Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Center for Inherited Disease Research, Dept. of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Genes (Basel). 2022 Dec 24;14(1):61. doi: 10.3390/genes14010061.
Recent genome wide association studies have identified 89 common genetic variants robustly associated with ischemic stroke and primarily located in non-coding regions. To evaluate the contribution of coding variants, which are mostly rare, we performed an exome array analysis on 106,101 SNPs for 9721 ischemic stroke cases from the SiGN Consortium, and 12,345 subjects with no history of stroke from the Health Retirement Study and SiGN consortium. We identified 15 coding variants significantly associated with all ischemic stroke at array-wide threshold (i.e., < 4.7 × 10), including two common SNPs in that have previously been associated with stroke. Twelve of the remaining 13 variants were extremely rare in European Caucasians (MAF < 0.1%) and the associations were driven by African American samples. There was no evidence for replication of these associations in either TOPMed Stroke samples ( = 5613 cases) or UK Biobank ( = 5874 stroke cases), although power to replicate was very low given the low allele frequencies of the associated variants and a shortage of samples from diverse ancestries. Our study highlights the need for acquiring large, well-powered diverse cohorts to study rare variants, and the technical challenges using array-based genotyping technologies for rare variant genotyping.
最近的全基因组关联研究已经确定了 89 个与缺血性中风密切相关的常见遗传变异体，这些变异体主要位于非编码区域。为了评估编码变异体的贡献，我们对来自 SiGN 联盟的 9721 例缺血性中风病例和来自健康退休研究和 SiGN 联盟的 12345 例无中风病史的个体进行了外显子组分析。我们在 SiGN 联盟的全基因组范围内确定了 15 个编码变异体与所有缺血性中风显著相关（即 < 4.7×10），其中包括先前与中风相关的 中的两个常见 SNP。其余 13 个变异体中的 12 个在欧洲白种人中非常罕见（MAF < 0.1%），这些关联是由非裔美国人样本驱动的。在 TOPMed Stroke 样本（=5613 例）或 UK Biobank（=5874 例中风病例）中，这些关联没有证据得到复制，尽管由于相关变异体的等位基因频率较低以及来自不同祖先的样本短缺，复制的可能性非常低。我们的研究强调了需要获得大型、功能强大的多样化队列来研究罕见变异体，以及使用基于阵列的基因分型技术进行罕见变异体基因分型的技术挑战。
