The STROMICS genome study: deep whole-genome sequencing and analysis of 10K Chinese patients with ischemic stroke reveal complex genetic and phenotypic interplay

Cell Discovery

Article

Xin Jin¹  Mingyan Fang¹  Xun Xu²  Jian Wang³  Xi Chen⁴  Chaolong Wang⁵  Yilong Wang⁶  Yong Jiang⁷  Zixiao Li⁷  Xia Meng⁷  Jinxi Lin⁷  Yang Liu⁸  Hao Li⁸  Yanfeng Shi⁸  Zhe Xu⁸  Yanran Li⁸  Si Cheng⁹  Yongjun Wang⁹  Jing Jing^1,10  Yaou Liu^1,11  Yunyun Duan^1,11  Shengzhe Bian^1,12  Siyang Liu^1,13 

[1] BGI-Shenzhen, Shenzhen, Guangdong, China;BGI-Shenzhen, Shenzhen, Guangdong, China;Guangdong Provincial Key Laboratory of Genome Read and Write, BGI-Shenzhen, Shenzhen, Guangdong, China;BGI-Shenzhen, Shenzhen, Guangdong, China;James D. Watson Institute of Genome Sciences, Hangzhou, Zhejiang, China;BGI-Tianjin, BGI-Shenzhen, Tianjin, China;Department of Epidemiology and Biostatistics, Ministry of Education Key Laboratory of Environment and Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China;Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China;Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China;China National Clinical Research Center for Neurological Diseases, Beijing, China;Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China;China National Clinical Research Center for Neurological Diseases, Beijing, China;Center of excellence for Omics Research (CORe), Beijing Tiantan Hospital, Capital Medical University, Beijing, China;Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China;China National Clinical Research Center for Neurological Diseases, Beijing, China;Changping Laboratory, Beijing, China;Clinical Center for Precision Medicine in Stroke, Capital Medical University, Beijing, China;Center of excellence for Omics Research (CORe), Beijing Tiantan Hospital, Capital Medical University, Beijing, China;Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China;China National Clinical Research Center for Neurological Diseases, Beijing, China;Tiantan Neuroimaging Center of Excellence, Beijing, China;Department of Radiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China;School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, Guangdong, China;School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, Guangdong, China;BGI-Shenzhen, Shenzhen, Guangdong, China;

关键词: ;   

DOI  :  10.1038/s41421-023-00582-8

 received in 2022-10-18, accepted in 2023-06-21,  发布年份 2023

来源: Springer

【 摘 要 】

Ischemic stroke is a leading cause of global mortality and long-term disability. However, there is a paucity of whole-genome sequencing studies on ischemic stroke, resulting in limited knowledge of the interplay between genomic and phenotypic variations among affected patients. Here, we outline the STROMICS design and present the first whole-genome analysis on ischemic stroke by deeply sequencing and analyzing 10,241 stroke patients from China. We identified 135.59 million variants, > 42% of which were novel. Notable disparities in allele frequency were observed between Chinese and other populations for 89 variants associated with stroke risk and 10 variants linked to response to stroke medications. We investigated the population structure of the participants, generating a map of genetic selection consisting of 31 adaptive signals. The adaption of the MTHFR rs1801133-G allele, which links to genetically evaluated VB9 (folate acid) in southern Chinese patients, suggests a gene-specific folate supplement strategy. Through genome-wide association analysis of 18 stroke-related traits, we discovered 10 novel genetic-phenotypic associations and extensive cross-trait pleiotropy at 6 lipid-trait loci of therapeutic relevance. Additionally, we found that the set of loss-of-function and cysteine-altering variants present in the causal gene NOTCH3 for the autosomal dominant stroke disorder CADASIL displayed a broad neuro-imaging spectrum. These findings deepen our understanding of the relationship between the population and individual genetic layout and clinical phenotype among stroke patients, and provide a foundation for future efforts to utilize human genetic knowledge to investigate mechanisms underlying ischemic stroke outcomes, discover novel therapeutic targets, and advance precision medicine.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

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