A human iPSC-array-based GWAS identifies a virus susceptibility locus in the NDUFA4 gene and functional variants Journal Article
| Authors: | Han, Y.; Tan, L.; Zhou, T.; Yang, L.; Carrau, L.; Lacko, L. A.; Saeed, M.; Zhu, J.; Zhao, Z.; Nilsson-Payant, B. E.; Lira Neto, F. T.; Cahir, C.; Giani, A. M.; Chai, J. C.; Li, Y.; Dong, X.; Moroziewicz, D.; The NYSCF Global Stem Cell Array Team; Paull, D.; Zhang, T.; Koo, S.; Tan, C.; Danziger, R.; Ba, Q.; Feng, L.; Chen, Z.; Zhong, A.; Wise, G. J.; Xiang, J. Z.; Wang, H.; Schwartz, R. E.; tenOever, B. R.; Noggle, S. A.; Rice, C. M.; Qi, Q.; Evans, T.; Chen, S. |
| Article Title: | A human iPSC-array-based GWAS identifies a virus susceptibility locus in the NDUFA4 gene and functional variants |
| Abstract: | 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. © 2022 The Author(s) |
| Keywords: | genome-wide association study; single-nucleotide polymorphism; dengue virus; mtdna; sars-cov-2; type i interferon; ipsc array; isogenic hipsc lines; ndufa4; risk allele |
| Journal Title: | Cell Stem Cell |
| Volume: | 29 |
| Issue: | 10 |
| ISSN: | 1934-5909 |
| Publisher: | Cell Press |
| Date Published: | 2022-10-06 |
| Start Page: | 1475 |
| End Page: | 1490.e6 |
| Language: | English |
| DOI: | 10.1016/j.stem.2022.09.008 |
| PROVIDER: | scopus |
| PMCID: | PMC9550219 |
| PUBMED: | 36206731 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 November 2022 -- Source: Scopus |
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