Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study.
Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study.
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DOI：
10.1016/s1474-4422(15)00338-5
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发表时间：
2016-02
期刊：
影响因子：
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通讯作者：
International Stroke Genetics Consortium (ISGC)
中科院分区：
文献类型：
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作者：
NINDS Stroke Genetics Network (SiGN);International Stroke Genetics Consortium (ISGC)
通过全基因组关联研究（GWAS）发现疾病相关位点是识别人类疾病新生物学途径的主要方法。迄今为止，GWAS 受到样本量相对较小的限制，产生的与缺血性中风相关的位点也相对较少。国家神经疾病研究所中风遗传学网络 (NINDS-SiGN) 是一个国际联盟，它采用系统的方法进行表型分析，并产生了迄今为止最大的缺血性中风 GWAS。为了确定与缺血性中风相关的遗传位点，我们进行了两阶段全基因组关联研究。第一阶段包括 16,851 例具有最先进表型的病例和 32,473 例无中风对照。病例年龄在 16 岁至 104 岁之间，于 1989 年至 2012 年间招募，并由经过集中培训和认证的调查人员使用基于网络的中风病因分类 (CCS) 协议进行亚型分类。我们通过识别在（几乎）相同的阵列上进行基因分型且具有相似的遗传祖先背景的样本来构建病例对照层。使用从全基因组序列数据生成的密集插补参考面板对数据进行清理和插补。在每个层内针对每种可用表型进行全基因组测试，并使用反方差加权固定效应荟萃分析合并汇总水平结果。第二阶段包括对 20,941 个病例和 364,736 个无中风对照中的 1,372 个 SNP 进行计算机查找，之前根据当地标准使用 TOAST 分类系统对病例进行亚型分类。然后在最终的荟萃分析中对这两个阶段进行联合分析。我们在 TSPAN2 附近的 1p13.2 处发现了一个与大动脉粥样硬化 (LAA) 相关中风相关的新位点（rs12122341 = 1·21 处的 G 等位基因的 I 期 OR = 1·21，p = 4.50 × 10−8；II 期 OR = 1·19，p = 1·30 × 10−9）。我们还证实了先前研究中报道的与缺血性中风密切相关的四个基因座，包括用于心源性中风的 PITX2 和 ZFHX3，以及用于左心耳中风的 HDAC9。 ALDH2 附近的 12q24 位点最初与所有缺血性中风相关，但与任何特定亚型无关，在小动脉中风的荟萃分析中超出了全基因组显着性。其他基因座，包括 NINJ2，尚未得到确认。我们的结果鉴定出一种新的左心耳中风易感基因，现在表明迄今为止 GWAS 涉及的所有位点都是亚型特异性的。需要进行后续研究来确定 TSPAN2 附近的基因座是否能产生预防中风的新治疗方法。鉴于这些关联的亚型特异性，SiGN 中丰富的表型可能对缺血性中风的进一步遗传发现至关重要。国立神经疾病和中风研究所 (NINDS)、国立卫生研究院 (NIH)。
The discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading approach to the identification of novel biological pathways for human disease. To date, GWAS have had been limited by relatively small sample sizes and yielded relatively few loci associated with ischemic stroke The National Institute of Neurological Disorders Stroke Genetics Network (NINDS-SiGN) is an international consortium that has taken a systematic approach to phenotyping and produced the largest ischemic stroke GWAS to date. In order to identify genetic loci associated with ischemic stroke, we performed a two-stage genome-wide association study. The first stage consisted of 16,851 cases with state-of-the-art phenotyping and 32,473 stroke-free controls. Cases were aged 16 to 104 years, recruited between 1989 and 2012, and subtyped by centrally trained and certified investigators using the web-based protocol, Causative Classification of Stroke (CCS). We constructed case-control strata by identify samples genotyped on (nearly) identical arrays and of similar genetic ancestral background. Data was cleaned and imputed using dense imputation reference panels generated from whole-genome sequence data. Genome-wide testing was performed within each stratum for each available phenotype, and summary level results were combined using inverse variance-weighted fixed effects meta-analysis. The second stage consisted of in silico look-ups of 1,372 SNPs in 20,941 cases and 364,736 stroke-free controls, with cases previously subtyped using the TOAST classification system according to local standards. The two stages were then jointly analyzed in a final meta-analysis. We identified a novel locus at 1p13.2 near TSPAN2 associated with large artery atherosclerosis (LAA)-related stroke (stage I OR for the G allele at rs12122341 = 1·21, p = 4.50 × 10−8; stage II OR = 1·19, p = 1·30 × 10−9). We also confirmed four loci robustly associated with ischemic stroke and reported in prior studies, including PITX2 and ZFHX3 for cardioembolic stroke, and HDAC9 for LAA stroke. The 12q24 locus near ALDH2, originally associated with all ischemic stroke but not with any specific subtype, exceeded genome-wide significance in the meta-analysis of small artery stroke. Other loci, including NINJ2, were not confirmed. Our results identify a novel LAA-stroke susceptibility gene and now indicate that all loci implicated by GWAS to date are subtype specific. Follow-up studies will be necessary to determine whether the locus near TSPAN2 yields a novel therapeutic approach to stroke prevention. Given the subtype-specificity of these associations, the rich phenotyping available in SiGN is likely to prove vital for further genetic discovery in ischemic stroke. National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH).