Distant regulatory effects of genetic variation in multiple human tissues
Brian Jo,Yiping He,Benjamin J. Strober,Princy Parsana,François Aguet,Andrew A. Brown,SE Castel,Eric R. Gamazon,Ariel D. H. Gewirtz,Genna Gliner,Buhm Han,Alice He,Ey Kang,Ian C. McDowell,Xiao Li,Pejman Mohammadi,Christine B. Peterson,Gerald Quon,Ashis Saha,Ayellet V. Segrè,Jae Hoon Sul,TJ Sullivan,Kristin G. Ardlie,Christopher D. Brown,Donald F. Conrad,Nancy J. Cox,Emmanouil T. Dermitzakis,Eskin E,Manolis Kellis,Tuuli Lappalainen,Chiara Sabatti,Barbara E. Engelhardt,Alexis Battle +32 more
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TLDR
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.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 data, 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.read more
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Integrative analysis of 111 reference human epigenomes
Anshul Kundaje,Wouter Meuleman,Jason Ernst,Angela Yen,Pouya Kheradpour,Zhizhuo Zhang,Jianrong Wang,Lucas D. Ward,Abhishek Sarkar,Gerald Quon,Matthew L. Eaton,Yi-Chieh Wu,Andreas R. Pfenning,Xinchen Wang,Melina Claussnitzer,Yaping Liu,Mukul S. Bansal,Soheil Feizi-Khankandi,Ah Ram Kim,Richard C Sallari,Nicholas A Sinnott-Armstrong,Laurie A. Boyer,Elizabeta Gjoneska,Li-Huei Tsai,Manolis Kellis +24 more
TL;DR: In this article, the authors describe the integrative analysis of 111 reference human epigenomes generated as part of the NIH Roadmap Epigenomics Consortium, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression.
Journal ArticleDOI
An Expanded View of Complex Traits: From Polygenic to Omnigenic
TL;DR: It is proposed that gene regulatory networks are sufficiently interconnected such that all genes expressed in disease-relevant cells are liable to affect the functions of core disease-related genes and that most heritability can be explained by effects on genes outside core pathways.
Reference EntryDOI
National Institute of Neurological Disorders and Stroke
Milton Budoff,Tamara J. Martin +1 more
TL;DR: Marmosets are poised to be a central player to advance the core mission of the NINDS, as their brains retain the typical anatomical and functional organization of the primate brain and the species exhibits the breadth of cognitive sophistication that distinguishes primates from other taxonomic groups.
Journal ArticleDOI
Co-expression networks reveal the tissue-specific regulation of transcription and splicing
Ashis Saha,Yungil Kim,Ariel D. H. Gewirtz,Brian Jo,Chuan Gao,Ian C. McDowell,Barbara E. Engelhardt,Alexis Battle,François Aguet,Kristin G. Ardlie,Beryl B. Cummings,Beryl B. Cummings,Ellen Gelfand,Gad Getz,Gad Getz,Kane Hadley,Robert E. Handsaker,Robert E. Handsaker,Katherine H. Huang,Seva Kashin,Seva Kashin,Konrad J. Karczewski,Konrad J. Karczewski,Monkol Lek,Monkol Lek,Xiao Li,Daniel G. MacArthur,Daniel G. MacArthur,Jared L. Nedzel,Duyen T. Nguyen,Michael S. Noble,Ayellet V. Segrè,Casandra A. Trowbridge,Taru Tukiainen,Taru Tukiainen,Nathan S. Abell,Brunilda Balliu,Ruth Barshir,Omer Basha,Gireesh K. Bogu,Andrew A. Brown,Andrew A. Brown,Christopher D. Brown,Stephane E. Castel,Lin Chen,Colby Chiang,Donald F. Conrad,Nancy J. Cox,Farhan N. Damani,Joe R. Davis,Olivier Delaneau,Olivier Delaneau,Emmanouil T. Dermitzakis,Emmanouil T. Dermitzakis,Eleazar Eskin,Pedro G. Ferreira,Laure Fresard,Eric R. Gamazon,Eric R. Gamazon,Diego Garrido-Martín,Genna Gliner,Michael J. Gloudemans,Roderic Guigó,Ira M. Hall,Buhm Han,Yuan He,Farhad Hormozdiari,Cédric Howald,Cédric Howald,Hae Kyung Im,Eun Yong Kang,Sarah Kim-Hellmuth,Tuuli Lappalainen,Gen Li,Xin Li,Boxiang Liu,Serghei Mangul,Mark I. McCarthy,Mark I. McCarthy,Mark I. McCarthy,Pejman Mohammadi,Jean Monlong,Jean Monlong,Stephen B. Montgomery,Manuel Muñoz-Aguirre,Manuel Muñoz-Aguirre,Anne Ndungu,Dan L. Nicolae,Andrew B. Nobel,Meritxell Oliva,Halit Ongen,Halit Ongen,John Palowitch,Nikolaos I Panousis,Nikolaos I Panousis,Panagiotis Papasaikas,YoSon Park,Princy Parsana,Anthony Payne,Christine B. Peterson,Jie Quan,Ferran Reverter,Ferran Reverter,Chiara Sabatti,Michael Sammeth,Alexandra J. Scott,Andrey A. Shabalin,Reza Sodaei,Matthew Stephens,Barbara E. Stranger,Benjamin J. Strober,Jae Hoon Sul,Emily K. Tsang,Sarah Urbut,Martijn van de Bunt,Martijn van de Bunt,Gao Wang,Xiaoquan Wen,Fred A. Wright,Hualin S. Xi,Esti Yeger-Lotem,Zachary Zappala,Judith B. Zaugg,Yi-Hui Zhou,Joshua M. Akey,Daniel Bates,Joanne Chan,Melina Claussnitzer,Melina Claussnitzer,Melina Claussnitzer,Kathryn Demanelis,Morgan Diegel,Jennifer A. Doherty,Andrew P. Feinberg,Marian S. Fernando,Jessica Halow,Kasper D. Hansen,Kasper D. Hansen,Eric Haugen,Peter Hickey,Lei Hou,Farzana Jasmine,Ruiqi Jian,Lihua Jiang,Audra K. Johnson,Rajinder Kaul,Manolis Kellis,Muhammad G. Kibriya,Kristen Lee,Jin Billy Li,Qin Li,Jessica Lin,Jessica Lin,Shin Lin,Shin Lin,Sandra Linder,Caroline Linke,Yaping Liu,Matthew T. Maurano,Benoit Molinie,Jemma Nelson,Fidencio J. Neri,Yongjin Park,Brandon L. Pierce,Nicola J. Rinaldi,Lindsay F. Rizzardi,Richard Sandstrom,Andrew D. Skol,Kevin S. Smith,Michael Snyder,John A. Stamatoyannopoulos,Hua Tang,Li Wang,Meng Wang,Nicholas Van Wittenberghe,Fan Wu,Rui Zhang,Concepcion R. Nierras,Philip A. Branton,Latarsha J. Carithers,Ping Guan,Helen M. Moore,Abhi Rao,Jimmie B. Vaught,Sarah E. Gould,Nicole C. Lockart,Casey Martin,Jeffery P. Struewing,Simona Volpi,Anjené M. Addington,Susan E. Koester,A. Roger Little,Lori E. Brigham,Richard Hasz,Marcus Hunter,Christopher Johns,Mark D. Johnson,Gene Kopen,William F. Leinweber,John T. Lonsdale,Alisa McDonald,Bernadette Mestichelli,Kevin Myer,Brian Roe,Michael F. Salvatore,Saboor Shad,Jeffrey A. Thomas,Gary Walters,Michael Washington,Joseph Wheeler,Jason Bridge,Barbara A. Foster,Bryan Gillard,Ellen Karasik,Rachna Kumar,Mark Miklos,Michael T. Moser,Scott D. Jewell,Robert G. Montroy,Daniel C. Rohrer,Dana R. Valley,David A. Davis,Deborah C. Mash,Anita H. Undale,Anna M. Smith,David E. Tabor,Nancy Roche,Jeffrey McLean,Negin Vatanian,Karna Robinson,Leslie H. Sobin,Mary Barcus,Kimberly M. Valentino,Liqun Qi,Steven Hunter,Pushpa Hariharan,Shilpi Singh,Ki Sung Um,Takunda Matose,Maria M. Tomaszewski,Laura Barker,Maghboeba Mosavel,Laura A. Siminoff,Heather M. Traino,Paul Flicek,Thomas Juettemann,Magali Ruffier,Dan Sheppard,Kieron Taylor,Stephen J. Trevanion,Daniel R. Zerbino,Brian Craft,Mary Goldman,Maximilian Haeussler,W. James Kent,Christopher Lee,Benedict Paten,Kate R. Rosenbloom,John Vivian,Jingchun Zhu +259 more
TL;DR: These networks are built that additionally capture the regulation of relative isoform abundance and splicing, along with tissue-specific connections unique to each of a diverse set of tissues, and provide an improved understanding of the complex relationships of the human transcriptome across tissues.
Posted ContentDOI
Trans effects on gene expression can drive omnigenic inheritance
TL;DR: This work provides a formal model in which genetic contributions to complex traits can be partitioned into direct effects from core genes, and indirect effects from peripheral genes acting as trans-regulators, and proposes a framework for understanding key features of the architecture of complex traits.
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