Isogenic human trophectoderm cells demonstrate the role of NDUFA4 and associated variants in ZIKV infection
Yang L., Han Y., Zhou T., Lacko LA., Saeed M., Tan C., Danziger R., Zhu J., Zhao Z., Cahir C., Giani AM., Li Y., Dong X., Moroziewicz D., Paull D., Chen Z., Zhong A., Noggle SA., Rice CM., Qi Q., Evans T., Chen S.
Population-based genome-wide association studies (GWAS) normally require a large sample size, which can be labor intensive and costly. Recently, we reported a human induced pluripotent stem cell (hiPSC) array-based GWAS method, identifying NDUFA4 as a host factor for Zika virus (ZIKV) infection. In this study, we extended our analysis to trophectoderm cells, which constitute one of the major routes of mother-to-fetus transmission of ZIKV during pregnancy. We differentiated hiPSCs from various donors into trophectoderm cells. We then infected cells carrying loss of function mutations in NDUFA4, harboring risk versus non-risk alleles of SNPs (rs917172 and rs12386620) or having deletions in the NDUFA4 cis-regulatory region with ZIKV. We found that loss/reduction of NDUFA4 suppressed ZIKV infection in trophectoderm cells. This study validated our published hiPSC array-based system as a useful platform for GWAS and confirmed the role of NDUFA4 as a susceptibility locus for ZIKV in disease-relevant trophectoderm cells.