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, Chelsea S.
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.
N1 - Funding Information:
This work was supported by the National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (K23NS086873, U01NS069763, R01NS093870, and 5R01NS059727). Lund Stroke Register has been supported by the Swedish Heart and Lung Foundation, Skåne University Hospital, Region Skåne, the Freemasons Lodge of Instruction EOS in Lund, Foundation of Färs & Frosta (one of Sparbanken Skåne’s ownership Foundations), Lund University, the Swedish Stroke Association. Studies from Spain have been supported by Spain Ministry of Health (Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III Federación Española de Enfermedades Raras, RD12/0042/0020). Dr. Anderson was supported by the American Brain Foundation and received support from the Massachusetts General Hospital Institute for Heart, Vascular, and Stroke Care. Dr Falcone is supported by a Yale Pepper Scholar Award (P30AG021342) and the Neurocritical Care Society Research Fellowship.
Publisher Copyright:
© 2018 Lippincott Williams and Wilkins. All rights reserved.
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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U2 - 10.1161/STROKEAHA.117.020091
DO - 10.1161/STROKEAHA.117.020091
M3 - Article
C2 - 29915124
AN - SCOPUS:85060390549
VL - 49
SP - 1618
EP - 1625
JO - Stroke
JF - Stroke
SN - 0039-2499
IS - 7
ER -