From the Center for Genomic Medicine (S.M., W.J.D., F.R., C.E.K., C.D.A., J.R.).
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.).
Stroke. 2018 Jul;49(7):1618-1625. doi: 10.1161/STROKEAHA.117.020091. Epub 2018 Jun 18.
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.
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.
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).
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.
血肿体积是自发性脑出血（ICH）临床结局的重要决定因素。我们进行了一项血肿体积的全基因组关联研究（GWAS），旨在确定ICH 原发性脑损伤病理生理学中涉及的新的生物学途径。
我们对欧洲血统的 ICH 患者进行了 2 阶段（发现和复制）病例对照全基因组关联研究。我们利用入院头部 CT 通过半自动计算机辅助技术计算血肿体积。经过质量控制和插补后，有 700 万个遗传变异可供与 ICH 体积进行关联测试，分别在脑叶性和非脑叶性 ICH 病例中使用线性回归进行。使用 ordinal 和 logistic 回归分别对信号值<5×10的信号进行复制，并测试与入院格拉斯哥昏迷量表（Glasgow coma scale）和 3 个月后 ICH 二分（0-2 与 3-6）改良 Rankin 量表的关联。
发现阶段包括 394 例 ICH 病例（228 例脑叶性和 166 例非脑叶性），确定了 2 个易感基因座：22q13 上的一个基因组区域包含 （最上位单核苷酸多态性 rs9614326：β，1.84；SE，0.32；=4.4×10），与脑叶性 ICH 体积相关，以及 （最上位单核苷酸多态性 rs11655160：β，0.95；SE，0.17；=4.3×10），与非脑叶性 ICH 体积相关。复制阶段包括 240 例 ICH 病例（71 例脑叶性和 169 例非脑叶性），证实了与 =0.04（meta 分析 =2.5×10；异质性， =0.16）的关联，但与 22q13 无关（=0.49）。在多变量分析中，rs11655160 还与入院格拉斯哥昏迷量表评分较低（优势比，0.17；=0.004）和 3 个月后改良 Rankin 量表评分不良的风险增加（优势比，1.94；=0.045）相关。
我们确定了 作为非脑叶性 ICH 血肿体积、临床严重程度和功能结局的新易感风险基因座。需要在其他种族中进行复制和后续转化研究，以阐明观察到的关联所介导的机制。
