffi, Alessandro Howard, Timothy D. Worrall, Bradford B. Ayres, Alison M. Martini, Sharyl R. Greenberg, Steven M. Norrving, Bo Cuadrado-Godia, Elisa Battey, Thomas W.K. Haverbusch, Mary Langefeld, Carl D. Anderson, Christopher D. Valant, Valerie Brown, Devin L. Comeau, Mary E. Jimenez-Conde, Jordi Woo, Jessica G. Freudenberger, Paul Lindgren, Arne Woo, Daniel Montaner, Joan Brown, W. Mark Baedorf-Kassis, Sylvia Sun, Guangyun Stögerer, Eva-Maria Kidwell, Chelsea S. Schwab, Kristin Viswanathan, Anand Radmanesh, Farid |
| AuthorAffiliation | 1 Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA 13 Department of Neurology, Medical University of Graz, Graz 8036, Austria 21 Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA 02114, USA 4 The J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA 02114, USA 20 Department of Radiology, Jagiellonian University Medical College, Krakow 31-008, Poland 22 Stroke Center, Harborview Medical Center, University of Washington, Seattle, WA 98104, USA 14 Division of Neuroradiology, Department of Radiology, Medical University of Graz, Graz 8036, Austria 33 Stroke Prevention Research Unit, Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford OX3 9DU, UK 7 Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest University, Winston-Salem, NC 27157, USA 17 Department of Neurology, Neurovascular Research Unit, Institut Hospi |
| AuthorAffiliation_xml | – name: 28 Department of Neurology, University of Arizona, Tucson, AZ 85724, USA – name: 20 Department of Radiology, Jagiellonian University Medical College, Krakow 31-008, Poland – name: 33 Stroke Prevention Research Unit, Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford OX3 9DU, UK – name: 26 Department of Neurology and Public Health Sciences, University of Virginia Health System, Charlottesville, VA 22908, USA – name: 11 Department of Neurology, Jagiellonian University Medical College, Krakow 31-008, Poland – name: 24 Stroke Program, Department of Neurology, University of Michigan Health System, Ann Arbor, MI 48109, USA – name: 12 Institute of Molecular Biology and Medical Biochemistry, Medical University Graz, Graz 8010, Austria – name: 27 Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA – name: 30 Stroke Pharmacogenomics and Genetics, Fundació Docència i Recerca Mútuaterrassa, Barcelona 08010, Spain – name: 31 Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich 80539, Germany – name: 22 Stroke Center, Harborview Medical Center, University of Washington, Seattle, WA 98104, USA – name: 4 The J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA 02114, USA – name: 18 Cardiovascular Epidemiology and Genetics Research Group, Institut Hospital del Mar d’Investigacions Mèdiques, Barcelona 08003, Spain – name: 1 Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA – name: 21 Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA 02114, USA – name: 29 Neurovascular Research Laboratory and Neurovascular Unit, Institut de Recerca, Hospital Vall d’Hebron, Universitat Autonoma de Barcelona, Barcelona 08035, Spain – name: 8 Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA – name: 15 Department of Clinical Sciences Lund, Neurology, Lund University, Lund 221 85, Sweden – name: 16 Department of Neurology, Skåne University Hospital, Lund 221 85, Sweden – name: 6 Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA – name: 9 Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA – name: 5 Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02141, USA – name: 32 Munich Cluster for Systems Neurology (Synergy), Munich 80539, Germany – name: 13 Department of Neurology, Medical University of Graz, Graz 8036, Austria – name: 23 Department of Neurology, Stroke Division, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA – name: 3 Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA – name: 10 Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA – name: 19 John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL 33136, USA – name: 2 Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA – name: 7 Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest University, Winston-Salem, NC 27157, USA – name: 14 Division of Neuroradiology, Department of Radiology, Medical University of Graz, Graz 8036, Austria – name: 25 Department of Neurology, University of Florida College of Medicine, Jacksonville, FL 32209, USA – name: 17 Department of Neurology, Neurovascular Research Unit, Institut Hospital del Mar d’Investigacions Mèdiques, Universitat Autonoma de Barcelona/DCEXS-UPF, Barcelona 08003, Spain |
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Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA 02114, USA – sequence: 62 givenname: Peter M. surname: Rothwell fullname: Rothwell, Peter M. organization: Stroke Prevention Research Unit, Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford OX3 9DU, UK – sequence: 63 givenname: Arne surname: Lindgren fullname: Lindgren, Arne organization: Department of Clinical Sciences Lund, Neurology, Lund University, Lund 221 85, Sweden – sequence: 64 givenname: Agnieszka surname: Slowik fullname: Slowik, Agnieszka organization: Department of Neurology, Jagiellonian University Medical College, Krakow 31-008, Poland – sequence: 65 givenname: Reinhold surname: Schmidt fullname: Schmidt, Reinhold organization: Department of Neurology, Medical University of Graz, Graz 8036, Austria – sequence: 66 givenname: Carl D. surname: Langefeld fullname: Langefeld, Carl D. organization: Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest University, Winston-Salem, NC 27157, USA – sequence: 67 givenname: Jonathan surname: Rosand fullname: Rosand, Jonathan email: jrosand@partners.org organization: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA |
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| Copyright | 2014 The American Society of Human Genetics Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. Copyright Cell Press Apr 3, 2014 2014 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved. 2014 The American Society of Human Genetics |
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| CorporateAuthor | the International Stroke Genetics Consortium International Stroke Genetics Consortium Institutionen för kliniska vetenskaper, Lund Lunds universitet Profile areas and other strong research environments Lund University Department of Clinical Sciences, Lund Neurology, Lund Strategiska forskningsområden (SFO) EpiHealth: Epidemiology for Health Faculty of Medicine Strategic research areas (SRA) Section IV Medicinska fakulteten Sektion IV Profilområden och andra starka forskningsmiljöer Neurologi, Lund |
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| IngestDate | Tue Sep 09 22:43:02 EDT 2025 Thu Aug 21 14:20:20 EDT 2025 Thu Sep 04 19:29:21 EDT 2025 Fri Sep 05 10:40:32 EDT 2025 Fri Jul 25 19:36:21 EDT 2025 Thu Jul 24 02:15:58 EDT 2025 Thu Apr 24 23:11:36 EDT 2025 Thu Sep 18 00:02:55 EDT 2025 Fri Feb 23 02:29:31 EST 2024 |
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| Issue | 4 |
| Language | English |
| License | http://www.elsevier.com/open-access/userlicense/1.0 Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 These authors contributed equally to this work These authors contributed equally to this work and are co-senior authors |
| OpenAccessLink | https://www.sciencedirect.com/science/article/pii/S0002929714000706 |
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| SubjectTerms | Basic Medicine Brain damage Case-Control Studies Cerebral Hemorrhage - genetics Chromosomes Chromosomes, Human, Pair 1 Genetic Predisposition to Disease Genome-Wide Association Study Genomics Hemorrhage Humans Medical and Health Sciences Medical Genetics and Genomics (including Gene Therapy) Medicin och hälsovetenskap Medicinsk genetik och genomik (Här ingår: Genterapi) Medicinska och farmaceutiska grundvetenskaper Meta-analysis Quantitative Trait Loci |
| Title | Meta-analysis of Genome-wide Association Studies Identifies 1q22 as a Susceptibility Locus for Intracerebral Hemorrhage |
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