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      • Record: found
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      Genetic effects on gene expression across human tissues

      GTEx consortium

      Nature

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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.

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          Most cited references 37

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          Genetic dissection of transcriptional regulation in budding yeast.

          To begin to understand the genetic architecture of natural variation in gene expression, we carried out genetic linkage analysis of genomewide expression patterns in a cross between a laboratory strain and a wild strain of Saccharomyces cerevisiae. Over 1500 genes were differentially expressed between the parent strains. Expression levels of 570 genes were linked to one or more different loci, with most expression levels showing complex inheritance patterns. The loci detected by linkage fell largely into two categories: cis-acting modulators of single genes and trans-acting modulators of many genes. We found eight such trans-acting loci, each affecting the expression of a group of 7 to 94 genes of related function.
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            IRF family of transcription factors as regulators of host defense.

            Interferon regulatory factors (IRFs) constitute a family of transcription factors that commonly possess a novel helix-turn-helix DNA-binding motif. Following the initial identification of two structurally related members, IRF-1 and IRF-2, seven additional members have now been reported. In addition, virally encoded IRFs, which may interfere with cellular IRFs, have also been identified. Thus far, intensive functional analyses have been done on IRF-1, revealing a remarkable functional diversity of this transcription factor in the regulation of cellular response in host defense. Indeed, IRF-1 selectively modulates different sets of genes, depending on the cell type and/or the nature of cellular stimuli, in order to evoke appropriate responses in each. More recently, much attention has also been focused on other IRF family members. Their functional roles, through interactions with their own or other members of the family of transcription factors, are becoming clearer in the regulation of host defense, such as innate and adaptive immune responses and oncogenesis.
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              Characterizing the genetic basis of transcriptome diversity through RNA-sequencing of 922 individuals.

              Understanding the consequences of regulatory variation in the human genome remains a major challenge, with important implications for understanding gene regulation and interpreting the many disease-risk variants that fall outside of protein-coding regions. Here, we provide a direct window into the regulatory consequences of genetic variation by sequencing RNA from 922 genotyped individuals. We present a comprehensive description of the distribution of regulatory variation--by the specific expression phenotypes altered, the properties of affected genes, and the genomic characteristics of regulatory variants. We detect variants influencing expression of over ten thousand genes, and through the enhanced resolution offered by RNA-sequencing, for the first time we identify thousands of variants associated with specific phenotypes including splicing and allelic expression. Evaluating the effects of both long-range intra-chromosomal and trans (cross-chromosomal) regulation, we observe modularity in the regulatory network, with three-dimensional chromosomal configuration playing a particular role in regulatory modules within each chromosome. We also observe a significant depletion of regulatory variants affecting central and critical genes, along with a trend of reduced effect sizes as variant frequency increases, providing evidence that purifying selection and buffering have limited the deleterious impact of regulatory variation on the cell. Further, generalizing beyond observed variants, we have analyzed the genomic properties of variants associated with expression and splicing and developed a Bayesian model to predict regulatory consequences of genetic variants, applicable to the interpretation of individual genomes and disease studies. Together, these results represent a critical step toward characterizing the complete landscape of human regulatory variation.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                9 December 2017
                11 October 2017
                22 January 2018
                : 550
                : 7675
                : 204-213
                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.

                Article
                NIHMS925370
                10.1038/nature24277
                5776756
                29022597

                This work is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) licence. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons licence, users will need to obtain permission from the licence holder to reproduce the material. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                Reprints and permissions information is available at www.nature.com/reprints.

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