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17p12 Influences Hematoma Volume and Outcome in Spontaneous Intracerebral Hemorrhage

Marini, Sandro; Devan, William J.; Radmanesh, Farid; Miyares, Laura; Poterba, Timothy; Hansen, Björn M. LU ; Norrving, Bo LU ; Jimenez-Conde, Jordi; Giralt-Steinhauer, Eva and Elosua, Roberto, et al. (2018) In Stroke 49(7). p.1618-1625
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... (More)

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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published
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keywords
cerebral hemorrhage, genetics, genome-wide association study, humans, neuroimaging
in
Stroke
volume
49
issue
7
pages
8 pages
publisher
American Heart Association
external identifiers
  • scopus:85060390549
ISSN
0039-2499
DOI
10.1161/STROKEAHA.117.020091
language
English
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yes
id
09e4fb26-3135-4d8f-ae83-c8c40e1b0c21
date added to LUP
2019-02-04 12:25:45
date last changed
2019-02-27 05:12:00
@article{09e4fb26-3135-4d8f-ae83-c8c40e1b0c21,
  abstract     = {<p>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&lt;5×10<sup>-</sup> <sup>8</sup> 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<sup>-8</sup>) 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<sup>-8</sup>) 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<sup>-9</sup>; 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.</p>},
  author       = {Marini, Sandro and Devan, William J. and Radmanesh, Farid and Miyares, Laura and Poterba, Timothy and Hansen, Björn M. and Norrving, Bo and Jimenez-Conde, Jordi and Giralt-Steinhauer, Eva and Elosua, Roberto and Cuadrado-Godia, Elisa and Soriano, Carolina and Roquer, Jaume and Kourkoulis, Christina E. and Ayres, Alison M. and Schwab, Kristin and Tirschwell, David L. and Selim, Magdy and Brown, Devin L. and Silliman, Scott L. and Worrall, Bradford B. and Meschia, James F. and Kidwell, Chelsea S. and Montaner, Joan and Fernandez-Cadenas, Israel and Delgado, Pilar and Greenberg, Steven M. and Lindgren, Arne and Matouk, Charles and Sheth, Kevin N. and Woo, Daniel and Anderson, Christopher D. and Rosand, Jonathan and Falcone, Guido J.},
  issn         = {0039-2499},
  keyword      = {cerebral hemorrhage,genetics,genome-wide association study,humans,neuroimaging},
  language     = {eng},
  number       = {7},
  pages        = {1618--1625},
  publisher    = {American Heart Association},
  series       = {Stroke},
  title        = {17p12 Influences Hematoma Volume and Outcome in Spontaneous Intracerebral Hemorrhage},
  url          = {http://dx.doi.org/10.1161/STROKEAHA.117.020091},
  volume       = {49},
  year         = {2018},
}