Identification of rare and common regulatory variants in pluripotent cells using population-scale transcriptomics

Induced pluripotent stem cells (iPSCs) are an established cellular system to study the impact of genetic variants in derived cell types and developmental contexts. However, in their pluripotent state, the disease impact of genetic variants is less well known. Here, we integrate data from 1,367 human...

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Published inNature genetics Vol. 53; no. 3; pp. 313 - 321
Main Authors Bonder, Marc Jan, Smail, Craig, Gloudemans, Michael J., Frésard, Laure, Jakubosky, David, D’Antonio, Matteo, Li, Xin, Ferraro, Nicole M., Carcamo-Orive, Ivan, Mirauta, Bogdan, Seaton, Daniel D., Cai, Na, Vakili, Dara, Horta, Danilo, Zhao, Chunli, Zastrow, Diane B., Bonner, Devon E., Wheeler, Matthew T., Kilpinen, Helena, Knowles, Joshua W., Smith, Erin N., Frazer, Kelly A., Montgomery, Stephen B., Stegle, Oliver
Format Journal Article
LanguageEnglish
Published New York Nature Publishing Group US 01.03.2021
Nature Publishing Group
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Summary:Induced pluripotent stem cells (iPSCs) are an established cellular system to study the impact of genetic variants in derived cell types and developmental contexts. However, in their pluripotent state, the disease impact of genetic variants is less well known. Here, we integrate data from 1,367 human iPSC lines to comprehensively map common and rare regulatory variants in human pluripotent cells. Using this population-scale resource, we report hundreds of new colocalization events for human traits specific to iPSCs, and find increased power to identify rare regulatory variants compared with somatic tissues. Finally, we demonstrate how iPSCs enable the identification of causal genes for rare diseases. Integrative data analysis of 1,367 human iPSC lines maps common and rare regulatory variants that colocalize with loci associated with human traits and diseases.
Bibliography:Shared first authors, contributed equally to this work
Shared last authors, contributed equally to this work
The main analyses and data preparations were performed by M.J.B. and C.S.; D.J. and M.D. performed structural variant calling and analysis; N.M.F. performed GTEx v7 data processing; L.F. and X.L. performed rare variant annotation and interpretation; H.K. and D.V. annotated and validated the rare disease variants and genes for the HipSci rare disease samples; M.J.G. performed the colocalization analysis; M.J.B., D.S., B.M. and D.H. developed the eQTL software; C.Z. generated iPSC lines for UDN rare disease samples; N.C., I.C.-O., Y.P. assisted with data processing and analysis; M.J.B., C.S., M.J.G., S.B.M., O.S. wrote the manuscript; I.C.-O., N.C., N.M.F., K.A.F., L.F., M.J.G., D.J., M.T.W., D.B.Z., B.M. assisted in editing the manuscript; M.J.B., C.S., E.S., K.A.F., O.S., S.B.M. conceived and oversaw the study.
Author contributions
ISSN:1061-4036
1546-1718
DOI:10.1038/s41588-021-00800-7