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Distant regulatory effects of genetic variation in multiple human tissues

Brian Jo, Yuan He, Benjamin J. Strober, Princy Parsana, François Aguet, Andrew A. Brown, Stephane E. Castel, Eric R. Gamazon, Ariel Gewirtz, Genna Gliner, Buhm Han, Amy Z. He, Eun Yong Kang, Ian C. McDowell, Xiao Li, Pejman Mohammadi, Christine B. Peterson, Gerald Quon, Ashis Saha, Ayellet V. Segrè, Jae Hoon Sul, Timothy J. Sullivan, Kristin G. Ardlie, Christopher D. Brown, Donald F. Conrad, Nancy J. Cox, Emmanouil T. Dermitzakis, Eleazar Eskin, Manolis Kellis, Tuuli Lappalainen, Chiara Sabatti, GTEx Consortium, View ORCID ProfileBarbara E. Engelhardt, View ORCID ProfileAlexis Battle
doi: https://doi.org/10.1101/074419
Brian Jo
1Lewis Sigler Institute, Princeton University, Princeton, NJ 08540
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Yuan He
2Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21218
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Benjamin J. Strober
2Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21218
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Princy Parsana
3Department of Computer Science, Johns Hopkins University, Baltimore, MD 21218
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François Aguet
4The Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142
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Andrew A. Brown
5Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland
6Institute for Genetics and Genomics in Geneva (iG3), University of Geneva, 1211 Geneva, Switzerland
7Swiss Institute of Bioinformatics, 1211 Geneva, Switzerland
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Stephane E. Castel
8New York Genome Center, 101 Avenue of the Americas, New York, NY, 10013
9Department of Systems Biology, Columbia University Medical Center, New York, NY 10032
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Eric R. Gamazon
10Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Canter, Nashville, TN 37232
11Department of Clinical Epidemiology, Biostatistics and Bioinformatics and Department of Psychiatry, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
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Ariel Gewirtz
1Lewis Sigler Institute, Princeton University, Princeton, NJ 08540
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Genna Gliner
12Department of Operations Research and Financial Engineering, Princeton University, Princeton, NJ 08540
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Buhm Han
13Department of Convergence Medicine, University of Ulsan College of Medicine, Asian Medical Center, Korea
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Amy Z. He
3Department of Computer Science, Johns Hopkins University, Baltimore, MD 21218
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Eun Yong Kang
14Department of Computer Science, University of California, Los Angeles, CA 90095
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Ian C. McDowell
15Computational Biology & Bioinformatics Graduate Program, Duke University, Durham, NC 27708
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Xiao Li
4The Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142
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Pejman Mohammadi
8New York Genome Center, 101 Avenue of the Americas, New York, NY, 10013
9Department of Systems Biology, Columbia University Medical Center, New York, NY 10032
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Christine B. Peterson
16Department of Biostatistics, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Houston, TX 77030
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Gerald Quon
4The Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142
17Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge, MA, 02139
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Ashis Saha
3Department of Computer Science, Johns Hopkins University, Baltimore, MD 21218
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Ayellet V. Segrè
4The Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142
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Jae Hoon Sul
18Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095
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Timothy J. Sullivan
4The Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142
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Kristin G. Ardlie
4The Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142
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Christopher D. Brown
19University of Pennsylvania, Perelman School of Medicine, Department of Genetics, Philadelphia, PA, 19104
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Donald F. Conrad
20Department of Genetics, Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri
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Nancy J. Cox
10Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Canter, Nashville, TN 37232
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Emmanouil T. Dermitzakis
5Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland
6Institute for Genetics and Genomics in Geneva (iG3), University of Geneva, 1211 Geneva, Switzerland
7Swiss Institute of Bioinformatics, 1211 Geneva, Switzerland
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Eleazar Eskin
14Department of Computer Science, University of California, Los Angeles, CA 90095
21Department of Human Genetics, University of California, Los Angeles, CA 90095
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Manolis Kellis
4The Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142
17Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge, MA, 02139
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Tuuli Lappalainen
8New York Genome Center, 101 Avenue of the Americas, New York, NY, 10013
9Department of Systems Biology, Columbia University Medical Center, New York, NY 10032
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Chiara Sabatti
22Departments of Biomedical Data Science and Statistics, HRP Redwood building, Stanford, CA 94305-5404
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Barbara E. Engelhardt
23Princeton University, Department of Computer Science, Center for Statistics and Machine Learning, 35 Olden Street, Princeton, NJ 08540
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  • ORCID record for Barbara E. Engelhardt
  • For correspondence: ajbattle@cs.jhu.edu bee@princeton.edu
Alexis Battle
3Department of Computer Science, Johns Hopkins University, Baltimore, MD 21218
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  • ORCID record for Alexis Battle
  • For correspondence: ajbattle@cs.jhu.edu bee@princeton.edu
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Abstract

Understanding the genetics of gene regulation provides information on the cellular mechanisms through which genetic variation influences complex traits. Expression quantitative trait loci, or eQTLs, are enriched for polymorphisms that have been found to be associated with disease risk. While most analyses of human data has focused on regulation of expression by nearby variants (cis-eQTLs), distal or trans-eQTLs may have broader effects on the transcriptome and important phenotypic consequences, necessitating a comprehensive study of the effects of genetic variants on distal gene transcription levels. In this work, we identify trans-eQTLs in the Genotype Tissue Expression (GTEx) project data1, consisting of 449 individuals with RNA-sequencing data across 44 tissue types. We find 81 genes with a trans-eQTL in at least one tissue, and we demonstrate that trans-eQTLs are more likely than cis-eQTLs to have effects specific to a single tissue. We evaluate the genomic and functional properties of trans-eQTL variants, identifying strong enrichment in enhancer elements and Piwi-interacting RNA clusters. Finally, we describe three tissue-specific regulatory loci underlying relevant disease associations: 9q22 in thyroid that has a role in thyroid cancer, 5q31 in skeletal muscle, and a previously reported master regulator near KLF14 in adipose. These analyses provide a comprehensive characterization of trans-eQTLs across human tissues, which contribute to an improved understanding of the tissue-specific cellular mechanisms of regulatory genetic variation.

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Posted September 09, 2016.
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Distant regulatory effects of genetic variation in multiple human tissues
Brian Jo, Yuan He, Benjamin J. Strober, Princy Parsana, François Aguet, Andrew A. Brown, Stephane E. Castel, Eric R. Gamazon, Ariel Gewirtz, Genna Gliner, Buhm Han, Amy Z. He, Eun Yong Kang, Ian C. McDowell, Xiao Li, Pejman Mohammadi, Christine B. Peterson, Gerald Quon, Ashis Saha, Ayellet V. Segrè, Jae Hoon Sul, Timothy J. Sullivan, Kristin G. Ardlie, Christopher D. Brown, Donald F. Conrad, Nancy J. Cox, Emmanouil T. Dermitzakis, Eleazar Eskin, Manolis Kellis, Tuuli Lappalainen, Chiara Sabatti, GTEx Consortium, Barbara E. Engelhardt, Alexis Battle
bioRxiv 074419; doi: https://doi.org/10.1101/074419
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Distant regulatory effects of genetic variation in multiple human tissues
Brian Jo, Yuan He, Benjamin J. Strober, Princy Parsana, François Aguet, Andrew A. Brown, Stephane E. Castel, Eric R. Gamazon, Ariel Gewirtz, Genna Gliner, Buhm Han, Amy Z. He, Eun Yong Kang, Ian C. McDowell, Xiao Li, Pejman Mohammadi, Christine B. Peterson, Gerald Quon, Ashis Saha, Ayellet V. Segrè, Jae Hoon Sul, Timothy J. Sullivan, Kristin G. Ardlie, Christopher D. Brown, Donald F. Conrad, Nancy J. Cox, Emmanouil T. Dermitzakis, Eleazar Eskin, Manolis Kellis, Tuuli Lappalainen, Chiara Sabatti, GTEx Consortium, Barbara E. Engelhardt, Alexis Battle
bioRxiv 074419; doi: https://doi.org/10.1101/074419

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