Variants at APOE influence risk of deep and lobar intracerebral hemorrhage
Alessandro Biffi MD
Center for Human Genetic Research, Massachusetts General Hospital, Boston MA
Department of Neurology, Massachusetts General Hospital, Boston MA
Program in Medical and Population Genetics, Broad Institute, Cambridge MA
Search for more papers by this authorAkshata Sonni BS
Center for Human Genetic Research, Massachusetts General Hospital, Boston MA
Department of Neurology, Massachusetts General Hospital, Boston MA
Program in Medical and Population Genetics, Broad Institute, Cambridge MA
Search for more papers by this authorChristopher D. Anderson MD
Center for Human Genetic Research, Massachusetts General Hospital, Boston MA
Department of Neurology, Massachusetts General Hospital, Boston MA
Program in Medical and Population Genetics, Broad Institute, Cambridge MA
Search for more papers by this authorBrett Kissela MD, MSc
Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, OH
Search for more papers by this authorJeremiasz M. Jagiella MD, PhD
Department of Neurology, Jagiellonian University Medical College, Krakow, Poland
Search for more papers by this authorHelena Schmidt MD
Institute of Molecular Biology and Medical Biochemistry, Medical University Graz, Austria
Search for more papers by this authorJordi Jimenez-Conde MD, PhD
Neurovascular Research Unit, Department of Neurology, Institut Municipal d'Investigació Medica-Hospital del Mar, Universitat Autonoma de Barcelona, Barcelona, Spain
Program in Inflammation and Cardiovascular Disorders, Institut Municipal d'Investigació Medica-Hospital del Mar, Universitat Autonoma de Barcelona, Barcelona, Spain
Search for more papers by this authorBjörn M. Hansen BS
Department of Clinical Sciences Lund Neurology, Lund University, Lund, Sweden
Department of Neurology, Skåne University Hospital, Lund, Sweden
Search for more papers by this authorIsrael Fernandez-Cadenas PhD
Neurovascular Research Laboratory and Neurovascular Unit, Institut de Recerca, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
Search for more papers by this authorLynelle Cortellini MSc
Center for Human Genetic Research, Massachusetts General Hospital, Boston MA
Department of Neurology, Massachusetts General Hospital, Boston MA
Program in Medical and Population Genetics, Broad Institute, Cambridge MA
Search for more papers by this authorAlison Ayres BA
Department of Neurology, Massachusetts General Hospital, Boston MA
Search for more papers by this authorKristin Schwab BA
Department of Neurology, Massachusetts General Hospital, Boston MA
Search for more papers by this authorKarol Juchniewicz PhD
Department of Neurology, Jagiellonian University Medical College, Krakow, Poland
Search for more papers by this authorAndrzej Urbanik MD, PhD
Department of Neurology, Jagiellonian University Medical College, Krakow, Poland
Search for more papers by this authorNatalia S. Rost MD
Center for Human Genetic Research, Massachusetts General Hospital, Boston MA
Department of Neurology, Massachusetts General Hospital, Boston MA
Program in Medical and Population Genetics, Broad Institute, Cambridge MA
Search for more papers by this authorAnand Viswanathan MD, PhD
Department of Neurology, Massachusetts General Hospital, Boston MA
Search for more papers by this authorThomas Seifert-Held MD
Department of Neurology, Medical University Graz, Austria
Search for more papers by this authorEva-Maria Stoegerer MD
Department of Neurology, Medical University Graz, Austria
Search for more papers by this authorMarta Tomás MD, PhD
Genes and Disease Program, Center for Genomic Regulation (CRG), National Genotyping Center (CeGen), CIBERESP and Pompeu Fabra University (UPF), Barcelona, Spain
Search for more papers by this authorRaquel Rabionet PhD
Genes and Disease Program, Center for Genomic Regulation (CRG), National Genotyping Center (CeGen), CIBERESP and Pompeu Fabra University (UPF), Barcelona, Spain
Search for more papers by this authorXavier Estivill MD, PhD
Genes and Disease Program, Center for Genomic Regulation (CRG), National Genotyping Center (CeGen), CIBERESP and Pompeu Fabra University (UPF), Barcelona, Spain
Search for more papers by this authorDevin L. Brown MD, MSc
Stroke Program, Department of Neurology, University of Michigan Health System, Ann Harbor, MI
Search for more papers by this authorScott L. Silliman MD
Department of Neurology, University of Florida College of Medicine, Jacksonville, FL
Search for more papers by this authorMagdy Selim MD
Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA
Search for more papers by this authorBradford B. Worrall MD, MSc
Department of Neurology and Public Health Sciences, University of Virginia Health System, Charlottesville, VA
Search for more papers by this authorJames F. Meschia MD
Department of Neurology, Mayo Clinic, Jacksonville, FL
Search for more papers by this authorJoan Montaner MD, PhD
Neurovascular Research Laboratory and Neurovascular Unit, Institut de Recerca, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
Search for more papers by this authorArne Lindgren MD, PhD
Department of Clinical Sciences Lund Neurology, Lund University, Lund, Sweden
Department of Neurology, Skåne University Hospital, Lund, Sweden
Search for more papers by this authorJaume Roquer MD
Neurovascular Research Unit, Department of Neurology, Institut Municipal d'Investigació Medica-Hospital del Mar, Universitat Autonoma de Barcelona, Barcelona, Spain
Program in Inflammation and Cardiovascular Disorders, Institut Municipal d'Investigació Medica-Hospital del Mar, Universitat Autonoma de Barcelona, Barcelona, Spain
Search for more papers by this authorReinhold Schmidt MD
Department of Neurology, Medical University Graz, Austria
Search for more papers by this authorSteven M. Greenberg MD, PhD
Department of Neurology, Massachusetts General Hospital, Boston MA
Search for more papers by this authorAgnieszka Slowik MD, PhD
Department of Neurology, Jagiellonian University Medical College, Krakow, Poland
Search for more papers by this authorJoseph P. Broderick MD
Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, OH
Search for more papers by this authorDaniel Woo MD, MSc
Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, OH
Search for more papers by this authorCorresponding Author
Jonathan Rosand MD, MSc
Center for Human Genetic Research, Massachusetts General Hospital, Boston MA
Department of Neurology, Massachusetts General Hospital, Boston MA
Program in Medical and Population Genetics, Broad Institute, Cambridge MA
Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, CPZN-6818, Boston, MA 02114Search for more papers by this authoron behalf of the International Stroke Genetics Consortium
Search for more papers by this authorAlessandro Biffi MD
Center for Human Genetic Research, Massachusetts General Hospital, Boston MA
Department of Neurology, Massachusetts General Hospital, Boston MA
Program in Medical and Population Genetics, Broad Institute, Cambridge MA
Search for more papers by this authorAkshata Sonni BS
Center for Human Genetic Research, Massachusetts General Hospital, Boston MA
Department of Neurology, Massachusetts General Hospital, Boston MA
Program in Medical and Population Genetics, Broad Institute, Cambridge MA
Search for more papers by this authorChristopher D. Anderson MD
Center for Human Genetic Research, Massachusetts General Hospital, Boston MA
Department of Neurology, Massachusetts General Hospital, Boston MA
Program in Medical and Population Genetics, Broad Institute, Cambridge MA
Search for more papers by this authorBrett Kissela MD, MSc
Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, OH
Search for more papers by this authorJeremiasz M. Jagiella MD, PhD
Department of Neurology, Jagiellonian University Medical College, Krakow, Poland
Search for more papers by this authorHelena Schmidt MD
Institute of Molecular Biology and Medical Biochemistry, Medical University Graz, Austria
Search for more papers by this authorJordi Jimenez-Conde MD, PhD
Neurovascular Research Unit, Department of Neurology, Institut Municipal d'Investigació Medica-Hospital del Mar, Universitat Autonoma de Barcelona, Barcelona, Spain
Program in Inflammation and Cardiovascular Disorders, Institut Municipal d'Investigació Medica-Hospital del Mar, Universitat Autonoma de Barcelona, Barcelona, Spain
Search for more papers by this authorBjörn M. Hansen BS
Department of Clinical Sciences Lund Neurology, Lund University, Lund, Sweden
Department of Neurology, Skåne University Hospital, Lund, Sweden
Search for more papers by this authorIsrael Fernandez-Cadenas PhD
Neurovascular Research Laboratory and Neurovascular Unit, Institut de Recerca, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
Search for more papers by this authorLynelle Cortellini MSc
Center for Human Genetic Research, Massachusetts General Hospital, Boston MA
Department of Neurology, Massachusetts General Hospital, Boston MA
Program in Medical and Population Genetics, Broad Institute, Cambridge MA
Search for more papers by this authorAlison Ayres BA
Department of Neurology, Massachusetts General Hospital, Boston MA
Search for more papers by this authorKristin Schwab BA
Department of Neurology, Massachusetts General Hospital, Boston MA
Search for more papers by this authorKarol Juchniewicz PhD
Department of Neurology, Jagiellonian University Medical College, Krakow, Poland
Search for more papers by this authorAndrzej Urbanik MD, PhD
Department of Neurology, Jagiellonian University Medical College, Krakow, Poland
Search for more papers by this authorNatalia S. Rost MD
Center for Human Genetic Research, Massachusetts General Hospital, Boston MA
Department of Neurology, Massachusetts General Hospital, Boston MA
Program in Medical and Population Genetics, Broad Institute, Cambridge MA
Search for more papers by this authorAnand Viswanathan MD, PhD
Department of Neurology, Massachusetts General Hospital, Boston MA
Search for more papers by this authorThomas Seifert-Held MD
Department of Neurology, Medical University Graz, Austria
Search for more papers by this authorEva-Maria Stoegerer MD
Department of Neurology, Medical University Graz, Austria
Search for more papers by this authorMarta Tomás MD, PhD
Genes and Disease Program, Center for Genomic Regulation (CRG), National Genotyping Center (CeGen), CIBERESP and Pompeu Fabra University (UPF), Barcelona, Spain
Search for more papers by this authorRaquel Rabionet PhD
Genes and Disease Program, Center for Genomic Regulation (CRG), National Genotyping Center (CeGen), CIBERESP and Pompeu Fabra University (UPF), Barcelona, Spain
Search for more papers by this authorXavier Estivill MD, PhD
Genes and Disease Program, Center for Genomic Regulation (CRG), National Genotyping Center (CeGen), CIBERESP and Pompeu Fabra University (UPF), Barcelona, Spain
Search for more papers by this authorDevin L. Brown MD, MSc
Stroke Program, Department of Neurology, University of Michigan Health System, Ann Harbor, MI
Search for more papers by this authorScott L. Silliman MD
Department of Neurology, University of Florida College of Medicine, Jacksonville, FL
Search for more papers by this authorMagdy Selim MD
Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA
Search for more papers by this authorBradford B. Worrall MD, MSc
Department of Neurology and Public Health Sciences, University of Virginia Health System, Charlottesville, VA
Search for more papers by this authorJames F. Meschia MD
Department of Neurology, Mayo Clinic, Jacksonville, FL
Search for more papers by this authorJoan Montaner MD, PhD
Neurovascular Research Laboratory and Neurovascular Unit, Institut de Recerca, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
Search for more papers by this authorArne Lindgren MD, PhD
Department of Clinical Sciences Lund Neurology, Lund University, Lund, Sweden
Department of Neurology, Skåne University Hospital, Lund, Sweden
Search for more papers by this authorJaume Roquer MD
Neurovascular Research Unit, Department of Neurology, Institut Municipal d'Investigació Medica-Hospital del Mar, Universitat Autonoma de Barcelona, Barcelona, Spain
Program in Inflammation and Cardiovascular Disorders, Institut Municipal d'Investigació Medica-Hospital del Mar, Universitat Autonoma de Barcelona, Barcelona, Spain
Search for more papers by this authorReinhold Schmidt MD
Department of Neurology, Medical University Graz, Austria
Search for more papers by this authorSteven M. Greenberg MD, PhD
Department of Neurology, Massachusetts General Hospital, Boston MA
Search for more papers by this authorAgnieszka Slowik MD, PhD
Department of Neurology, Jagiellonian University Medical College, Krakow, Poland
Search for more papers by this authorJoseph P. Broderick MD
Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, OH
Search for more papers by this authorDaniel Woo MD, MSc
Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, OH
Search for more papers by this authorCorresponding Author
Jonathan Rosand MD, MSc
Center for Human Genetic Research, Massachusetts General Hospital, Boston MA
Department of Neurology, Massachusetts General Hospital, Boston MA
Program in Medical and Population Genetics, Broad Institute, Cambridge MA
Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, CPZN-6818, Boston, MA 02114Search for more papers by this authoron behalf of the International Stroke Genetics Consortium
Search for more papers by this authorAbstract
Objective
Prior studies investigating the association between APOE alleles ε2/ε4 and risk of intracerebral hemorrhage (ICH) have been inconsistent and limited to small sample sizes, and did not account for confounding by population stratification or determine which genetic risk model was best applied.
Methods
We performed a large-scale genetic association study of 2189 ICH cases and 4041 controls from 7 cohorts, which were analyzed using additive models for ε2 and ε4. Results were subsequently meta-analyzed using a random effects model. A proportion of the individuals (322 cases, 357 controls) had available genome-wide data to adjust for population stratification.
Results
Alleles ε2 and ε4 were associated with lobar ICH at genome-wide significance levels (odds ratio [OR] = 1.82, 95% confidence interval [CI] = 1.50–2.23, p = 6.6 × 10−10; and OR = 2.20, 95%CI = 1.85–2.63, p = 2.4 × 10−11, respectively). Restriction of analysis to definite/probable cerebral amyloid angiopathy ICH uncovered a stronger effect. Allele ε4 was also associated with increased risk for deep ICH (OR = 1.21, 95% CI = 1.08–1.36, p = 2.6 × 10−4). Risk prediction evaluation identified the additive model as best for describing the effect of APOE genotypes.
Interpretation
APOE ε2 and ε4 are independent risk factors for lobar ICH, consistent with their known associations with amyloid biology. In addition, we present preliminary findings on a novel association between APOE ε4 and deep ICH. Finally, we demonstrate that an additive model for these APOE variants is superior to other forms of genetic risk modeling previously applied. ANN NEUROL 2010
Supporting Information
Additional Supporting Information may be found in the online version of this article.
| Filename | Description |
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| ANA_22134_sm_suppfig-S1.tif237.7 KB | Supporting Figure S1 |
| ANA_22134_sm_suppTable-S1.doc181.5 KB | Supporting Table S1 |
| ANA_22134_sm_suppInfo.doc15 KB | Supporting Information |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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