Department of Neurology, Baotou Central Hospital, Baotou, China.
Mol Brain. 2020 May 25;13(1):82. doi: 10.1186/s13041-020-00620-6.
To expand our current understanding of the genetic basis of subarachnoid hemorrhage (SAH), and reveal the susceptibility genes in SAH risk.
We conducted whole-exome sequencing (WES) in a cohort of 196 individuals, including 94 SAH patients and 94 controls, as well as 8 samples that belong to two pedigrees. Systematically examination for rare variations (through direct genotyping) and common variations (through genotyping and imputation) for SAHs were performed in this study.
A total of 16,029 single-nucleotide polymorphisms (SNPs) and 108,999 short indels were detected in all samples, and among them, 30 SNPs distributed on 17 genes presented a strong association signal with SAH. Two novel pathogenic gene variants were identified as associated risk loci, including mutation in TPO and PALD1. The statistical analysis for rare, damaging variations in SAHs identified several susceptibility genes which were involved in degradation of the extracellular matrix and transcription factor signal pathways. And 25 putative pathogenic genes for SAH were also identified basic on functional interaction network analysis with the published SAH-associated genes. Additionally, pedigree analysis revealed autosomal dominant inheritance of pathogenic genes.
Systematical analysis revealed a key role for rare variations in SAH risk and discovered SNPs in new complex loci. Our study expanded the list of candidate genes associated with SAH risk, and will facilitate the investigation of disease-related mechanisms and potential clinical therapies.
拓展我们对蛛网膜下腔出血（SAH）遗传基础的现有认识，并揭示 SAH 风险的易感基因。
我们对包括 94 例 SAH 患者和 94 例对照在内的 196 名个体进行了全外显子组测序（WES），以及对两个家系的 8 个样本进行了全外显子组测序。本研究对 SAH 的罕见变异（通过直接基因分型）和常见变异（通过基因分型和插入）进行了系统检查。
在所有样本中总共检测到 16029 个单核苷酸多态性（SNP）和 108999 个短插入缺失，其中 17 个基因上分布的 30 个 SNP 与 SAH 存在强烈的关联信号。鉴定出两个新的致病基因突变，包括 TPO 和 PALD1 基因突变。对 SAH 中罕见、有害变异的统计分析确定了几个涉及细胞外基质降解和转录因子信号通路的易感基因。基于与已发表的 SAH 相关基因的功能互作网络分析，还鉴定出 25 个可能与 SAH 相关的致病基因。此外，家系分析显示致病基因呈常染色体显性遗传。
系统分析揭示了罕见变异在 SAH 风险中的关键作用，并发现了新的复杂基因座中的 SNP。本研究扩展了与 SAH 风险相关的候选基因列表，并将有助于研究疾病相关机制和潜在的临床治疗方法。
