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

Sarah Kim-Hellmuth; François Aguet; Meritxell Oliva; Manuel Muñoz-Aguirre; Silva Kasela; Valentin Wucher; Stephane E Castel; Andrew R Hamel; Ana Viñuela; Amy L Roberts; Serghei Mangul; Xiaoquan Wen; Gao Wang; Alvaro N Barbeira; Diego Garrido-Martín; Brian B 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

doi:10.1126/science.aaz8528

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

Science. 2020 Sep 11;369(6509):eaaz8528. doi: 10.1126/science.aaz8528.

Authors

Sarah Kim-Hellmuth^#^{1

2

3}, François Aguet^#⁴, Meritxell Oliva^{5

6}, Manuel Muñoz-Aguirre^{7

8}, Silva Kasela^{2

3}, Valentin Wucher⁷, Stephane E Castel^{2

3}, Andrew R Hamel^{4

9}, Ana Viñuela^{10

11

12

13}, Amy L Roberts¹⁰, Serghei Mangul^{14

15}, Xiaoquan Wen¹⁶, Gao Wang¹⁷, Alvaro N Barbeira⁵, Diego Garrido-Martín⁷, Brian B Nadel¹⁸, Yuxin Zou¹⁹, Rodrigo Bonazzola⁵, Jie Quan²⁰, Andrew Brown^{11

21}, Angel Martinez-Perez²², José Manuel Soria²²; GTEx Consortium; Gad Getz^{4

23

24}, Emmanouil T Dermitzakis^{11

12

13}, Kerrin S Small¹⁰, Matthew Stephens¹⁷, Hualin S Xi²⁵, Hae Kyung Im⁵, Roderic Guigó^{7

26}, Ayellet V Segrè^{4

9}, Barbara E Stranger^{5

27}, Kristin G Ardlie⁴, Tuuli Lappalainen^{28

3}

Collaborators

GTEx Consortium:
François Aguet, Shankara Anand, Kristin G Ardlie, Stacey Gabriel, Gad A Getz, Aaron Graubert, Kane Hadley, Robert E Handsaker, Katherine H Huang, Seva Kashin, Xiao Li, Daniel G MacArthur, Samuel R Meier, Jared L Nedzel, Duyen T Nguyen, Ayellet V Segrè, Ellen Todres, Brunilda Balliu, Alvaro N Barbeira, Alexis Battle, Rodrigo Bonazzola, Andrew Brown, Christopher D Brown, Stephane E Castel, Donald F Conrad, Daniel J Cotter, Nancy Cox, Sayantan Das, Olivia M de Goede, Emmanouil T Dermitzakis, Jonah Einson, Barbara E Engelhardt, Eleazar Eskin, Tiffany Y Eulalio, Nicole M Ferraro, Elise D Flynn, Laure Fresard, Eric R Gamazon, Diego Garrido-Martín, Nicole R Gay, Michael J Gloudemans, Roderic Guigó, Andrew R Hame, Yuan He, Paul J Hoffman, Farhad Hormozdiari, Lei Hou, Hae Kyung Im, Brian Jo, Silva Kasela, Manolis Kellis, Sarah Kim-Hellmuth, Alan Kwong, Tuuli Lappalainen, Xin Li, Yanyu Liang, Serghei Mangul, Pejman Mohammadi, Stephen B Montgomery, Manuel Muñoz-Aguirre, Daniel C Nachun, Andrew B Nobel, Meritxell Oliva, YoSon Park, Yongjin Park, Princy Parsana, Abhiram S Rao, Ferran Reverter, John M Rouhana, Chiara Sabatti, Ashis Saha, Matthew Stephens, Barbara E Stranger, Benjamin J Strober, Nicole A Teran, Ana Viñuela, Gao Wang, Xiaoquan Wen, Fred Wright, Valentin Wucher, Yuxin Zou, Pedro G Ferreira, Gen Li, Marta Melé, Esti Yeger-Lotem, Mary E Barcus, Debra Bradbury, Tanya Krubit, Jeffrey A McLean, Liqun Qi, Karna Robinson, Nancy V Roche, Anna M Smith, Leslie Sobin, David E Tabor, Anita Undale, Jason Bridge, Lori E Brigham, Barbara A Foster, Bryan M Gillard, Richard Hasz, Marcus Hunter, Christopher Johns, Mark Johnson, Ellen Karasik, Gene Kopen, William F Leinweber, Alisa McDonald, Michael T Moser, Kevin Myer, Kimberley D Ramsey, Brian Roe, Saboor Shad, Jeffrey A Thomas, Gary Walters, Michael Washington, Joseph Wheeler, Scott D Jewell, Daniel C Rohrer, Dana R Valley, David A Davis, Deborah C Mash, Philip A Branton, Laura K Barker, Heather M Gardiner, Maghboeba Mosavel, Laura A Siminoff, Paul Flicek, Maximilian Haeussler, Thomas Juettemann, W James Kent, Christopher M Lee, Conner C Powell, Kate R Rosenbloom, Magali Ruffier, Dan Sheppard, Kieron Taylor, Stephen J Trevanion, Daniel R Zerbino, Nathan S Abell, Joshua Akey, Lin Chen, Kathryn Demanelis, Jennifer A Doherty, Andrew P Feinberg, Kasper D Hansen, Peter F Hickey, Farzana Jasmine, Lihua Jiang, Rajinder Kaul, Muhammad G Kibriya, Jin Billy Li, Qin Li, Shin Lin, Sandra E Linder, Brandon L Pierce, Lindsay F Rizzardi, Andrew D Skol, Kevin S Smith, Michael Snyder, John Stamatoyannopoulos, Hua Tang, Meng Wang, Latarsha J Carithers, Ping Guan, Susan E Koester, A Roger Little, Helen M Moore, Concepcion R Nierras, Abhi K Rao, Jimmie B Vaught, Simona Volpi

Affiliations

¹ Statistical Genetics, Max Planck Institute of Psychiatry, Munich, Germany. skimhellmuth@gmail.com tlappalainen@nygenome.org.
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.
²⁸ New York Genome Center, New York, NY, USA. skimhellmuth@gmail.com tlappalainen@nygenome.org.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cells / metabolism
Gene Expression Regulation*
Humans
Organ Specificity
Quantitative Trait Loci*
RNA, Long Noncoding / genetics
Transcriptome*

Substances

RNA, Long Noncoding

Abstract

Publication types

MeSH terms

Substances

Grants and funding