Genetic effects on gene expression across human tissues

Abstract

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of disease.

Author notes

Correspondence and requests for materials should be addressed to A.B. ( ajbattle@ 123456cs.jhu.edu ), C.D.Br. ( chrbro@ 123456pennmedicine.upenn.edu ), B.E.E. ( bee@ 123456princeton.edu ) & S.B.M. ( smontgom@ 123456stanford.edu )

Lead analysts: François Aguet ¹ *, Andrew A. Brown ^{2, 3, 4} *, Stephane E. Castel ^{5, 6} *, Joe R. Davis ^{7, 8} *, Yuan He ⁹ *, Brian Jo ¹⁰ *, Pejman Mohammadi ^{5, 6} *, YoSon Park ¹¹ *, Princy Parsana ¹² *, Ayellet V. Segrè ¹ *, Benjamin J. Strober ⁹ *, Zachary Zappala ^{7, 8} *

Laboratory, Data Analysis & Coordinating Center (LDACC): Beryl B. Cummings ^{1, 13} , Ellen T. Gelfand ¹ , Kane Hadley ¹ , Katherine H. Huang ¹ , Monkol Lek ^{1, 13} , Xiao Li ¹ , Jared L. Nedzel ¹ , Duyen Y. Nguyen ¹ , Michael S. Noble ¹ , Timothy J. Sullivan ¹ , Taru Tukiainen ^{1, 13} , Daniel G. MacArthur ^{1, 13} , Gad Getz ^{1, 14}

NIH program management: Anjene Addington ¹⁵ , Ping Guan ¹⁶ , Susan Koester ¹⁵ , A. Roger Little ¹⁷ , Nicole C. Lockhart ¹⁸ , Helen M. Moore ¹⁶ , Abhi Rao ¹⁶ , Jeffery P. Struewing ¹⁹ , Simona Volpi ¹⁹

Biospecimen collection: Lori E. Brigham ²⁰ , Richard Hasz ²¹ , Marcus Hunter ²² , Christopher Johns ²³ , Mark Johnson ²⁴ , Gene Kopen ²⁵ , William F. Leinweber ²⁵ , John T. Lonsdale ²⁵ , Alisa McDonald ²⁵ , Bernadette Mestichelli ²⁵ , Kevin Myer ²² , Bryan Roe ²² , Michael Salvatore ²⁵ , Saboor Shad ²⁵ , Jeffrey A. Thomas ²⁵ , Gary Walters ²⁴ , Michael Washington ²⁴ , Joseph Wheeler ²³ , Jason Bridge ²⁶ , Barbara A. Foster ²⁷ , Bryan M. Gillard ²⁷ , Ellen Karasik ²⁷ , Rachna Kumar ²⁷ , Mark Miklos ²⁶ , Michael T. Moser ²⁷ , Scott D. Jewell ²⁸ , Robert G. Montroy ²⁸ , Daniel C. Rohrer ²⁸ , Dana Valley ²⁸ , Deborah C. Mash ²⁹ , David A. Davis ²⁹

Pathology: Leslie Sobin ³⁰ , Mary E. Barcus ³⁰ , Philip A. Branton ¹⁶

eQTL manuscript working group: Nathan S. Abell ^{7, 8} , Brunilda Balliu ⁸ , Olivier Delaneau ^{2, 3, 4} , Laure Frésard ⁸ , Eric R. Gamazon ³¹ , Diego Garrido-Martín ^{32, 33} , Ariel D. H. Gewirtz ¹⁰ , Genna Gliner ³⁴ , Michael J. Gloudemans ^{8, 35} , Buhm Han ³⁶ , Amy Z. He ¹² , Farhad Hormozdiari ³⁷ , Xin Li ⁸ , Boxiang Liu ^{8, 38} , Eun Yong Kang ³⁹ , Ian C. McDowell ⁴⁰ , Halit Ongen ^{2, 3, 4} , John J. Palowitch ⁴¹ , Christine B. Peterson ⁴² , Gerald Quon ^{1, 43} , Stephan Ripke ^{13, 44} , Ashis Saha ¹² , Andrey A. Shabalin ⁴⁵ , Tyler C. Shimko ^{7, 8} , Jae Hoon Sul ⁴⁶ , Nicole A. Teran ^{7, 8} , Emily K. Tsang ^{8, 35} , Hailei Zhang ¹ , Yi-Hui Zhou ⁴⁷ , Carlos D. Bustamante ^{7, 48} , Nancy J. Cox ³¹ , Roderic Guigó ^{32, 33} , Manolis Kellis ^{1, 43} , Mark I. McCarthy ^{49, 50, 51} , Donald F. Conrad ^{52, 53} , Eleazar Eskin ^{37, 39} , Gen Li ⁵⁴ , Andrew B. Nobel ⁴¹ , Chiara Sabatti ^{48, 55} , Barbara E. Stranger ⁵⁶ , Xiaoquan Wen ⁵⁷ , Fred A. Wright ⁵⁸ , Kristin G. Ardlie ¹ , Emmanouil T. Dermitzakis ^{2, 3, 4} , Tuuli Lappalainen ^{5, 6}

Corresponding authors: Alexis Battle ^{12 §} , Christopher D. Brown ^{11 §} , Barbara E. Engelhardt ^{59 §} & Stephen B. Montgomery ^{7, 8 §}

[1]

The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.

[2]

Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland.

[3]

Institute for Genetics and Genomics in Geneva (iG3), University of Geneva, 1211 Geneva, Switzerland.

[4]

Swiss Institute of Bioinformatics, 1211 Geneva, Switzerland.

[5]

New York Genome Center, New York, New York 10013, USA.

[6]

Department of Systems Biology, Columbia University, New York, New York 10032, USA.

[7]

Department of Genetics, Stanford University, Stanford, California 94305, USA.

[8]

Department of Pathology, Stanford University, Stanford, California 94305, USA.

[9]

Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland 21218, USA.

[10]

Lewis Sigler Institute, Princeton University, Princeton, New Jersey 08450, USA.

[11]

Department of Genetics and Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

[12]

Department of Computer Science, Johns Hopkins University, Baltimore, Maryland 21218, USA.

[13]

Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

[14]

Massachusetts General Hospital Cancer Center and Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.

[15]

Division of Neuroscience and Basic Behavioral Science, National Institute of Mental Health, Bethesda, Maryland 20892, USA.

[16]

Biorepositories and Biospecimen Research Branch, Cancer Diagnosis Program, National Cancer Institute, Bethesda, Maryland 20892, USA.

[17]

Division of Neuroscience and Behavior, National Institute on Drug Abuse, Bethesda, Maryland 20892, USA.

[18]

Division of Genomics and Society, National Human Genome Research Institute, Bethesda, Maryland 20892, USA.

[19]

Division of Genomic Medicine, National Human Genome Research Institute, Bethesda, Maryland 20892, USA.

[20]

Washington Regional Transplant Community, Annandale, Virginia 22003, USA.

[21]

Gift of Life Donor Program, Philadelphia, Pennsylvania 19103, USA.

[22]

LifeGift, Houston, Texas 77055, USA.

[23]

Center for Organ Recovery and Education, Pittsburgh, Pennsylvania 15238, USA.

[24]

LifeNet Health, Virginia Beach, Virginia 23453, USA.

[25]

National Disease Research Interchange, Philadelphia, Pennsylvania 19103, USA.

[26]

Unyts, Buffalo, New York 14203, USA.

[27]

Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.

[28]

Van Andel Research Institute, Grand Rapids, Michegan 49503, USA.

[29]

Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA.

[30]

Leidos Biomedical Research Inc., Rockville, Maryland 20852, USA.

[31]

Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA.

[32]

Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, 88, 08003 Barcelona, Spain.

[33]

Universitat Pompeu Fabra (UPF), 08002 Barcelona, Spain.

[34]

Department of Operations Research and Financial Engineering, Princeton University, Princeton, New Jersey 84540, USA.

[35]

Biomedical Informatics Program, Stanford University, Stanford, California 94305, USA.

[36]

Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, Korea.

[37]

Department of Human Genetics, University of California, Los Angeles, California 90095, USA.

[38]

Department of Biology, Stanford University, Stanford, California 94305, USA.

[39]

Department of Computer Science, University of California, Los Angeles, California 90095, USA.

[40]

Computational Biology and Bioinformatics Graduate Program, Duke University, Durham, North Carolina 27708, USA.

[41]

Department of Statistics and Operations Research, University of North Carolina, Chapel Hill, North Carolina 27599, USA.

[42]

Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

[43]

Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge, Massachusetts 02139, USA.

[44]

Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.

[45]

Center for Biomarker Research and Personalized Medicine, Virginia Commonwealth University, Richmond, Virginia 23298, USA.

[46]

Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, California 90095, USA.

[47]

Bioinformatics Research Center and Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina 27695, USA.

[48]

Department of Biomedical Data Science, Stanford University, Stanford, California 94305, USA.

[49]

Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK.

[50]

Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK.

[51]

Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford OX3 7LE, UK.

[52]

Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

[53]

Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

[54]

Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York 10032, USA.

[55]

Department of Statistics, Stanford University, Stanford, California 94305, USA.

[56]

Section of Genetic Medicine, Department of Medicine, Institute for Genomics and Systems Biology, Center for Data Intensive Science, University of Chicago, Chicago, Illinois 60637, USA.

[57]

Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.

[58]

Bioinformatics Research Center, Departments of Statistics and Biological Sciences, North Carolina State University, Raleigh, North Carolina 27695, USA.

[59]

Department of Computer Science and Center for Statistics and Machine Learning, Princeton University, Princeton, New Jersey 08540, USA.

[*]

These authors contributed equally to this work.

[§]

These authors jointly supervised this work.

Journal

Journal ID (nlm-journal-id): 0410462

Journal ID (pubmed-jr-id): 6011

Journal ID (nlm-ta): Nature

Journal ID (iso-abbrev): Nature

Title: Nature

ISSN (Print): 0028-0836

ISSN (Electronic): 1476-4687

Publication date Nihms-submitted 9 December 2017

Publication date (Print): 11 October 2017

Publication date PMC-release 22 January 2018

Volume: 550

Issue: 7675

Pages: 204-213

PubMed ID: 29022597

PMC ID: 5776756

DOI: 10.1038/nature24277

Manuscript ID: NIHMS925370

License:

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Subject: Article