| Title | A human iPSC-array-based GWAS identifies a virus susceptibility locus in the NDUFA4 gene and functional variants. |
| Publication Type | Journal Article |
| Year of Publication | 2022 |
| Authors | Han, Y, Tan, L, Zhou, T, Yang, L, Carrau, L, Lacko, LA, Saeed, M, Zhu, J, Zhao, Z, Nilsson-Payant, BE, Neto, FTenorio Li, Cahir, C, Giani, AMaria, Chai, JChou, Li, Y, Dong, X, Moroziewicz, D, Paull, D, Zhang, T, Koo, S, Tan, C, Danziger, R, Ba, Q, Feng, L, Chen, Z, Zhong, A, Wise, GJ, Xiang, JZ, Wang, H, Schwartz, RE, tenOever, BR, Noggle, SA, Rice, CM, Qi, Q, Evans, T, Chen, S |
| Corporate Authors | NYSCF Global Stem Cell Array Team |
| Journal | Cell Stem Cell |
| Volume | 29 |
| Issue | 10 |
| Pagination | 1475-1490.e6 |
| Date Published | 2022 Oct 06 |
| ISSN | 1875-9777 |
| 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. |
| DOI | 10.1016/j.stem.2022.09.008 |
| Alternate Journal | Cell Stem Cell |
| PubMed ID | 36206731 |