17p12 Influences Hematoma Volume and Outcome in Spontaneous Intracerebral Hemorrhage

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 primar...

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Authors: Marini, S, Devan, WJ, Radmanesh, F, Miyares, L, Poterba, T, Hansen, BM, Norrving, B, Jimenez-Conde, J, Giralt-Steinhauer, E, Elosua, R, Cuadrado-Godia, E, Soriano, C, Roquer, J, Kourkoulis, CE, Ayres, AM, Schwab, K, Tirschwell, DL, Selim, M, Brown, DL, Silliman, SL, Worrall, BB, Meschia, JF, Kidwell, CS, Montaner, J, Fernandez-Cadenas, I, Delgado, P, Greenberg, SM, Lindgren, A, Matouk, C, Sheth, KN, Woo, D, Anderson, CD, Rosand, J, Falcone, GJ
Format: article
Status:Published version
Publication Date:2018
Country:España
Institution:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repository:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p3505
Online Access:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=3505
Access Level:Open access
Keyword:cerebral hemorrhage
genetics
genome-wide association study
humans
neuroimaging
Description
Summary: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<5x10(-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: , 1.84; SE, 0.32; P=4.4x10(-8)) for lobar ICH volume and an intergenic region overlying numerous copy number variants on 17p12 (top single-nucleotide polymorphism rs11655160: , 0.95; SE, 0.17; P=4.3x10(-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=2.5x10(-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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