Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage

Daniel Woo; Guido J Falcone; William J Devan; W Mark Brown; Alessandro Biffi; Timothy D Howard; Christopher D Anderson; H Bart Brouwers; Valerie Valant; Thomas W K Battey; Farid Radmanesh; Miriam R Raffeld; Sylvia Baedorf-Kassis; Ranjan Deka; Jessica G Woo; Lisa J Martin; Mary Haverbusch; Charles J Moomaw; Guangyun Sun; Joseph P Broderick; Matthew L Flaherty; Sharyl R Martini; Dawn O Kleindorfer; Brett Kissela; Mary E Comeau; Jeremiasz M Jagiella; Helena Schmidt; Paul Freudenberger; Alexander Pichler; Christian Enzinger; Björn M Hansen; Bo Norrving; Jordi Jimenez-Conde; Eva Giralt-Steinhauer; Roberto Elosua; Elisa Cuadrado-Godia; Carolina Soriano; Jaume Roquer; Peter Kraft; Alison M Ayres; Kristin Schwab; Jacob L McCauley; Joanna Pera; Andrzej Urbanik; Natalia S Rost; Joshua N Goldstein; Anand Viswanathan; Eva-Maria Stögerer; David L Tirschwell; Magdy Selim; Devin L Brown; Scott L Silliman; Bradford B Worrall; James F Meschia; Chelsea S Kidwell; Joan Montaner; Israel Fernandez-Cadenas; Pilar Delgado; Rainer Malik; Martin Dichgans; Steven M Greenberg; Peter M Rothwell; Arne Lindgren; Agnieszka Slowik; Reinhold Schmidt; Carl D Langefeld; Jonathan Rosand

doi:10.1016/j.ajhg.2014.02.012

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Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage

Journal article

Open access

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Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage

Daniel Woo, Guido J Falcone, William J Devan, W Mark Brown, Alessandro Biffi, Timothy D Howard, Christopher D Anderson, H Bart Brouwers, Valerie Valant, Thomas W K Battey, …

American journal of human genetics, Vol.94(4), pp.511-521

2014-04-03

DOI: https://doi.org/10.1016/j.ajhg.2014.02.012

PMCID: PMC3980413

PMID: 24656865

Abstract

Genetic Predisposition to Disease

Genome-Wide Association Study

Chromosomes, Human, Pair 1

Humans

Cerebral Hemorrhage - genetics

Quantitative Trait Loci

Case-Control Studies

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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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.189 Genome Studies; 1.189.455 Genome-Wide Association Studies
Web Of Science research areas: Genetics & Heredity
ESI research areas: Molecular Biology & Genetics

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Title: Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage
Creators: Daniel Woo - Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. Electronic address: daniel.woo@uc.edu
Guido J Falcone - 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
William J Devan - 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
W Mark Brown - Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest University, Winston-Salem, NC 27157, USA
Alessandro Biffi - 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
Timothy D Howard - Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest University, Winston-Salem, NC 27157, USA
Christopher D Anderson - 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
H Bart Brouwers - 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
Valerie Valant - 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
Thomas W K Battey - 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
Farid Radmanesh - 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
Miriam R Raffeld - 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
Sylvia Baedorf-Kassis - 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
Ranjan Deka - Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Jessica G Woo - Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
Lisa J Martin - Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
Mary Haverbusch - Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Charles J Moomaw - Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Guangyun Sun - Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Joseph P Broderick - Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Matthew L Flaherty - Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Sharyl R Martini - Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Dawn O Kleindorfer - Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Brett Kissela - Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Mary E Comeau - Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest University, Winston-Salem, NC 27157, USA
Jeremiasz M Jagiella - Department of Neurology, Jagiellonian University Medical College, Krakow 31-008, Poland
Helena Schmidt - Institute of Molecular Biology and Medical Biochemistry, Medical University Graz, Graz 8010, Austria
Paul Freudenberger - Institute of Molecular Biology and Medical Biochemistry, Medical University Graz, Graz 8010, Austria
Alexander Pichler - Department of Neurology, Medical University of Graz, Graz 8036, Austria
Christian Enzinger - Department of Neurology, Medical University of Graz, Graz 8036, Austria; Division of Neuroradiology, Department of Radiology, Medical University of Graz, Graz 8036, Austria
Björn M Hansen - Department of Clinical Sciences Lund, Neurology, Lund University, Lund 221 85, Sweden; Department of Neurology, Skåne University Hospital, Lund 221 85, Sweden
Bo Norrving - Department of Clinical Sciences Lund, Neurology, Lund University, Lund 221 85, Sweden; Department of Neurology, Skåne University Hospital, Lund 221 85, Sweden
Jordi Jimenez-Conde - 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
Eva Giralt-Steinhauer - 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
Roberto Elosua - 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
Elisa Cuadrado-Godia - 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
Carolina Soriano - 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
Jaume Roquer - 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
Peter Kraft - Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA
Alison M Ayres - The J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA 02114, USA
Kristin Schwab - The J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA 02114, USA
Jacob L McCauley - John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL 33136, USA
Joanna Pera - Department of Neurology, Jagiellonian University Medical College, Krakow 31-008, Poland
Andrzej Urbanik - Department of Radiology, Jagiellonian University Medical College, Krakow 31-008, Poland
Natalia S Rost - 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
Joshua N Goldstein - Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
Anand Viswanathan - The J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA 02114, USA
Eva-Maria Stögerer - Department of Neurology, Medical University of Graz, Graz 8036, Austria
David L Tirschwell - Stroke Center, Harborview Medical Center, University of Washington, Seattle, WA 98104, USA
Magdy Selim - Department of Neurology, Stroke Division, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
Devin L Brown - Stroke Program, Department of Neurology, University of Michigan Health System, Ann Arbor, MI 48109, USA
Scott L Silliman - Department of Neurology, University of Florida College of Medicine, Jacksonville, FL 32209, USA
Bradford B Worrall - Department of Neurology and Public Health Sciences, University of Virginia Health System, Charlottesville, VA 22908, USA
James F Meschia - Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA
Chelsea S Kidwell - Department of Neurology, University of Arizona, Tucson, AZ 85724, USA
Joan Montaner - Neurovascular Research Laboratory and Neurovascular Unit, Institut de Recerca, Hospital Vall d'Hebron, Universitat Autonoma de Barcelona, Barcelona 08035, Spain
Israel Fernandez-Cadenas - 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
Pilar Delgado - Neurovascular Research Laboratory and Neurovascular Unit, Institut de Recerca, Hospital Vall d'Hebron, Universitat Autonoma de Barcelona, Barcelona 08035, Spain
Rainer Malik - 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
Martin Dichgans - 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
Steven M Greenberg - The J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA 02114, USA
Peter M Rothwell - Stroke Prevention Research Unit, Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford OX3 9DU, UK
Arne Lindgren - Department of Clinical Sciences Lund, Neurology, Lund University, Lund 221 85, Sweden; Department of Neurology, Skåne University Hospital, Lund 221 85, Sweden
Agnieszka Slowik - Department of Neurology, Jagiellonian University Medical College, Krakow 31-008, Poland
Reinhold Schmidt - Department of Neurology, Medical University of Graz, Graz 8036, Austria
Carl D Langefeld - Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest University, Winston-Salem, NC 27157, USA
Jonathan Rosand - 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
Publication Details: American journal of human genetics, Vol.94(4), pp.511-521
Publisher: United States
Grant note: R01 NS030678 / NINDS NIH HHS 5K23NS059774 / NINDS NIH HHS K23 NS059774 / NINDS NIH HHS R18 HS017690 / AHRQ HHS Wellcome Trust U01 NS036695 / NINDS NIH HHS T32 NS047996 / NINDS NIH HHS U01 NS069763 / NINDS NIH HHS NS069763 / NINDS NIH HHS NS36695 / NINDS NIH HHS 095626 / Wellcome Trust R01 NS070941 / NINDS NIH HHS U10 NS077311 / NINDS NIH HHS M01 RR000042 / NCRR NIH HHS UL1 TR001425 / NCATS NIH HHS R01 HL098065 / NHLBI NIH HHS R01 NS062675 / NINDS NIH HHS R01 NS036695 / NINDS NIH HHS P50NS061343 / NINDS NIH HHS R01 NS059727 / NINDS NIH HHS R01NS059727 / NINDS NIH HHS NS30678 / NINDS NIH HHS U01 NS074425 / NINDS NIH HHS
Academic Unit: Miller School of Medicine; John P. Hussman Institute for Human Genomics; UMMG Dept of Human Genetics (Dr. John T. Macdonald Foundation)
Language: English
Resource Type: Journal article
PMID: 24656865
PMCID: PMC3980413
Record Identifier: 991031562094202976