Cell type–specific genetic regulation of gene expression across human tissues

Author:

Kim-Hellmuth Sarah123ORCID,Aguet François4ORCID,Oliva Meritxell56ORCID,Muñoz-Aguirre Manuel78ORCID,Kasela Silva23ORCID,Wucher Valentin7ORCID,Castel Stephane E.23ORCID,Hamel Andrew R.49ORCID,Viñuela Ana10111213ORCID,Roberts Amy L.10ORCID,Mangul Serghei1415ORCID,Wen Xiaoquan16,Wang Gao17ORCID,Barbeira Alvaro N.5ORCID,Garrido-Martín Diego7ORCID,Nadel Brian B.18ORCID,Zou Yuxin19ORCID,Bonazzola Rodrigo5ORCID,Quan Jie20ORCID,Brown Andrew1121ORCID,Martinez-Perez Angel22ORCID,Soria José Manuel22,Getz Gad42324ORCID,Dermitzakis Emmanouil T.111213ORCID,Small Kerrin S.10ORCID,Stephens Matthew17ORCID,Xi Hualin S.25ORCID,Im Hae Kyung5ORCID,Guigó Roderic726ORCID,Segrè Ayellet V.49ORCID,Stranger Barbara E.527ORCID,Ardlie Kristin G.4ORCID,Lappalainen Tuuli23ORCID,

Affiliation:

1. Statistical Genetics, Max Planck Institute of Psychiatry, Munich, Germany.

2. New York Genome Center, New York, NY, USA.

3. Department of Systems Biology, Columbia University, New York, NY, USA.

4. The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

5. Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA.

6. Department of Public Health Sciences, University of Chicago, Chicago, IL, USA.

7. Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Barcelona, Catalonia, Spain.

8. Department of Statistics and Operations Research, Universitat Politècnica de Catalunya (UPC), Barcelona, Catalonia, Spain.

9. Ocular Genomics Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.

10. Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK.

11. Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.

12. Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland.

13. Swiss Institute of Bioinformatics, Geneva, Switzerland.

14. Department of Computer Science, University of California, Los Angeles, Los Angeles, CA, USA.

15. Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, Los Angeles, CA, USA.

16. Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.

17. Department of Human Genetics, University of Chicago, Chicago, IL, USA.

18. Department of Molecular, Cellular, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA.

19. Department of Statistics, University of Chicago, Chicago, IL, USA.

20. Inflammation & Immunology, Pfizer, Cambridge, MA, USA.

21. Population Health and Genomics, University of Dundee, Dundee, Scotland, UK.

22. Unit of Genomic of Complex Diseases, Institut d’Investigació Biomèdica Sant Pau (IIB-Sant Pau), Barcelona, Spain.

23. Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.

24. Harvard Medical School, Boston, MA, USA.

25. Foundational Neuroscience Center, AbbVie, Cambridge, MA, USA.

26. Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain.

27. Center for Genetic Medicine, Department of Pharmacology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.

Abstract

The Genotype-Tissue Expression (GTEx) project has identified expression and splicing quantitative trait loci in cis (QTLs) for the majority of genes across a wide range of human tissues. However, the functional characterization of these QTLs has been limited by the heterogeneous cellular composition of GTEx tissue samples. We mapped 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 expression QTLs (eQTLs) provide finer resolution to tissue specificity than bulk tissue cis-eQTLs. Analyses of genetic associations with 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.

Funder

NIH Office of the Director

European Commission

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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