17p12 Influences Hematoma Volume and Outcome in Spontaneous Intracerebral Hemorrhage

Research output: Contribution to journalArticle

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.

Details

Authors
  • Sandro Marini
  • William J. Devan
  • Farid Radmanesh
  • Laura Miyares
  • Timothy Poterba
  • 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. Silliman
  • Bradford B. Worrall
  • James F. Meschia
  • Chelsea S. Kidwell
  • Joan Montaner
  • Israel Fernandez-Cadenas
  • Pilar Delgado
  • Steven M. Greenberg
  • Charles Matouk
  • Kevin N. Sheth
  • Daniel Woo
  • Christopher D. Anderson
  • Jonathan Rosand
  • Guido J. Falcone
Organisations
External organisations
  • University of Arizona
  • Yale University
  • Harvard University
  • Hospital de Sant Pau
  • Autonomous University of Barcelona
  • University of Cincinnati
  • Broad Institute
  • Massachusetts General Hospital
  • Skåne University Hospital
  • Hospital del Mar Medical Research Institute
  • University of Washington
  • Beth Israel Deaconess Medical Center
  • University of Michigan
  • University of Florida
  • University of Virginia Health System
  • Mayo Clinic Florida
  • Vall d'Hebron University Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurology
  • Medical Genetics

Keywords

  • cerebral hemorrhage, genetics, genome-wide association study, humans, neuroimaging
Original languageEnglish
Pages (from-to)1618-1625
Number of pages8
JournalStroke
Volume49
Issue number7
Publication statusPublished - 2018
Publication categoryResearch
Peer-reviewedYes