Biological Sciences Division
Published May 8, 2018 | Version v1
Journal article Open

Determining the genetic basis of anthracycline-cardiotoxicity by molecular response QTL mapping in induced cardiomyocytes

Creators

  • 1. Stanford University
  • 2. University of Chicago
  • 3. Mayo Clinic

Description

Anthracycline-induced cardiotoxicity (ACT) is a key limiting factor in setting optimal chemotherapy regimes, with almost half of patients expected to develop congestive heart failure given high doses. However, the genetic basis of sensitivity to anthracyclines remains unclear. We created a panel of iPSC-derived cardiomyocytes from 45 individuals and performed RNA-seq after 24 hr exposure to varying doxorubicin dosages. The transcriptomic response is substantial: the majority of genes are differentially expressed and over 6000 genes show evidence of differential splicing, the later driven by reduced splicing fidelity in the presence of doxorubicin. We show that inter-individual variation in transcriptional response is predictive of in vitro cell damage, which in turn is associated with in vivo ACT risk. We detect 447 response-expression quantitative trait loci (QTLs) and 42 response-splicing QTLs, which are enriched in lower ACT GWAS p-values, supporting the in vivo relevance of our map of genetic regulation of cellular response to anthracyclines.

Data availability

All the custom analysis scripts used for this project are available at https://github.com/davidaknowles/dox (Knowles and Blischak, 2017). The suez response eQTL mapping R package is available at https://github.com/davidaknowles/suez (Knowles, 2017). The following data are available as Supplementary Data: 1) differential expression cluster assignments, 2) significant (5% FDR) eQTLs and sQTLs, 3) differential splicing results, 4) levels of cardiac troponin and the predicted transcriptomic response. In addition to the Supplementary Data included with this paper, further results are hosted at Dryad (doi:10.5061/dryad.r5t8d04) including 1) gene-by-sample matrix of RNA-seq quantification (log counts per million), 2) LeafCutter intron excision quantification 3) p-values for all tested eQTLs, reQTLs, sQTLs, and rsQTLs, 4) RARG variant response and marginal trans-eQTLs, 5) RIN, RNA concentration and other technical covariates, 6) embryoid body imaging for all iPSC lines. The RNA-seq FASTQ files will be added to the dbGaP database (Tryka et al., 2014) under dbGaP accession phs000185 (https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000185). The genotype data files cannot be shared because releasing genotype data from a subset of individuals in the pedigree would enable the reconstruction of genotypes of other members of the pedigree, which would violate the original protocol approved by the research ethics board (Livne et al., 2015). The summary statistics for the ACT GWAS were given to us by the authors of the study (Schneider et al., 2016; Serie et al. 2017).

The following data sets were generated:

Knowles DACourtney K BurrowsJohn D BlischakCarole OberJonathan K PritchardYoav Gilad (2018) Expression and splicing quantification, eQTLs and sQTLs Available at Dryad Digital Repository under a CC0 Public Domain Dedication. http://dx.doi.org/10.5061/dryad.r5t8d04

Courtney K BurrowsKnowles DAJohn D BlischakKristen M PattersonCarole OberJonathan K PritchardYoav Gilad (2018) Genetic Studies in the Hutterites Available at dbGaP via dbGaP Authorized Access (accession no. phs000185.v5.p1). https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000185

Files

elife-33480-v2.pdf

Files (11.9 MB)

Name Size Download all
Article
md5:a2c36180739f8fca100c5532577d8625
7.4 MB Preview Download
Additional files
md5:fd21441ae74d43cf51181234c5f13c85
4.5 MB Preview Download

Additional details

Identifiers

DOI
10.7554/eLife.33480.001
Other
oai:uchicago.tind.io:9861

Funding

National Institutes of Health
HL092206
Howard Hughes Medical Institute
National Institutes of Health
HG008140
National Institutes of Health
HG009431
National Institutes of Health
TL1 TR 432-7

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Human Genetics, Medicine