Journal
STROKE
Volume 49, Issue 7, Pages 1618-1625Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/STROKEAHA.117.020091
Keywords
cerebral hemorrhage; genetics; genome-wide association study; humans; neuroimaging
Categories
Funding
- National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke [K23NS086873, U01NS069763, R01NS093870, 5R01NS059727]
- Swedish Heart and Lung Foundation, Skane University Hospital, Region Skane
- Freemasons Lodge of Instruction EOS in Lund
- Foundation of Fars Frosta
- Lund University
- Swedish Stroke Association
- Spain Ministry of Health (Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III Federacion Espanola de Enfermedades Raras) [RD12/0042/0020]
- American Brain Foundation
- Massachusetts General Hospital Institute for Heart, Vascular, and Stroke Care
- Yale Pepper Scholar Award [P30AG021342]
- Neurocritical Care Society Research Fellowship
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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<5x10(-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: , 1.84; SE, 0.32; P=4.4x10(-8)) for lobar ICH volume and an intergenic region overlying numerous copy number variants on 17p12 (top single-nucleotide polymorphism rs11655160: , 0.95; SE, 0.17; P=4.3x10(-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=2.5x10(-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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