Stroke 2018 07 18;49(7):1618-1625. Epub 2018 Jun 18.
Massachusetts General Hospital, Boston; Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale University School of Medicine, New Haven, CT (L.M., C.M., K.N.S., G.J.F.)
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 <5×10 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 (top single-nucleotide polymorphism rs9614326: β, 1.84; SE, 0.32; =4.4×10) for lobar ICH volume and an intergenic region overlying numerous copy number variants on (top single-nucleotide polymorphism rs11655160: β, 0.95; SE, 0.17; =4.3×10) for nonlobar ICH volume. The replication included 240 ICH cases (71 lobar and 169 nonlobar) and corroborated the association for (=0.04; meta-analysis =2.5×10; heterogeneity, =0.16) but not for 22q13 (=0.49). In multivariable analysis, rs11655160 was also associated with lower admission Glasgow coma scale (odds ratio, 0.17; =0.004) and increased risk of poor 3-month modified Rankin Scale (odds ratio, 1.94; =0.045).
Conclusions: We identified 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.