17p12 Influences Hematoma Volume and Outcome in Spontaneous Intracerebral Hemorrhage

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title = "17p12 Influences Hematoma Volume and Outcome in Spontaneous Intracerebral Hemorrhage",
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.",
keywords = "cerebral hemorrhage, genetics, genome-wide association study, humans, neuroimaging",
author = "Sandro Marini and Devan, {William J.} and Farid Radmanesh and Laura Miyares and Timothy Poterba and Hansen, {Bj{\"o}rn M.} and Bo Norrving and Jordi Jimenez-Conde and Eva Giralt-Steinhauer and Roberto Elosua and Elisa Cuadrado-Godia and Carolina Soriano and Jaume Roquer and Kourkoulis, {Christina E.} and Ayres, {Alison M.} and Kristin Schwab and Tirschwell, {David L.} and Magdy Selim and Brown, {Devin L.} and Silliman, {Scott L.} and Worrall, {Bradford B.} and Meschia, {James F.} and Kidwell, {Chelsea S.} and Joan Montaner and Israel Fernandez-Cadenas and Pilar Delgado and Greenberg, {Steven M.} and Arne Lindgren and Charles Matouk and Sheth, {Kevin N.} and Daniel Woo and Anderson, {Christopher D.} and Jonathan Rosand and Falcone, {Guido J.}",
year = "2018",
doi = "10.1161/STROKEAHA.117.020091",
language = "English",
volume = "49",
pages = "1618--1625",
journal = " Stroke: a journal of cerebral circulation",
issn = "1524-4628",
publisher = "American Heart Association",
number = "7",