Cell Stem Cell. 2017 Apr 6;20(4):533-546.e7. doi: 10.1016/j.stem.2017.03.009.

Large-Scale Profiling Reveals the Influence of Genetic Variation on Gene Expression in Human Induced Pluripotent Stem Cells.

DeBoever C¹, Li H², Jakubosky D³, Benaglio P⁴, Reyna J², Olson KM⁵, Huang H⁶, Biggs W⁷, Sandoval E⁷, D'Antonio M², Jepsen K², Matsui H², Arias A⁴, Ren B⁸, Nariai N⁴, Smith EN⁴, D'Antonio-Chronowska A², Farley EK⁹, Frazer KA¹⁰.

Abstract

In this study, we used whole-genome sequencing and gene expression profiling of 215 human induced pluripotent stem cell (iPSC) lines from different donors to identify genetic variants associated with RNA expression for 5,746 genes. We were able to predict causal variants for these expression quantitative trait loci (eQTLs) that disrupt transcription factor binding and validated a subset of them experimentally. We also identified copy-number variant (CNV) eQTLs, including some that appear to affect gene expression by altering the copy number of intergenic regulatory regions. In addition, we were able to identify effects on gene expression of rare genic CNVs and regulatory single-nucleotide variants and found that reactivation of gene expression on the X chromosome depends on gene chromosomal position. Our work highlights the value of iPSCs for genetic association analyses and provides a unique resource for investigating the genetic regulation of gene expression in pluripotent cells.