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Cell type specific genetic regulation of gene expression across human tissues

View ORCID ProfileSarah Kim-Hellmuth, François Aguet, Meritxell Oliva, Manuel Muñoz-Aguirre, Valentin Wucher, Silva Kasela, Stephane E. Castel, Andrew R. Hamel, View ORCID ProfileAna Viñuela, Amy L. Roberts, Serghei Mangul, Xiaoquan Wen, Gao Wang, Alvaro N. Barbeira, Diego Garrido-Martín, Brian Nadel, Yuxin Zou, Rodrigo Bonazzola, Jie Quan, Andrew Brown, View ORCID ProfileAngel Martinez-Perez, José Manuel Soria, GTEx Consortium, Gad Getz, Emmanouil T. Dermitzakis, Kerrin S. Small, Matthew Stephens, Hualin S. Xi, Hae Kyung Im, Roderic Guigó, Ayellet V. Segrè, Barbara E. Stranger, Kristin G. Ardlie, Tuuli Lappalainen
doi: https://doi.org/10.1101/806117
Sarah Kim-Hellmuth
1Statistical Genetics, Max Planck Institute of Psychiatry, Munich, Germany
2New York Genome Center, New York, NY, USA
3Department of Systems Biology, Columbia University, New York, NY, USA
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  • ORCID record for Sarah Kim-Hellmuth
  • For correspondence: skimhellmuth@gmail.com tlappalainen@nygenome.org
François Aguet
4The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Meritxell Oliva
5Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, USA
6Department of Public Health Sciences, The University of Chicago, Chicago, IL, USA
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Manuel Muñoz-Aguirre
7Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Barcelona, Catalonia, Spain
8Department of Statistics and Operations Research, Universitat Politècnica de Catalunya (UPC), Barcelona, Catalonia, Spain
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Valentin Wucher
7Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Barcelona, Catalonia, Spain
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Silva Kasela
2New York Genome Center, New York, NY, USA
3Department of Systems Biology, Columbia University, New York, NY, USA
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Stephane E. Castel
2New York Genome Center, New York, NY, USA
3Department of Systems Biology, Columbia University, New York, NY, USA
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Andrew R. Hamel
4The Broad Institute of MIT and Harvard, Cambridge, MA, USA
9Ocular Genomics Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
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Ana Viñuela
10Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK
11Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
12Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland
13Swiss Institute of Bioinformatics, Geneva, Switzerland
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Amy L. Roberts
10Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK
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Serghei Mangul
14Department of Computer Science, University of California, Los Angeles, Los Angeles, CA, USA
15Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA, USA
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Xiaoquan Wen
16Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA
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Gao Wang
17Department of Human Genetics, University of Chicago, Chicago, IL, USA
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Alvaro N. Barbeira
5Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, USA
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Diego Garrido-Martín
7Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Barcelona, Catalonia, Spain
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Brian Nadel
18Department of Molecular, Cellular, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA
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Yuxin Zou
19Department of Statistics, University of Chicago, Chicago, IL, USA
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Rodrigo Bonazzola
5Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, USA
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Jie Quan
20Inflammation & Immunology, Pfizer, Cambridge, MA, USA
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Andrew Brown
11Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
21Population Health and Genomics, University of Dundee, Dundee, Scotland, UK
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Angel Martinez-Perez
22Unit of Genomic of Complex Diseases, Institut d’Investigació Biomèdica Sant Pau (IIB-Sant Pau), Barcelona. Spain
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José Manuel Soria
22Unit of Genomic of Complex Diseases, Institut d’Investigació Biomèdica Sant Pau (IIB-Sant Pau), Barcelona. Spain
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Gad Getz
4The Broad Institute of MIT and Harvard, Cambridge, MA, USA
23Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
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Emmanouil T. Dermitzakis
11Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
12Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland
13Swiss Institute of Bioinformatics, Geneva, Switzerland
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Kerrin S. Small
10Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK
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Matthew Stephens
17Department of Human Genetics, University of Chicago, Chicago, IL, USA
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Hualin S. Xi
24Foundational Neuroscience Center, AbbVie, Cambridge, MA, USA
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Hae Kyung Im
5Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, USA
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Roderic Guigó
7Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Barcelona, Catalonia, Spain
25Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain
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Ayellet V. Segrè
4The Broad Institute of MIT and Harvard, Cambridge, MA, USA
9Ocular Genomics Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
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Barbara E. Stranger
5Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, USA
26Center for Genetic Medicine, Department of Pharmacology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
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Kristin G. Ardlie
4The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Tuuli Lappalainen
2New York Genome Center, New York, NY, USA
3Department of Systems Biology, Columbia University, New York, NY, USA
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  • For correspondence: skimhellmuth@gmail.com tlappalainen@nygenome.org
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Abstract

The Genotype-Tissue Expression (GTEx) project has identified expression and splicing quantitative trait loci (cis-QTLs) for the majority of genes across a wide range of human tissues. However, the interpretation of these QTLs has been limited by the heterogeneous cellular composition of GTEx tissue samples. Here, we map interactions between computational estimates of cell type abundance and genotype to identify cell type interaction QTLs for seven cell types and show that cell type interaction eQTLs provide finer resolution to tissue specificity than bulk tissue cis-eQTLs. Analyses of genetic associations to 87 complex traits show a contribution from cell type interaction QTLs and enables the discovery of hundreds of previously unidentified colocalized loci that are masked in bulk tissue.

One Sentence Summary Estimated cell type abundances from bulk RNA-seq across tissues reveal the cellular specificity of quantitative trait loci.

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Posted October 17, 2019.
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Cell type specific genetic regulation of gene expression across human tissues
Sarah Kim-Hellmuth, François Aguet, Meritxell Oliva, Manuel Muñoz-Aguirre, Valentin Wucher, Silva Kasela, Stephane E. Castel, Andrew R. Hamel, Ana Viñuela, Amy L. Roberts, Serghei Mangul, Xiaoquan Wen, Gao Wang, Alvaro N. Barbeira, Diego Garrido-Martín, Brian Nadel, Yuxin Zou, Rodrigo Bonazzola, Jie Quan, Andrew Brown, Angel Martinez-Perez, José Manuel Soria, GTEx Consortium, Gad Getz, Emmanouil T. Dermitzakis, Kerrin S. Small, Matthew Stephens, Hualin S. Xi, Hae Kyung Im, Roderic Guigó, Ayellet V. Segrè, Barbara E. Stranger, Kristin G. Ardlie, Tuuli Lappalainen
bioRxiv 806117; doi: https://doi.org/10.1101/806117
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Cell type specific genetic regulation of gene expression across human tissues
Sarah Kim-Hellmuth, François Aguet, Meritxell Oliva, Manuel Muñoz-Aguirre, Valentin Wucher, Silva Kasela, Stephane E. Castel, Andrew R. Hamel, Ana Viñuela, Amy L. Roberts, Serghei Mangul, Xiaoquan Wen, Gao Wang, Alvaro N. Barbeira, Diego Garrido-Martín, Brian Nadel, Yuxin Zou, Rodrigo Bonazzola, Jie Quan, Andrew Brown, Angel Martinez-Perez, José Manuel Soria, GTEx Consortium, Gad Getz, Emmanouil T. Dermitzakis, Kerrin S. Small, Matthew Stephens, Hualin S. Xi, Hae Kyung Im, Roderic Guigó, Ayellet V. Segrè, Barbara E. Stranger, Kristin G. Ardlie, Tuuli Lappalainen
bioRxiv 806117; doi: https://doi.org/10.1101/806117

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