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, Stella 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

7 Citations (Scopus)

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

Fingerprint

Cerebral Hemorrhage
Hematoma
Glasgow Coma Scale
Genome-Wide Association Study
Single Nucleotide Polymorphism
Odds Ratio
Intergenic DNA
Quality Control
Brain Injuries
Meta-Analysis
Linear Models
Logistic Models
Head
Tomography

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., ... 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

17p12 Influences Hematoma Volume and Outcome in Spontaneous Intracerebral Hemorrhage. / Marini, Sandro; Devan, William J.; Radmanesh, Farid; Miyares, Laura; Poterba, Timothy; Hansen, Björn M.; Norrving, Bo; Jimenez-Conde, Jordi; Giralt-Steinhauer, Eva; Elosua, Roberto; Cuadrado-Godia, Elisa; Soriano, Carolina; Roquer, Jaume; Kourkoulis, Christina E.; Ayres, Alison M.; Schwab, Kristin; Tirschwell, David L.; Selim, Magdy; Brown, Devin L.; Silliman, Scott L.; Worrall, Bradford B.; Meschia, James F.; Kidwell, Stella; Montaner, Joan; Fernandez-Cadenas, Israel; Delgado, Pilar; Greenberg, Steven M.; Lindgren, Arne; Matouk, Charles; Sheth, Kevin N.; Woo, Daniel; Anderson, Christopher D.; Rosand, Jonathan; Falcone, Guido J.

In: Stroke, Vol. 49, No. 7, 01.07.2018, p. 1618-1625.

Research output: Contribution to journalArticle

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, S, Montaner, J, Fernandez-Cadenas, I, Delgado, P, Greenberg, SM, Lindgren, A, Matouk, C, Sheth, KN, Woo, D, Anderson, CD, Rosand, J & Falcone, GJ 2018, '17p12 Influences Hematoma Volume and Outcome in Spontaneous Intracerebral Hemorrhage', Stroke, vol. 49, no. 7, pp. 1618-1625. https://doi.org/10.1161/STROKEAHA.117.020091
Marini S, Devan WJ, Radmanesh F, Miyares L, Poterba T, Hansen BM et al. 17p12 Influences Hematoma Volume and Outcome in Spontaneous Intracerebral Hemorrhage. Stroke. 2018 Jul 1;49(7):1618-1625. https://doi.org/10.1161/STROKEAHA.117.020091
Marini, Sandro ; Devan, William J. ; Radmanesh, Farid ; Miyares, Laura ; Poterba, Timothy ; Hansen, Björn M. ; Norrving, Bo ; Jimenez-Conde, Jordi ; Giralt-Steinhauer, Eva ; Elosua, Roberto ; Cuadrado-Godia, Elisa ; Soriano, Carolina ; Roquer, Jaume ; Kourkoulis, Christina E. ; Ayres, Alison M. ; Schwab, Kristin ; Tirschwell, David L. ; Selim, Magdy ; Brown, Devin L. ; Silliman, Scott L. ; Worrall, Bradford B. ; Meschia, James F. ; Kidwell, Stella ; Montaner, Joan ; Fernandez-Cadenas, Israel ; Delgado, Pilar ; Greenberg, Steven M. ; Lindgren, Arne ; Matouk, Charles ; Sheth, Kevin N. ; Woo, Daniel ; Anderson, Christopher D. ; Rosand, Jonathan ; Falcone, Guido J. / 17p12 Influences Hematoma Volume and Outcome in Spontaneous Intracerebral Hemorrhage. In: Stroke. 2018 ; Vol. 49, No. 7. pp. 1618-1625.
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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.",
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TY - JOUR

T1 - 17p12 Influences Hematoma Volume and Outcome in Spontaneous Intracerebral Hemorrhage

AU - Marini, Sandro

AU - Devan, William J.

AU - Radmanesh, Farid

AU - Miyares, Laura

AU - Poterba, Timothy

AU - Hansen, Björn M.

AU - Norrving, Bo

AU - Jimenez-Conde, Jordi

AU - Giralt-Steinhauer, Eva

AU - Elosua, Roberto

AU - Cuadrado-Godia, Elisa

AU - Soriano, Carolina

AU - Roquer, Jaume

AU - Kourkoulis, Christina E.

AU - Ayres, Alison M.

AU - Schwab, Kristin

AU - Tirschwell, David L.

AU - Selim, Magdy

AU - Brown, Devin L.

AU - Silliman, Scott L.

AU - Worrall, Bradford B.

AU - Meschia, James F.

AU - Kidwell, Stella

AU - Montaner, Joan

AU - Fernandez-Cadenas, Israel

AU - Delgado, Pilar

AU - Greenberg, Steven M.

AU - Lindgren, Arne

AU - Matouk, Charles

AU - Sheth, Kevin N.

AU - Woo, Daniel

AU - Anderson, Christopher D.

AU - Rosand, Jonathan

AU - Falcone, Guido J.

PY - 2018/7/1

Y1 - 2018/7/1

N2 - 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.

AB - 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.

KW - cerebral hemorrhage

KW - genetics

KW - genome-wide association study

KW - humans

KW - neuroimaging

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