Meta-analysis of Genome-wide Association Studies Identifies 1q22 as a Susceptibility Locus for Intracerebral Hemorrhage
Meta-analysis of Genome-wide Association Studies Identifies 1q22 as a Susceptibility Locus for Intracerebral Hemorrhage
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DOI：
10.1016/j.ajhg.2014.02.012
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发表时间：
2014-04-03
影响因子：
9.8
通讯作者：
Rosand, Jonathan
中科院分区：
文献类型：
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作者：
Woo, Daniel;Falcone, Guido J.;Rosand, Jonathan
脑出血（ICH）是预后最差的卒中亚型，目前尚无成熟的急性治疗方法。根据脑内破裂血管的位置，将 ICH 分为脑叶型或非脑叶型。这些不同的位置也预示着不同的潜在血管病变。遗传力估计表明遗传因素对这两个地点的 ICH 风险有重大影响。我们报告了一项针对这种情况的全基因组关联研究，该研究对招募欧洲血统个体的六项研究的数据进行了荟萃分析。病例受试者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分为脑叶或非脑叶。无 ICH 的对照受试者是从门诊诊所或随机数字拨号中抽取的。利用直接和全基因组基因分型在独立的多种族样本中对发现队列中发现的 p < 1 x 10(-6) 信号进行复制。发现阶段包括 1,545 名个体的病例队列（664 名脑叶病例和 881 名非肺叶病例）和 1,481 名个体的对照队列，并确定了两个易感位点：对于脑叶 ICH，染色体区域 12q21.1（rs11179580，比值比 [OR] = 1.56，p = 7.0 x 10(-8)）；对于非脑叶 ICH，染色体区域 1q22 (rs2984613，OR = 1.44，p 1.6 x 10(-8))。该复制包括 1,681 例个体的病例队列（484 例肺叶病例和 1,194 例非肺叶病例）和 2,261 例个体的对照队列，并证实了 1q22 的关联（p = 6.5 x 10(-4)；荟萃分析 p = 2.2 x 10(-10)），但没有证实 12q21.1 的关联（p = 0.55；荟萃分析 p = 2.6×10(-5))。这些结果证明了 ICH 亚型之间的生物异质性，并强调了相应确定 ICH 病例的重要性。
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 x 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 x 10(-8)); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p 1.6 x 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 x 10(-4); meta-analysis p = 2.2 x 10(-10)) but not for 12q21.1 (p = 0.55; metaanalysis p = 2.6 x 10(-5)). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly.