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

doi:10.1016/j.ajhg.2014.02.012

Meta-Analysis

. 2014 Apr 3;94(4):511-21.

doi: 10.1016/j.ajhg.2014.02.012. Epub 2014 Mar 20.

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

Daniel Woo¹, Guido J Falcone², William J Devan³, W Mark Brown⁴, Alessandro Biffi³, Timothy D Howard⁴, Christopher D Anderson³, H Bart Brouwers³, Valerie Valant³, Thomas W K Battey³, Farid Radmanesh³, Miriam R Raffeld³, Sylvia Baedorf-Kassis³, Ranjan Deka⁵, Jessica G Woo⁶, Lisa J Martin⁷, Mary Haverbusch⁸, Charles J Moomaw⁸, Guangyun Sun⁵, Joseph P Broderick⁸, Matthew L Flaherty⁸, Sharyl R Martini⁸, Dawn O Kleindorfer⁸, Brett Kissela⁸, Mary E Comeau⁴, Jeremiasz M Jagiella⁹, Helena Schmidt¹⁰, Paul Freudenberger¹⁰, Alexander Pichler¹¹, Christian Enzinger¹², Björn M Hansen¹³, Bo Norrving¹³, Jordi Jimenez-Conde¹⁴, Eva Giralt-Steinhauer¹⁴, Roberto Elosua¹⁴, Elisa Cuadrado-Godia¹⁴, Carolina Soriano¹⁴, Jaume Roquer¹⁴, Peter Kraft¹⁵, Alison M Ayres¹⁶, Kristin Schwab¹⁶, Jacob L McCauley¹⁷, Joanna Pera⁹, Andrzej Urbanik¹⁸, Natalia S Rost³, Joshua N Goldstein¹⁹, Anand Viswanathan¹⁶, Eva-Maria Stögerer¹¹, David L Tirschwell²⁰, Magdy Selim²¹, Devin L Brown²², Scott L Silliman²³, Bradford B Worrall²⁴, James F Meschia²⁵, Chelsea S Kidwell²⁶, Joan Montaner²⁷, Israel Fernandez-Cadenas²⁸, Pilar Delgado²⁷, Rainer Malik²⁹, Martin Dichgans²⁹, Steven M Greenberg¹⁶, Peter M Rothwell³⁰, Arne Lindgren¹³, Agnieszka Slowik⁹, Reinhold Schmidt¹¹, Carl D Langefeld⁴, Jonathan Rosand³¹; International Stroke Genetics Consortium

Affiliations

¹ Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. Electronic address: daniel.woo@uc.edu.
² 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.
³ 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.
⁴ Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest University, Winston-Salem, NC 27157, USA.
⁵ Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
⁶ Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
⁷ Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
⁸ Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
⁹ Department of Neurology, Jagiellonian University Medical College, Krakow 31-008, Poland.
¹⁰ Institute of Molecular Biology and Medical Biochemistry, Medical University Graz, Graz 8010, Austria.
¹¹ Department of Neurology, Medical University of Graz, Graz 8036, Austria.
¹² Department of Neurology, Medical University of Graz, Graz 8036, Austria; Division of Neuroradiology, Department of Radiology, Medical University of Graz, Graz 8036, Austria.
¹³ Department of Clinical Sciences Lund, Neurology, Lund University, Lund 221 85, Sweden; Department of Neurology, Skåne University Hospital, Lund 221 85, Sweden.
¹⁴ 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.
¹⁵ Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
¹⁶ The J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA 02114, USA.
¹⁷ John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL 33136, USA.
¹⁸ Department of Radiology, Jagiellonian University Medical College, Krakow 31-008, Poland.
¹⁹ Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
²⁰ Stroke Center, Harborview Medical Center, University of Washington, Seattle, WA 98104, USA.
²¹ Department of Neurology, Stroke Division, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
²² Stroke Program, Department of Neurology, University of Michigan Health System, Ann Arbor, MI 48109, USA.
²³ Department of Neurology, University of Florida College of Medicine, Jacksonville, FL 32209, USA.
²⁴ Department of Neurology and Public Health Sciences, University of Virginia Health System, Charlottesville, VA 22908, USA.
²⁵ Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA.
²⁶ Department of Neurology, University of Arizona, Tucson, AZ 85724, USA.
²⁷ Neurovascular Research Laboratory and Neurovascular Unit, Institut de Recerca, Hospital Vall d'Hebron, Universitat Autonoma de Barcelona, Barcelona 08035, Spain.
²⁸ 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.
²⁹ 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.
³⁰ Stroke Prevention Research Unit, Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford OX3 9DU, UK.
³¹ 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.

PMID: 24656865
PMCID: PMC3980413
DOI: 10.1016/j.ajhg.2014.02.012

Meta-Analysis

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

Daniel Woo et al. Am J Hum Genet. 2014.

. 2014 Apr 3;94(4):511-21.

doi: 10.1016/j.ajhg.2014.02.012. Epub 2014 Mar 20.

Authors

Affiliations

¹ Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. Electronic address: daniel.woo@uc.edu.
² 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.
³ 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.
⁴ Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest University, Winston-Salem, NC 27157, USA.
⁵ Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
⁶ Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
⁷ Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
⁸ Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
⁹ Department of Neurology, Jagiellonian University Medical College, Krakow 31-008, Poland.
¹⁰ Institute of Molecular Biology and Medical Biochemistry, Medical University Graz, Graz 8010, Austria.
¹¹ Department of Neurology, Medical University of Graz, Graz 8036, Austria.
¹² Department of Neurology, Medical University of Graz, Graz 8036, Austria; Division of Neuroradiology, Department of Radiology, Medical University of Graz, Graz 8036, Austria.
¹³ Department of Clinical Sciences Lund, Neurology, Lund University, Lund 221 85, Sweden; Department of Neurology, Skåne University Hospital, Lund 221 85, Sweden.
¹⁴ 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.
¹⁵ Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
¹⁶ The J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA 02114, USA.
¹⁷ John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL 33136, USA.
¹⁸ Department of Radiology, Jagiellonian University Medical College, Krakow 31-008, Poland.
¹⁹ Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
²⁰ Stroke Center, Harborview Medical Center, University of Washington, Seattle, WA 98104, USA.
²¹ Department of Neurology, Stroke Division, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
²² Stroke Program, Department of Neurology, University of Michigan Health System, Ann Arbor, MI 48109, USA.
²³ Department of Neurology, University of Florida College of Medicine, Jacksonville, FL 32209, USA.
²⁴ Department of Neurology and Public Health Sciences, University of Virginia Health System, Charlottesville, VA 22908, USA.
²⁵ Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA.
²⁶ Department of Neurology, University of Arizona, Tucson, AZ 85724, USA.
²⁷ Neurovascular Research Laboratory and Neurovascular Unit, Institut de Recerca, Hospital Vall d'Hebron, Universitat Autonoma de Barcelona, Barcelona 08035, Spain.
²⁸ 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.
²⁹ 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.
³⁰ Stroke Prevention Research Unit, Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford OX3 9DU, UK.
³¹ 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.

PMID: 24656865
PMCID: PMC3980413
DOI: 10.1016/j.ajhg.2014.02.012

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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Figures

**Figure 1**
Genome-wide Association Study Results Genome-wide association study results of autosomal SNPs: (A) all (lobar ICH and nonlobar ICH combined), (B) lobar ICH, and (C) nonlobar ICH. The plots show –log10-transformed p values for genotyped and imputed SNPs with respect to their physical positions. The threshold for association at genome-wide significance (p = 5 × 10⁻⁸) is shown by the upper dashed line, and the lower dashed line corresponds to p = 1 × 10⁻⁵. Landmark genes are indicated for loci that reached the threshold to pursue replication.

**Figure 2**
Meta-analysis Results Forest plots describing effect estimates for participating studies, as well as for the replication effort. Pooled estimates for odds ratios and 95% confidence intervals were calculated by fixed effects, inverse variance weighting meta-analysis. (A) Association results for rs11179580 at chromosomal region 12q21.1 in lobar ICH. (B) Association results for rs2984613 at chromosomal region 1q22 in nonlobar ICH. Results correspond to effect estimates when testing the major allele to depict genetic variation associated with increased risk of ICH.

**Figure 3**
Zoom Plots Regional association results. (A) Chromosomal region 1q22 in nonlobar ICH. (B) Chromosomal region 12q21.1 in lobar ICH. The index-associated SNP is labeled with violet color.

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References

1. Feigin V.L., Lawes C.M.M., Bennett D.A., Barker-Collo S.L., Parag V. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol. 2009;8:355–369. - PubMed
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1. Qureshi A.I., Mendelow A.D., Hanley D.F. Intracerebral haemorrhage. Lancet. 2009;373:1632–1644. - PMC - PubMed
1. Kissela B., Schneider A., Kleindorfer D., Khoury J., Miller R., Alwell K., Woo D., Szaflarski J., Gebel J., Moomaw C. Stroke in a biracial population: the excess burden of stroke among blacks. Stroke. 2004;35:426–431. - PubMed
1. Taylor C.L., Yuan Z., Selman W.R., Ratcheson R.A., Rimm A.A. Mortality rates, hospital length of stay, and the cost of treating subarachnoid hemorrhage in older patients: institutional and geographical differences. J. Neurosurg. 1997;86:583–588. - PubMed

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[1] Feigin V.L., Lawes C.M.M., Bennett D.A., Barker-Collo S.L., Parag V. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol. 2009;8:355–369. - PubMed

[2] Feigin V.L., Lawes C.M.M., Bennett D.A., Barker-Collo S.L., Parag V. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol. 2009;8:355–369. - PubMed

[3] Strong K., Mathers C., Bonita R. Preventing stroke: saving lives around the world. Lancet Neurol. 2007;6:182–187. - PubMed

[4] Strong K., Mathers C., Bonita R. Preventing stroke: saving lives around the world. Lancet Neurol. 2007;6:182–187. - PubMed

[5] Qureshi A.I., Mendelow A.D., Hanley D.F. Intracerebral haemorrhage. Lancet. 2009;373:1632–1644. - PMC - PubMed

[6] Qureshi A.I., Mendelow A.D., Hanley D.F. Intracerebral haemorrhage. Lancet. 2009;373:1632–1644. - PMC - PubMed

[7] Kissela B., Schneider A., Kleindorfer D., Khoury J., Miller R., Alwell K., Woo D., Szaflarski J., Gebel J., Moomaw C. Stroke in a biracial population: the excess burden of stroke among blacks. Stroke. 2004;35:426–431. - PubMed

[8] Kissela B., Schneider A., Kleindorfer D., Khoury J., Miller R., Alwell K., Woo D., Szaflarski J., Gebel J., Moomaw C. Stroke in a biracial population: the excess burden of stroke among blacks. Stroke. 2004;35:426–431. - PubMed

[9] Taylor C.L., Yuan Z., Selman W.R., Ratcheson R.A., Rimm A.A. Mortality rates, hospital length of stay, and the cost of treating subarachnoid hemorrhage in older patients: institutional and geographical differences. J. Neurosurg. 1997;86:583–588. - PubMed

[10] Taylor C.L., Yuan Z., Selman W.R., Ratcheson R.A., Rimm A.A. Mortality rates, hospital length of stay, and the cost of treating subarachnoid hemorrhage in older patients: institutional and geographical differences. J. Neurosurg. 1997;86:583–588. - PubMed

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

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

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