通过对台湾汉族人群进行广泛的全基因组测序发现罕见变异：在心血管医学中的应用。

Rare variants discovery by extensive whole-genome sequencing of the Han Chinese population in Taiwan: Applications to cardiovascular medicine.

机构信息

Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10002, Taiwan.

Department of Public Health, Institute of Epidemiology and Preventative Medicine and Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei 10617, Taiwan.

出版信息

J Adv Res. 2020 Dec 7;30:147-158. doi: 10.1016/j.jare.2020.12.003. eCollection 2021 May.

INTRODUCTION

A population-specific genomic reference is important for research and clinical practice, yet it remains unavailable for Han Chinese (HC) in Taiwan.

OBJECTIVES

We report the first whole genome sequencing (WGS) database of HC (1000 Taiwanese genome (1KTW-WGS)) and demonstrate several applications to cardiovascular medicine.

METHODS

Whole genomes of 997 HC were sequenced to at least 30X depth. A total of 20,117 relatively healthy HC individuals were genotyped using a customized Axiom GWAS array. We performed a genome-wide genotype imputation technique using IMPUTE2.

RESULTS

We identified 26.7 million single-nucleotide variants (SNVs) and 4.2 million insertions-deletions. Of the SNVs, 16.1% were novel relative to dbSNP (build 152), and 34.2% were novel relative to gnomAD. A total of 18,450 healthy HC individuals were genotyped using a customized Genome-Wide Association Study (GWAS) array. We identified hypertension-associated variants and developed a hypertension prediction model based on the correlation between the WGS data and GWAS data (combined clinical and genetic models, AUC 0.887), and also identified 3 novel hyperlipidemia-associated variants. Each individual carried an average of 16.42 (SD = 3.72) disease-causing variants. Additionally, we established an online (an important cardiac gene) database that can be used to explore racial differences. Finally, pharmacogenetics studies identified HC population-specific SNVs in genes ( and ) involved in drug metabolism and blood clotting.

CONCLUSION

This research demonstrates the benefits of constructing a population-specific genomic reference database for precision medicine.

简介

人群特异性基因组参考对于研究和临床实践非常重要，但台湾汉族（HC）人群仍然缺乏此类参考。

目的

我们报告了首个汉族人群的全基因组测序（WGS）数据库（1000 名台湾人基因组（1KTW-WGS）），并展示了其在心血管医学中的几个应用。

方法

对 997 名汉族个体的全基因组进行了至少 30X 深度测序。使用定制的 Axiom GWAS 阵列对 20117 名相对健康的汉族个体进行了全基因组基因型分型。我们使用 IMPUTE2 进行了全基因组基因型推断技术。

结果

我们鉴定了 2670 万个单核苷酸变异（SNVs）和 420 万个插入缺失。在这些 SNVs 中，有 16.1%相对于 dbSNP（build 152）是新的，34.2%相对于 gnomAD 是新的。使用定制的全基因组关联研究（GWAS）阵列对 18450 名健康的汉族个体进行了基因型分型。我们鉴定了与高血压相关的变异，并基于 WGS 数据与 GWAS 数据之间的相关性开发了一个高血压预测模型（联合临床和遗传模型，AUC 0.887），还鉴定了 3 个新的与高血脂相关的变异。每个个体平均携带 16.42 个（SD=3.72）致病变异。此外，我们建立了一个在线数据库（一个重要的心脏基因），可用于探索种族差异。最后，药物遗传学研究鉴定了汉族人群中参与药物代谢和血液凝固的基因（和）中的特异性 SNVs。