title: Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage.
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.
authors.affiliation: Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. Electronic address: daniel.woo@uc.edu.
authors.forename: Daniel
authors.initials: D
authors.lastname: Woo
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA; The J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02141, USA; Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Guido J
authors.initials: GJ
authors.lastname: Falcone
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA; The J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02141, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Devan
authors.affiliation: Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest University, Winston-Salem, NC 27157, USA.
authors.forename: W Mark
authors.initials: WM
authors.lastname: Brown
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA; The J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02141, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Biffi
authors.affiliation: Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest University, Winston-Salem, NC 27157, USA.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Howard
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA; The J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02141, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Anderson
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA; The J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02141, USA.
authors.forename: H Bart
authors.initials: HB
authors.lastname: Brouwers
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA; The J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02141, USA.
authors.forename: Valerie
authors.initials: V
authors.lastname: Valant
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA; The J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02141, USA.
authors.forename: Thomas W K
authors.initials: TW
authors.lastname: Battey
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA; The J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02141, USA.
authors.forename: Farid
authors.initials: F
authors.lastname: Radmanesh
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA; The J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02141, USA.
authors.forename: Miriam R
authors.initials: MR
authors.lastname: Raffeld
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA; The J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02141, USA.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Baedorf-Kassis
authors.affiliation: Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Ranjan
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authors.lastname: Deka
authors.affiliation: Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Jessica G
authors.initials: JG
authors.lastname: Woo
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Martin
authors.affiliation: Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Haverbusch
authors.affiliation: Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Moomaw
authors.affiliation: Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Guangyun
authors.initials: G
authors.lastname: Sun
authors.affiliation: Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Broderick
authors.affiliation: Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Flaherty
authors.affiliation: Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Sharyl R
authors.initials: SR
authors.lastname: Martini
authors.affiliation: Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Dawn O
authors.initials: DO
authors.lastname: Kleindorfer
authors.affiliation: Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Brett
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authors.affiliation: Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest University, Winston-Salem, NC 27157, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Comeau
authors.affiliation: Department of Neurology, Jagiellonian University Medical College, Krakow 31-008, Poland.
authors.forename: Jeremiasz M
authors.initials: JM
authors.lastname: Jagiella
authors.affiliation: Institute of Molecular Biology and Medical Biochemistry, Medical University Graz, Graz 8010, Austria.
authors.forename: Helena
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authors.lastname: Schmidt
authors.affiliation: Institute of Molecular Biology and Medical Biochemistry, Medical University Graz, Graz 8010, Austria.
authors.forename: Paul
authors.initials: P
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authors.affiliation: Department of Neurology, Medical University of Graz, Graz 8036, Austria.
authors.forename: Alexander
authors.initials: A
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authors.affiliation: Department of Neurology, Medical University of Graz, Graz 8036, Austria; Division of Neuroradiology, Department of Radiology, Medical University of Graz, Graz 8036, Austria.
authors.forename: Christian
authors.initials: C
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authors.affiliation: Department of Clinical Sciences Lund, Neurology, Lund University, Lund 221 85, Sweden; Department of Neurology, Skåne University Hospital, Lund 221 85, Sweden.
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authors.initials: BM
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authors.affiliation: Department of Clinical Sciences Lund, Neurology, Lund University, Lund 221 85, Sweden; Department of Neurology, Skåne University Hospital, Lund 221 85, Sweden.
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authors.affiliation: Department of Neurology, Neurovascular Research Unit, Institut Hospital del Mar d'Investigacions Mèdiques, Universitat Autonoma de Barcelona/DCEXS-UPF, Barcelona 08003, Spain; Cardiovascular Epidemiology and Genetics Research Group, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona 08003, Spain.
authors.forename: Jordi
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authors.lastname: Jimenez-Conde
authors.affiliation: Department of Neurology, Neurovascular Research Unit, Institut Hospital del Mar d'Investigacions Mèdiques, Universitat Autonoma de Barcelona/DCEXS-UPF, Barcelona 08003, Spain; Cardiovascular Epidemiology and Genetics Research Group, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona 08003, Spain.
authors.forename: Eva
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authors.lastname: Giralt-Steinhauer
authors.affiliation: Department of Neurology, Neurovascular Research Unit, Institut Hospital del Mar d'Investigacions Mèdiques, Universitat Autonoma de Barcelona/DCEXS-UPF, Barcelona 08003, Spain; Cardiovascular Epidemiology and Genetics Research Group, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona 08003, Spain.
authors.forename: Roberto
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authors.lastname: Elosua
authors.affiliation: Department of Neurology, Neurovascular Research Unit, Institut Hospital del Mar d'Investigacions Mèdiques, Universitat Autonoma de Barcelona/DCEXS-UPF, Barcelona 08003, Spain; Cardiovascular Epidemiology and Genetics Research Group, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona 08003, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Cuadrado-Godia
authors.affiliation: Department of Neurology, Neurovascular Research Unit, Institut Hospital del Mar d'Investigacions Mèdiques, Universitat Autonoma de Barcelona/DCEXS-UPF, Barcelona 08003, Spain; Cardiovascular Epidemiology and Genetics Research Group, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona 08003, Spain.
authors.forename: Carolina
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authors.affiliation: Department of Neurology, Neurovascular Research Unit, Institut Hospital del Mar d'Investigacions Mèdiques, Universitat Autonoma de Barcelona/DCEXS-UPF, Barcelona 08003, Spain; Cardiovascular Epidemiology and Genetics Research Group, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona 08003, Spain.
authors.forename: Jaume
authors.initials: J
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authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
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authors.affiliation: Department of Neurology, Jagiellonian University Medical College, Krakow 31-008, Poland.
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authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA; The J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02141, USA.
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authors.affiliation: Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
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authors.affiliation: The J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA 02114, USA.
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authors.affiliation: Department of Neurology, Medical University of Graz, Graz 8036, Austria.
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authors.affiliation: Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA.
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authors.affiliation: Department of Neurology, University of Arizona, Tucson, AZ 85724, USA.
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authors.affiliation: Neurovascular Research Laboratory and Neurovascular Unit, Institut de Recerca, Hospital Vall d'Hebron, Universitat Autonoma de Barcelona, Barcelona 08035, Spain.
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authors.affiliation: Neurovascular Research Laboratory and Neurovascular Unit, Institut de Recerca, Hospital Vall d'Hebron, Universitat Autonoma de Barcelona, Barcelona 08035, Spain; Stroke Pharmacogenomics and Genetics, Fundació Docència i Recerca Mútuaterrassa, Barcelona 08010, Spain.
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authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich 80539, Germany; Munich Cluster for Systems Neurology (Synergy), Munich 80539, Germany.
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authors.affiliation: Department of Neurology, Medical University of Graz, Graz 8036, Austria.
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authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA; The J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02141, USA. Electronic address: jrosand@partners.org.
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mesh_terms: D016022:Case-Control Studies; D002543:Cerebral Hemorrhage / Q000235:genetics*; D002878:Chromosomes, Human, Pair 1; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D040641:Quantitative Trait Loci