17p12 Influences Hematoma Volume and Outcome in Spontaneous Intracerebral Hemorrhage

Sandro Marini, William J. Devan, Farid Radmanesh, Laura Miyares, Timothy Poterba, Björn M. Hansen, Bo Norrving, Jordi Jimenez-Conde, Eva Giralt-Steinhauer, Roberto Elosua, Elisa Cuadrado-Godia, Carolina Soriano, Jaume Roquer, Christina E. Kourkoulis, Alison M. Ayres, Kristin Schwab, David L. Tirschwell, Magdy Selim, Devin L. Brown, Scott L. SillimanBradford B. Worrall, James F Meschia, Chelsea S. Kidwell, Joan Montaner, Israel Fernandez-Cadenas, Pilar Delgado, Steven M. Greenberg, Arne Lindgren, Charles Matouk, Kevin N. Sheth, Daniel Woo, Christopher D. Anderson, Jonathan Rosand, Guido J. Falcone

Research output: Contribution to journalArticle

8 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1618-1625
Number of pages8
JournalStroke
Volume49
Issue number7
DOIs
StatePublished - Jul 1 2018
Externally publishedYes

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Keywords

  • cerebral hemorrhage
  • genetics
  • genome-wide association study
  • humans
  • neuroimaging

ASJC Scopus subject areas

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialized Nursing

Cite this

Marini, S., Devan, W. J., Radmanesh, F., Miyares, L., Poterba, T., Hansen, B. M., Norrving, B., Jimenez-Conde, J., Giralt-Steinhauer, E., Elosua, R., Cuadrado-Godia, E., Soriano, C., Roquer, J., Kourkoulis, C. E., Ayres, A. M., Schwab, K., Tirschwell, D. L., Selim, M., Brown, D. L., ... Falcone, G. J. (2018). 17p12 Influences Hematoma Volume and Outcome in Spontaneous Intracerebral Hemorrhage. Stroke, 49(7), 1618-1625. https://doi.org/10.1161/STROKEAHA.117.020091