Genetics of growth rate in induced pluripotent stem cells

Induced pluripotent stem cells (iPSCs) enabled the generation of diverse cell types; however, certain fundamental biological properties, such as the genetic and epigenetic determinants of proliferation, remain poorly characterized. We quantified proliferation across 602 unique donors with a time-lapse imaging-based growth area under the curve (gAUC) phenotype and correlated gAUC with cell line gene expression and genotype. We identified 3,091 differentially expressed genes and found that rare deleterious variants in WDR54, TMEM250, and C2orf81 were associated with reduced iPSC growth. Notably, WDR54 was differentially expressed with respect to gAUC. Although no common variants were associated, common genetic variation explained 71%-75% of the variance. These results indicate a complex genetic architecture of iPSC growth rates, where rare, large-effect variants in important growth regulators are layered onto a highly polygenic background. These findings can impact the design of pooled iPSC-based studies and disease models, which may be confounded by intrinsic growth differences.