A human iPSC-array-based GWAS identifies a virus susceptibility locus in the NDUFA4 gene and functional variants.
A human iPSC-array-based GWAS identifies a virus susceptibility locus in the NDUFA4 gene and functional variants.
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DOI：
10.1016/j.stem.2022.09.008
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发表时间：
2022-10-06
期刊：
影响因子：
23.9
通讯作者：
Chen, Shuibing
中科院分区：
文献类型：
--
作者：
Han, Yuling;Tan, Lei;Zhou, Ting;Yang, Liuliu;Carrau, Lucia;Lacko, Lauretta A.;Saeed, Mohsan;Zhu, Jiajun;Zhao, Zeping;Nilsson-Payant, Benjamin E.;Neto, Filipe Tenorio Lira;Cahir, Clare;Giani, Alice Maria;Chai, Jin Chou;Li, Yang;Dong, Xue;Moroziewicz, Dorota;Paull, Daniel;Zhang, Tuo;Koo, Soyeon;Tan, Christina;Danziger, Ron;Ba, Qian;Feng, Lingling;Chen, Zhengming;Zhong, Aaron;Wise, Gilbert J.;Xiang, Jenny Z.;Wang, Hui;Schwartz, Robert E.;tenOever, Benjamin R.;Noggle, Scott A.;Rice, Charles M.;Qi, Qibin;Evans, Todd;Chen, Shuibing
以人群为基础的研究，以确定疾病相关的风险等位基因通常需要从大量的个人样本。在这里，我们报告了一种基于人类诱导多能干细胞（hiPSC）的筛选策略，将人类遗传学与病毒感染性联系起来。一项全基因组关联研究（GWAS）在NDUFA 4基因的顺式调控区发现了一组单核苷酸多态性（SNP），这与寨卡病毒（ZIKV）感染的易感性相关。NDUFA 4的缺失导致对ZIKV、登革热病毒和SARS-CoV-2感染的敏感性降低。携带SNP的非风险等位基因或缺失顺式调节区的等基因hiPSC系降低了对病毒感染的敏感性。机制研究表明，NDUFA 4的丢失/减少导致线粒体应激，这导致mtDNA的泄漏，从而上调I型干扰素信号传导。这项研究为iPSC阵列在GWAS中的应用提供了原理证明，并将NDUFA 4鉴定为以前未知的病毒感染易感基因座。我们进行了基于人iPSC的全基因组关联研究（GWAS）。该研究鉴定了与对ZIKV感染的容许性相关的SNP。报道了一项在全基因组关联研究中应用人类iPSC阵列的原理验证研究，并将NDUFA 4鉴定为先前未知的病毒感染易感性位点。
Population-based studies to identify disease-associated risk alleles typically require samples from a large number of individuals. Here, we report a human-induced pluripotent stem cell (hiPSC)-based screening strategy to link human genetics with viral infectivity. A genome-wide association study (GWAS) identified a cluster of single-nucleotide polymorphisms (SNPs) in a cis-regulatory region of the NDUFA4 gene, which was associated with susceptibility to Zika virus (ZIKV) infection. Loss of NDUFA4 led to decreased sensitivity to ZIKV, dengue virus, and SARS-CoV-2 infection. Isogenic hiPSC lines carrying non-risk alleles of SNPs or deletion of the cis-regulatory region lower sensitivity to viral infection. Mechanistic studies indicated that loss/reduction of NDUFA4 causes mitochondrial stress, which leads to the leakage of mtDNA and thereby upregulation of type I interferon signaling. This study provides proof-of-principle for the application of iPSC arrays in GWAS and identifies NDUFA4 as a previously unknown susceptibility locus for viral infection. We performed a human iPSC-based genome-wide association study (GWAS) This study identified SNPs associated with permissiveness to ZIKV infection Loss or reduction of NDUFA4 decreases sensitivity to ZIKV infection Loss or reduction of NDUFA4 upregulates type 1 interferon signaling In this study, Han et al. report a proof-of-principle study applying human iPSC arrays in genome-wide association studies and identify NDUFA4 as a previously unknown susceptibility locus for viral infection.
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影响因子：
29
作者：
Balsa, Eduardo;Marco, Ricardo;Antonio Enriquez, Jose
通讯作者：
Antonio Enriquez, Jose
影响因子：
64.8
作者：
COVID-19 Host Genetics Initiative
通讯作者：
COVID-19 Host Genetics Initiative
影响因子：
15.9
作者：
Matusali, Giulia;Houzet, Laurent;Dejucq-Rainsford, Nathalie
通讯作者：
Dejucq-Rainsford, Nathalie
影响因子：
--
作者：
Hooper, Sean D.;Johansson, Anna C. V.;Feuk, Lars
通讯作者：
Feuk, Lars
影响因子：
23.9
作者：
Jacob A;Morley M;Hawkins F;McCauley KB;Jean JC;Heins H;Na CL;Weaver TE;Vedaie M;Hurley K;Hinds A;Russo SJ;Kook S;Zacharias W;Ochs M;Traber K;Quinton LJ;Crane A;Davis BR;White FV;Wambach J;Whitsett JA;Cole FS;Morrisey EE;Guttentag SH;Beers MF;Kotton DN
通讯作者：
Kotton DN