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 in:Nature 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
Language:English
Published: New York Nature Publishing Group US 01.03.2021
Nature Publishing Group
Subjects:
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Agriculture
Animal Genetics and Genomics
Bardet-Biedl Syndrome - genetics
Biomedical and Life Sciences
Biomedicine
Calcium Channels - genetics
Cancer Research
Cell Line
Cerebellar Ataxia - genetics
Disease
DNA Methylation
Gene Expression
Gene Function
Genetic aspects
Genetic diversity
Genetic regulation
Genetic research
Genetic variance
Genetic Variation
Genomes
Genotype & phenotype
Human Genetics
Humans
Induced Pluripotent Stem Cells - cytology
Induced Pluripotent Stem Cells - physiology
Pluripotency
Polymorphism, Single Nucleotide
Proteins - genetics
Quantitative Trait Loci
Rare diseases
Rare Diseases - genetics
Regulatory Sequences, Nucleic Acid
Sequence Analysis, RNA
Stem cells
Whole Genome Sequencing
United Kingdom
ISSN:1061-4036, 1546-1718, 1546-1718
Online Access:Get full text
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Description
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.
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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
1546-1718
DOI:10.1038/s41588-021-00800-7