Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA; The J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02141, USA; Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
Am J Hum Genet. 2014 Apr 3;94(4):511-21. doi: 10.1016/j.ajhg.2014.02.012. Epub 2014 Mar 20.
Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10(-6) was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10(-8)); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10(-8)). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10(-4); meta-analysis p = 2.2 × 10(-10)) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10(-5)). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly.
脑出血（ICH）是预后最差的中风类型，目前尚无明确的急性治疗方法。ICH 根据破裂血管在大脑中的位置分为脑叶性或非脑叶性。这些不同的位置也预示着不同的潜在血管病理。遗传力估计表明，这两种位置的 ICH 风险都有很大的遗传因素。我们报告了一项针对这种疾病的全基因组关联研究，该研究对六项研究的数据进行了荟萃分析，这些研究招募了欧洲血统的个体。病例对象由对基因型数据不知情的神经科医生确定，并根据脑计算机断层扫描（brain computed tomography）将其分类为脑叶性或非脑叶性。ICH 无病例对照者从门诊诊所或随机数字拨号中抽样。在一个利用直接和全基因组基因分型的独立多民族样本中，对在发现队列中发现的信号进行了 p < 1 × 10(-6)的复制。发现阶段包括一个病例队列（1545 名患者，664 名脑叶性和 881 名非脑叶性病例）和一个对照队列（1481 名患者），并确定了两个易感基因座：脑叶性 ICH 的染色体 12q21.1 区（rs11179580，比值比[OR] = 1.56，p = 7.0 × 10(-8)）；非脑叶性 ICH 的染色体 1q22 区（rs2984613，OR = 1.44，p = 1.6 × 10(-8)）。复制队列包括一个病例队列（1681 名患者，484 名脑叶性和 1194 名非脑叶性病例）和一个对照队列（2261 名患者），并证实了 1q22 区的相关性（p = 6.5 × 10(-4)；荟萃分析 p = 2.2 × 10(-10)），但 12q21.1 区无相关性（p = 0.55；荟萃分析 p = 2.6 × 10(-5)）。这些结果表明，ICH 亚型存在生物学异质性，并强调了根据 ICH 病例进行分类的重要性。
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