Sandro Marini1, William J Devan1, Farid Radmanesh1, Laura Miyares2, Timothy Poterba3, Björn M Hansen4,5,6, Bo Norrving4,5,6, Jordi Jimenez-Conde7, Eva Giralt-Steinhauer7, Roberto Elosua7, Elisa Cuadrado-Godia7, Carolina Soriano7, Jaume Roquer7, Christina E Kourkoulis1, Alison M Ayres8, Kristin Schwab8, David L Tirschwell9, Magdy Selim10, Devin L Brown11, Scott L Silliman12, Bradford B Worrall13, James F Meschia14, Chelsea S Kidwell15, Joan Montaner16, Israel Fernandez-Cadenas16,17, Pilar Delgado16, Steven M Greenberg8, Arne Lindgren4,5,6, Charles Matouk2, Kevin N Sheth2, Daniel Woo18, Christopher D Anderson1,19,20, Jonathan Rosand1,19,20, Guido J Falcone21. 1. From the Center for Genomic Medicine (S.M., W.J.D., F.R., C.E.K., C.D.A., J.R.). 2. Massachusetts General Hospital, Boston; Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale University School of Medicine, New Haven, CT (L.M., C.M., K.N.S., G.J.F.). 3. Analytic and Translational Genetics Unit (T.P.). 4. Department of Neurology and Rehabilitation, Skåne University Hospital, Lund, Sweden (B.M.H., B.N., A.L.). 5. Department of Clinical Sciences Lund, Neurology, Lund University, Sweden (B.M.H., B.N., A.L.). 6. Department of Neurology and Rehabilitation Medicine, Skåne University Hospital, Lund, Sweden (B.M.H., B.N., A.L.). 7. Department of Neurology, Hospital del Mar Medical Research Institute (IMIM) (J.J.-C., E.G.-S., R.E., E.C.-G., C.S., J.R.). 8. Universitat Autónoma de Barcelona, Spain; Department of Neurology, J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA (A.M.A., K.S., S.M.G.). 9. Stroke Center, Harborview Medical Center, University of Washington, Seattle (D.L.T.). 10. Stroke Division, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (M.S.). 11. Stroke Program, Department of Neurology, University of Michigan, Ann Arbor (D.L.B.). 12. Department of Neurology, University of Florida College of Medicine, Jacksonville (S.L.S.). 13. Department of Neurology and Public Health Sciences, University of Virginia Health System, Charlottesville (B.B.W.). 14. Department of Neurology, Mayo Clinic, Jacksonville, FL (J.F.M.). 15. Department of Neurology, University of Arizona, Tucson (C.S.K.). 16. Neurovascular Research Laboratory and Neurovascular Unit, Institut de Recerca, Hospital Vall d'Hebron (J.M., I.F.-C., P.D.). 17. Stroke Pharmacogenomics and Genetics Sant Pau Institute of Research, Barcelona, Spain (I.F.-C.). 18. Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, OH (D.W.). 19. Division of Neurocritical Care and Emergency Neurology, Massachusetts General Hospital, Boston (C.D.A., J.R.). 20. Program in Medical and Population Genetics, Broad Institute, Boston (C.D.A., J.R). 21. Massachusetts General Hospital, Boston; Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale University School of Medicine, New Haven, CT (L.M., C.M., K.N.S., G.J.F.) guido.falcone@yale.edu.
Abstract
BACKGROUND AND PURPOSE: Hematoma volume is an important determinant of clinical outcome in spontaneous intracerebral hemorrhage (ICH). We performed a genome-wide association study (GWAS) of hematoma volume with the aim of identifying novel biological pathways involved in the pathophysiology of primary brain injury in ICH. METHODS: We conducted a 2-stage (discovery and replication) case-only genome-wide association study in patients with ICH of European ancestry. We utilized the admission head computed tomography to calculate hematoma volume via semiautomated computer-assisted technique. After quality control and imputation, 7 million genetic variants were available for association testing with ICH volume, which was performed separately in lobar and nonlobar ICH cases using linear regression. Signals with P<5×10-8 were pursued in replication and tested for association with admission Glasgow coma scale and 3-month post-ICH dichotomized (0-2 versus 3-6) modified Rankin Scale using ordinal and logistic regression, respectively. RESULTS: The discovery phase included 394 ICH cases (228 lobar and 166 nonlobar) and identified 2 susceptibility loci: a genomic region on 22q13 encompassing PARVB (top single-nucleotide polymorphism rs9614326: β, 1.84; SE, 0.32; P=4.4×10-8) for lobar ICH volume and an intergenic region overlying numerous copy number variants on 17p12 (top single-nucleotide polymorphism rs11655160: β, 0.95; SE, 0.17; P=4.3×10-8) for nonlobar ICH volume. The replication included 240 ICH cases (71 lobar and 169 nonlobar) and corroborated the association for 17p12 (P=0.04; meta-analysis P=2.5×10-9; heterogeneity, P=0.16) but not for 22q13 (P=0.49). In multivariable analysis, rs11655160 was also associated with lower admission Glasgow coma scale (odds ratio, 0.17; P=0.004) and increased risk of poor 3-month modified Rankin Scale (odds ratio, 1.94; P=0.045). CONCLUSIONS: We identified 17p12 as a novel susceptibility risk locus for hematoma volume, clinical severity, and functional outcome in nonlobar ICH. Replication in other ethnicities and follow-up translational studies are needed to elucidate the mechanism mediating the observed association.
BACKGROUND AND PURPOSE:Hematoma volume is an important determinant of clinical outcome in spontaneous intracerebral hemorrhage (ICH). We performed a genome-wide association study (GWAS) of hematoma volume with the aim of identifying novel biological pathways involved in the pathophysiology of primary brain injury in ICH. METHODS: We conducted a 2-stage (discovery and replication) case-only genome-wide association study in patients with ICH of European ancestry. We utilized the admission head computed tomography to calculate hematoma volume via semiautomated computer-assisted technique. After quality control and imputation, 7 million genetic variants were available for association testing with ICH volume, which was performed separately in lobar and nonlobar ICH cases using linear regression. Signals with P<5×10-8 were pursued in replication and tested for association with admission Glasgow coma scale and 3-month post-ICH dichotomized (0-2 versus 3-6) modified Rankin Scale using ordinal and logistic regression, respectively. RESULTS: The discovery phase included 394 ICH cases (228 lobar and 166 nonlobar) and identified 2 susceptibility loci: a genomic region on 22q13 encompassing PARVB (top single-nucleotide polymorphism rs9614326: β, 1.84; SE, 0.32; P=4.4×10-8) for lobar ICH volume and an intergenic region overlying numerous copy number variants on 17p12 (top single-nucleotide polymorphism rs11655160: β, 0.95; SE, 0.17; P=4.3×10-8) for nonlobar ICH volume. The replication included 240 ICH cases (71 lobar and 169 nonlobar) and corroborated the association for 17p12 (P=0.04; meta-analysis P=2.5×10-9; heterogeneity, P=0.16) but not for 22q13 (P=0.49). In multivariable analysis, rs11655160 was also associated with lower admission Glasgow coma scale (odds ratio, 0.17; P=0.004) and increased risk of poor 3-month modified Rankin Scale (odds ratio, 1.94; P=0.045). CONCLUSIONS: We identified 17p12 as a novel susceptibility risk locus for hematoma volume, clinical severity, and functional outcome in nonlobar ICH. Replication in other ethnicities and follow-up translational studies are needed to elucidate the mechanism mediating the observed association.
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