Single-cell RNA sequencing identifies celltype-specific cis-eQTLs and co-expression QTLs.
Monique G. P. van der Wijst,Harm Brugge,Dylan H. de Vries,Patrick Deelen,Morris A. Swertz,Lude Franke +5 more
TLDR
Single-cell RNA sequencing of ~25,000 peripheral blood mononuclear cells from 45 donors identifies new celltype-specific cis-eQTLs and genetic variants that significantly alter co-expression relationships (‘co-expression QTLs’).Abstract:
Genome-wide association studies have identified thousands of genetic variants that are associated with disease 1 . Most of these variants have small effect sizes, but their downstream expression effects, so-called expression quantitative trait loci (eQTLs), are often large 2 and celltype-specific3-5. To identify these celltype-specific eQTLs using an unbiased approach, we used single-cell RNA sequencing to generate expression profiles of ~25,000 peripheral blood mononuclear cells from 45 donors. We identified previously reported cis-eQTLs, but also identified new celltype-specific cis-eQTLs. Finally, we generated personalized co-expression networks and identified genetic variants that significantly alter co-expression relationships (which we termed 'co-expression QTLs'). Single-cell eQTL analysis thus allows for the identification of genetic variants that impact regulatory networks.read more
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Integrative single-cell analysis
Tim Stuart,Rahul Satija +1 more
TL;DR: Diverse approaches for integrative single-cell analysis are discussed, including experimental methods for profiling multiple omics types from the same cells, analytical approaches for extracting additional layers of information directly from scRNA-seq data and computational integration of omics data collected across different cell samples.
Posted ContentDOI
Unraveling the polygenic architecture of complex traits using blood eQTL metaanalysis
Urmo Võsa,Annique Claringbould,Harm-Jan Westra,Marc Jan Bonder,Patrick Deelen,Biao Zeng,Holger Kirsten,Ashis Saha,Roman Kreuzhuber,Silva Kasela,Natalia Pervjakova,Alvaes I,Marie-Julie Favé,Mawusse Agbessi,Mark W. Christiansen,Rick Jansen,Ilkka Seppälä,Lin Tong,Alexander Teumer,Katharina Schramm,Gibran Hemani,Joost Verlouw,Hanieh Yaghootkar,Reyhan Sonmez,Andrew A. Brown,Andrew A. Brown,Kukushkina,Anette Kalnapenkis,Sina Rüeger,Eleonora Porcu,Jaanika Kronberg-Guzman,Jarno Kettunen,Joseph E. Powell,Bernett Lee,Futao Zhang,Wibowo Arindrarto,Frank Beutner,Harm Brugge,Dmitreva J,Mahmoud Elansary,Benjamin P. Fairfax,Michel Georges,Bastiaan T. Heijmans,Mika Kähönen,Yungil Kim,Julian C. Knight,Peter Kovacs,Knut Krohn,Shuang Li,Markus Loeffler,Urko M. Marigorta,Hailiang Mei,Yukihide Momozawa,Martina Müller-Nurasyid,Matthias Nauck,Michel G. Nivard,Brenda W.J.H. Penninx,Jonathan K. Pritchard,Olli T. Raitakari,Rotzchke O,Eline Slagboom,Coen D.A. Stehouwer,Michael Stumvoll,Patrick F. Sullivan,Peter A C 't Hoen,Joachim Thiery,Anke Tönjes,van Dongen J,van Iterson M,Jan H. Veldink,Uwe Völker,C Wijmenga,Morris A. Swertz,Anand Kumar Andiappan,Grant W. Montgomery,Samuli Ripatti,Markus Perola,Z. Kutalik,Emmanouil T. Dermitzakis,Sven Bergmann,Timothy M. Frayling,van Meurs J,Holger Prokisch,Habibul Ahsan,Brandon L. Pierce,Terho Lehtimäki,D.I. Boomsma,Bruce M. Psaty,Sina A. Gharib,Philip Awadalla,Lili Milani,Willem H. Ouwehand,Kate Downes,Oliver Stegle,Alexis Battle,Jian Yang,Peter M. Visscher,Markus Scholz,Greg Gibson,Tõnu Esko,Lude Franke +100 more
TL;DR: It is observed that cis-eQTLs can be detected for 88% of the studied genes, but that they have a different genetic architecture compared to disease-associated variants, limiting the ability to use cis- eZTLs to pinpoint causal genes within susceptibility loci.
Journal ArticleDOI
Cell type–specific genetic regulation of gene expression across human tissues
Sarah Kim-Hellmuth,Sarah Kim-Hellmuth,François Aguet,Meritxell Oliva,Manuel Muñoz-Aguirre,Silva Kasela,Valentin Wucher,Stephane E. Castel,Andrew R. Hamel,Andrew R. Hamel,Ana Viñuela,Amy L. Roberts,Serghei Mangul,Serghei Mangul,Xiaoquan Wen,Gao Wang,Alvaro N. Barbeira,Diego Garrido-Martín,Brian B. Nadel,Yuxin Zou,Rodrigo Bonazzola,Jie Quan,Andrew A. Brown,Andrew A. Brown,Angel Martinez-Perez,José Manuel Soria,Gad Getz,Gad Getz,Emmanouil T. Dermitzakis,Emmanouil T. Dermitzakis,Kerrin S. Small,Matthew Stephens,Hualin S. Xi,Hae Kyung Im,Roderic Guigó,Ayellet V. Segrè,Ayellet V. Segrè,Barbara E. Stranger,Barbara E. Stranger,Kristin G. Ardlie,Tuuli Lappalainen +40 more
TL;DR: A growing number of in silico cell type deconvolution methods and associated reference panels with cell type–specific marker genes enable the robust estimation of the enrichment of specific cell types from bulk tissue gene expression data.
Journal ArticleDOI
Large eQTL meta-analysis reveals differing patterns between cerebral cortical and cerebellar brain regions.
Solveig K. Sieberts,Thanneer M. Perumal,Minerva M. Carrasquillo,Mariet Allen,Joseph S. Reddy,Gabriel E. Hoffman,Kristen K. Dang,John N. Calley,Phillip J. Ebert,James A. Eddy,Xue Wang,Anna K. Greenwood,Sara Mostafavi,Sara Mostafavi,S Akbarian,J Bendl,M S Breen,K Brennand,L Brown,A Browne,J D Buxbaum,A Charney,Andrew Chess,Couto L,Gregory E. Crawford,Devillers O,Bernie Devlin,Amanda Dobbyn,E Domenici,M Filosi,E Flatow,Nancy Francoeur,John F. Fullard,S E Gil,Kiran Girdhar,A Gulyás-Kovács,R.E. Gur,C G Hahn,Vahram Haroutunian,Mads E. Hauberg,Laura M. Huckins,Rivka Jacobov,Y Jiang,Jessica S. Johnson,Bibi Kassim,Y Kim,Lambertus Klei,Robin Kramer,Mario Lauria,Thomas Lehner,David A. Lewis,Barbara K. Lipska,Kelsey S. Montgomery,R Park,C Rosenbluh,Panagiotis Roussos,Douglas M. Ruderfer,G Senthil,Hardik Shah,Laura G. Sloofman,L Song,E Stahl,P.F. Sullivan,R Visintainer,J Wang,Y C Wang,Jennifer Wiseman,E Xia,W Zhang,Elizabeth Zharovsky,L Addis,S N Addo,David C. Airey,Matthias Arnold,David A. Bennett,Y Bi,K Biber,Colette Blach,E Bradhsaw,Paul Brennan,R Canet-Aviles,S Cao,A Cavalla,Yooree Chae,W W Chen,J Cheng,David A. Collier,J L Dage,Eric B. Dammer,J W Davis,John B. Davis,Derek Drake,D Duong,Brian J. Eastwood,Michelle E. Ehrlich,B Ellingson,B W Engelmann,S Esmaeelinieh,Daniel Felsky,Cory C. Funk,Chris Gaiteri +100 more
TL;DR: A colocalization analysis is applied to identify genes underlying the GWAS association peaks for schizophrenia and identify a potentially novel gene colocalized with lncRNA RP11-677M14.
Journal ArticleDOI
Transcriptional and Cellular Diversity of the Human Heart
Nathan R. Tucker,Mark Chaffin,Stephen J. Fleming,Amelia W. Hall,Victoria A. Parsons,Kenneth Bedi,Amer-Denis Akkad,Caroline N. Herndon,Alessandro Arduini,Irinna Papangeli,Carolina Roselli,François Aguet,Seung Hoan Choi,Kristin G. Ardlie,Mehrtash Babadi,Kenneth B. Margulies,Christian Stegmann,Patrick T. Ellinor +17 more
TL;DR: Using large-scale single nuclei RNA sequencing, the transcriptional and cellular diversity in the normal human heart was defined and the identification of discrete cell subtypes and differentially expressed genes within the heart will ultimately facilitate the development of new therapeutics for cardiovascular diseases.
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Visualizing Data using t-SNE
TL;DR: A new technique called t-SNE that visualizes high-dimensional data by giving each datapoint a location in a two or three-dimensional map, a variation of Stochastic Neighbor Embedding that is much easier to optimize, and produces significantly better visualizations by reducing the tendency to crowd points together in the center of the map.
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TL;DR: This study has demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in theBritish population is generally modest.
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Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets
Evan Z. Macosko,Evan Z. Macosko,Anindita Basu,Anindita Basu,Rahul Satija,Rahul Satija,James Nemesh,James Nemesh,Karthik Shekhar,Melissa Goldman,Melissa Goldman,Itay Tirosh,Allison R. Bialas,Nolan Kamitaki,Nolan Kamitaki,Emily M. Martersteck,John J. Trombetta,David A. Weitz,Joshua R. Sanes,Alex K. Shalek,Alex K. Shalek,Alex K. Shalek,Aviv Regev,Aviv Regev,Aviv Regev,Steven A. McCarroll,Steven A. McCarroll +26 more
TL;DR: Drop-seq will accelerate biological discovery by enabling routine transcriptional profiling at single-cell resolution by separating them into nanoliter-sized aqueous droplets, associating a different barcode with each cell's RNAs, and sequencing them all together.
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Massively parallel digital transcriptional profiling of single cells
Grace X.Y. Zheng,Jessica M. Terry,Phillip Belgrader,Paul Ryvkin,Zachary Bent,Ryan Wilson,Solongo B. Ziraldo,Tobias Daniel Wheeler,Geoffrey P. McDermott,Junjie Zhu,Mark T. Gregory,Joe Shuga,Luz Montesclaros,Jason G. Underwood,Donald A. Masquelier,Stefanie Y. Nishimura,Michael Schnall-Levin,Paul Wyatt,Christopher Hindson,Rajiv Bharadwaj,Alexander Wong,Kevin D. Ness,Lan Beppu,H. Joachim Deeg,Christopher McFarland,Keith R. Loeb,Keith R. Loeb,William J. Valente,William J. Valente,Nolan G. Ericson,Emily A. Stevens,Jerald P. Radich,Tarjei S. Mikkelsen,Benjamin J. Hindson,Jason H. Bielas +34 more
TL;DR: A droplet-based system that enables 3′ mRNA counting of tens of thousands of single cells per sample is described and sequence variation in the transcriptome data is used to determine host and donor chimerism at single-cell resolution from bone marrow mononuclear cells isolated from transplant patients.
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The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells
Cole Trapnell,Davide Cacchiarelli,Davide Cacchiarelli,Jonna Grimsby,Prapti Pokharel,Shuqiang Li,Michael A. Morse,Michael A. Morse,Niall J. Lennon,Kenneth J. Livak,Tarjei S. Mikkelsen,Tarjei S. Mikkelsen,John L. Rinn,John L. Rinn,John L. Rinn +14 more
TL;DR: Monocle is described, an unsupervised algorithm that increases the temporal resolution of transcriptome dynamics using single-cell RNA-Seq data collected at multiple time points that revealed switch-like changes in expression of key regulatory factors, sequential waves of gene regulation, and expression of regulators that were not known to act in differentiation.
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