Single-cell eQTL models reveal dynamic T cell state dependence of disease loci
Aparna Nathan,Samira Asgari,Kazuyoshi Ishigaki,Cristian Valencia,Tiffany Amariuta,Yang Luo,Jessica I. Beynor,Yuriy Baglaenko,Sara Suliman,Alkes L. Price,Leonid Lecca,Megan Murray,D. Branch Moody,Soumya Raychaudhuri +13 more
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TLDR
In this article , a single-cell Poisson model is used to analyse quantitative trait loci in memory T cells across continuous, dynamic cell states, revealing that the cell context is critical to understanding variation in eQTLs and their association with disease.Abstract:
Non-coding genetic variants may cause disease by modulating gene expression. However, identifying these expression quantitative trait loci (eQTLs) is complicated by differences in gene regulation across fluid functional cell states within cell types. These states—for example, neurotransmitter-driven programs in astrocytes or perivascular fibroblast differentiation—are obscured in eQTL studies that aggregate cells1,2. Here we modelled eQTLs at single-cell resolution in one complex cell type: memory T cells. Using more than 500,000 unstimulated memory T cells from 259 Peruvian individuals, we show that around one-third of 6,511 cis-eQTLs had effects that were mediated by continuous multimodally defined cell states, such as cytotoxicity and regulatory capacity. In some loci, independent eQTL variants had opposing cell-state relationships. Autoimmune variants were enriched in cell-state-dependent eQTLs, including risk variants for rheumatoid arthritis near ORMDL3 and CTLA4; this indicates that cell-state context is crucial to understanding potential eQTL pathogenicity. Moreover, continuous cell states explained more variation in eQTLs than did conventional discrete categories, such as CD4+ versus CD8+, suggesting that modelling eQTLs and cell states at single-cell resolution can expand insight into gene regulation in functionally heterogeneous cell types. A single-cell Poisson model is used to analyse eQTLs in memory T cells across continuous, dynamic cell states, revealing that the cell context is critical to understanding variation in eQTLs and their association with disease. read more
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Impact of the Human Cell Atlas on medicine
TL;DR: In this article , the authors lay out a vision for the potential of cell atlases to impact the future of medicine, and describe how advances over the past decade have begun to realize this potential in common complex diseases, infectious diseases (including COVID-19), rare diseases and cancer.
Posted ContentDOI
The missing link between genetic association and regulatory function
Connally Nj,Connally Nj,Connally Nj,Sumaiya Nazeen,Sumaiya Nazeen,Lee D,Lee D,Lee D,Huwenbo Shi,Huwenbo Shi,John A. Stamatoyannopoulos,Chun S,Chris Cotsapas,Chris Cotsapas,Christopher A. Cassa,Christopher A. Cassa,Shamil R. Sunyaev,Shamil R. Sunyaev,Shamil R. Sunyaev +18 more
TL;DR: In this article, the authors identified 139 genes in which protein-coding variants cause severe or familial forms of nine human traits, and then computed the association between common complex forms of the same traits and noncoding variation.
Journal ArticleDOI
The missing link between genetic association and regulatory function
TL;DR: In this article , the authors identify 220 gene-trait pairs in which protein-coding variants influence a complex trait or its Mendelian cognate, and find limited evidence that the baseline expression of trait-related genes explains GWAS associations, whether using colocalization methods (8% of genes implicated), transcription-wide association (2% of gene implicated), or a combination of regulatory annotations and distance (4%of genes implicated).
A compendium of genetic regulatory effects across pig tissues
Jinyan Teng,Yahui Gao,Hongwei Yin,Zhong-Yuan Bai,Shuli Liu,Haonan Zeng,Lijing Bai,Zexi Cai,Bingru Zhao,Xiujin Li,Zhiting Xu,Qing Lin,Zhangyuan Pan,Wenjing Yang,Xiao Ling Yu,Dawei Guan,Y Hou,Brittney N Keel,Gary A. Rohrer,Amanda K. Lindholm-Perry,William T. Oliver,Maria Ballester,Daniel Crespo-Piazuelo,Raquel Quintanilla,Oriol Canela-Xandri,Konrad Rawlik,Charley Xia,Yue Yao,Qianyi Zhao,Wenye Yao,Liu Yang,Houcheng Li,Huicong Zhang,Wang Liao,Tianshuo Chen,Peter Karlskov-Mortensen,Merete Fredholm,Marcel Amills,Alex Clop,Elisabetta Giuffra,Jun Wu,X. Cai,Shuqi Diao,Xiangchun Pan,Chen Wei,Jinghui Li,Hao Cheng,Sheng Wang,Guosheng Su,Goutam Sahana,Mogens Sandø Lund,Jack C. M. Dekkers,Luke M. Kramer,Christopher K. Tuggle,Ryan J. Corbett,Martin A. Green,Ole Madsen,Marta Gòdia,Dominique Rocha,Mathieu Charles,Congjun Li,Hubert Pausch,Xiaoxiang Hu,Laurent A. F. Frantz,Yonglun Luo,Lin Lin,Zhong-Yin Zhou,Zhe Zhang,Zitao Chen,Leilei Cui,Ruidong Xiang,Xia Shen,Pinghua Li,Ruihua Huang,Guoqing Tang,Mingzhou Li,Yunxiang K. Zhao,Guoqiang Yi,Zhonglin Tang,Jicai Jiang,Fuping Zhao,Xiaolong Yuan,Xiaodong Liu,Yaosheng Chen,Xuewen Xu,Shuhong Zhao,Pengju Zhao,Chris Haley,Huaijun Zhou,Qishan Wang,Yuchun Pan,Xiangdong Ding,Li Ma,Jiaqi Li,Pau Navarro,Qin Zhang,Bingjie Li,Albert Tenesa,Kui Li,George E. Liu,Ze Zhang,Lingzhao Fang +101 more
TL;DR: The Farm animal Genotype-Tissue Expression (FarmGTEx) project as mentioned in this paper has developed a comprehensive public resource of genetic regulatory variants in domestic animal species, which is essential for linking genetic polymorphisms to variation in phenotypes.
Posted ContentDOI
Tissue-specific enhancer-gene maps from multimodal single-cell data identify causal disease alleles
Saori Sakaue,Kathryn Weinand,Kushal K. Dey,Karthik A. Jagadeesh,Masahiro Kanai,Gerald F. Watts,Michael B. Brenner,Andrew McDavid,Laura T. Donlin,Kevin Wei,Antoinette Price,Soumya Raychaudhuri +11 more
TL;DR: SCENT (Single-Cell ENhancer Target gene mapping) as discussed by the authors is a nonparametric statistical method, which models association between enhancer chromatin accessibility and gene expression in single-cell multimodal RNA-seq and ATAC-seq data.
References
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Grant,Carla Gallo,Giovanni Poletti,Danish Saleheen,Asif Rasheed,Lisa D. Brooks,Adam Felsenfeld,Jean E. McEwen,Yekaterina Vaydylevich,Audrey Duncanson,Michael Dunn,Jeffery A. Schloss +517 more
TL;DR: The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations, and has reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-generation sequencing, deep exome sequencing, and dense microarray genotyping.
Journal ArticleDOI
Simple Combinations of Lineage-Determining Transcription Factors Prime cis-Regulatory Elements Required for Macrophage and B Cell Identities
Sven Heinz,Christopher Benner,Nathanael J. Spann,Eric Bertolino,Yin C. Lin,Peter Laslo,Jason X. Cheng,Cornelis Murre,Harinder Singh,Harinder Singh,Christopher K. Glass +10 more
TL;DR: It is demonstrated in macrophages and B cells that collaborative interactions of the common factor PU.1 with small sets of macrophage- or B cell lineage-determining transcription factors establish cell-specific binding sites that are associated with the majority of promoter-distal H3K4me1-marked genomic regions.
A global reference for human genetic variation
Adam Auton,Gonçalo R. Abecasis,David Altshuler,Richard Durbin,David R. Bentley,Aravinda Chakravarti,Andrew G. Clark,Peter Donnelly,Evan E. Eichler,Paul Flicek,Stacey Gabriel,Richard A. Gibbs,Eric D. Green,Matthew E. Hurles,Bartha Maria Knoppers,Jan O. Korbel,Eric S. Lander,Charles Kai-Wu Lee,Hans Lehrach,Elaine R. Mardis,Gabor T. Marth,Gil McVean,Deborah A. Nickerson,Jeanette Schmidt,Stephen T. Sherry,Jun Wang,Richard K. Wilson,Eric Boerwinkle,Harsha Doddapaneni,Yi Han,Viktoriya Korchina,Christie Kovar,Sandra J. Lee,Donna M. Muzny,Jeffrey G. Reid,Yiming Zhu,Yuqi Chang,Qiang Feng,Xiaodong Fang,Xiaosen Guo,Min Jian,Hui Jiang,Xin Jin,Tianming Lan,Guoqing Li,Jingxiang Li,Yingrui Li,Shengmao Liu,Xiao Liu,Yao Lu,Xuedi Ma,Meifang Tang,Bo Wang,Guangbiao Wang,Honglong Wu,Renhua Wu,Xun Xu,Ye Yin,Dandan Zhang,Wenwei Zhang,Jiao Zhao,Meiru Zhao,Xiaole Zheng,Namrata Gupta,Neda Gharani,Lorraine Toji,Norman P. Gerry,Alissa M. Resch,Jonathan Barker,Laura Clarke,Laurent Gil,Sarah E. Hunt,Gavin Kelman,Eugene Kulesha,Rasko Leinonen,William M. McLaren,Rajesh Radhakrishnan,Asier Roa,Dmitriy Smirnov,Richard Smith,Ian Streeter,Anja Thormann,Iliana Toneva,Brendan Vaughan,Xiangqun Zheng-Bradley,Russell J. Grocock,Sean Humphray,Terena James,Zoya Kingsbury,Ralf Sudbrak,M. Albrecht,Vyacheslav Amstislavskiy,Tatiana A. Borodina,Matthias Lienhard,Florian Mertes,Marc Sultan,Bernd Timmermann,Marie-Laure Yaspo,Lucinda Fulton,Robert S. Fulton,Victor Ananiev,Zinaida Belaia,Dimitriy Beloslyudtsev,Nathan Bouk,Chao Chen,Deanna M. Church,Robert M. Cohen,Charles Cook,John Garner,Timothy Hefferon,Mikhail Kimelman,Chunlei Liu,John Lopez,Peter Meric,Chris O’Sullivan,Yuri Ostapchuk,Lon Phan,Sergiy Ponomarov,Valerie A. Schneider,Eugene Shekhtman,Karl Sirotkin,Douglas J. Slotta,Hua Zhang,Senduran Balasubramaniam,John Burton,Petr Danecek,Thomas M. Keane,Anja Kolb-Kokocinski,Shane A. McCarthy,James Stalker,Michael A. Quail,Christopher Davies,Jeremy Gollub,Teresa Webster,Brant Wong,Yiping Zhan,Christopher L. Campbell,Yu Kong,Anthony Marcketta,Fuli Yu,Lilian Antunes,Matthew N. Bainbridge,Aniko Sabo,Zhuoyi Huang,Lachlan J. M. Coin,Lin Fang,Qibin Li,Zhenyu Li,Haoxiang Lin,Binghang Liu,Ruibang Luo,Haojing Shao,Yinlong Xie,Chen Ye,Chang Yu,Fan Zhang,Hancheng Zheng,Hongmei Zhu,Can Alkan,Elif Dal,Fatma Kahveci,Erik Garrison,Deniz Kural,Wan-Ping Lee,Wen Fung Leong,Michael Strömberg,Alistair Ward,Jiantao Wu,Mengyao Zhang,Mark J. Daly,Mark A. DePristo,Robert E. Handsaker,Eric Banks,Gaurav Bhatia,Guillermo del Angel,Giulio Genovese,Heng Li,Seva Kashin,Steven A. McCarroll,James Nemesh,Ryan Poplin,Seungtai Yoon,Jayon Lihm,Vladimir Makarov,Srikanth Gottipati,Alon Keinan,Juan L. Rodriguez-Flores,Tobias Rausch,Markus Hsi-Yang Fritz,Adrian M. Stütz,Kathryn Beal,Avik Datta,Javier Herrero,Graham R. S. Ritchie,Daniel R. Zerbino,Pardis C. Sabeti,Ilya Shlyakhter,Stephen F. Schaffner,Joseph J. Vitti,David Neil Cooper,Edward V. Ball,Peter D. Stenson,Bret Barnes,Markus J. Bauer,R. Keira Cheetham,Anthony J. Cox,Michael A. Eberle,Scott Kahn,Lisa Murray,John F. Peden,Richard Shaw,Eimear E. Kenny,Mark A. Batzer,Miriam K. Konkel,Jerilyn A. Walker,Daniel G. MacArthur,Monkol Lek,Ralf Herwig,Li Ding,Daniel C. Koboldt,David E. Larson,Kai Ye,Simon Gravel,Anand Swaroop,Emily Y. Chew,Tuuli Lappalainen,Yaniv Erlich,Melissa Gymrek,Thomas Willems,Jared T. Simpson,Mark D. Shriver,Jeffrey A. Rosenfeld,Carlos Bustamante,Stephen B. Montgomery,Francisco M. De La Vega,Jake K. Byrnes,Andrew Carroll,Marianne K. DeGorter,Phil Lacroute,Brian K. Maples,Alicia R. Martin,Andrés Moreno-Estrada,Suyash Shringarpure,Fouad Zakharia,Eran Halperin,Yael Baran,Eliza Cerveira,Jaeho Hwang,Ankit Malhotra,Dariusz Plewczynski,Kamen Radew,Mallory Romanovitch,Chengsheng Zhang,Fiona Hyland,David Craig,Alexis Christoforides,Nils Homer,Tyler Izatt,Ahmet Kurdoglu,Shripad Sinari,Kevin Squire,Chunlin Xiao,Jonathan Sebat,Danny Antaki,Madhusudan Gujral,Amina Noor,Kenny Ye,Esteban G. Burchard,Ryan D. Hernandez,Christopher R. Gignoux,David Haussler,Sol Katzman,W. James Kent,Bryan Howie,Andres Ruiz-Linares,Emmanouil T. Dermitzakis,Scott E. Devine,Hyun Min Kang,Jeffrey M. Kidd,Thomas W. Blackwell,Sean Caron,Wei Chen,S. Emery,Lars G. Fritsche,Christian Fuchsberger,Goo Jun,Bingshan Li,R. P. Lyons,Chris Scheller,Carlo Sidore,Shiya Song,Elzbieta Sliwerska,Daniel Taliun,Adrian Tan,Ryan P. Welch,Mary Kate Wing,Xiaowei Zhan,Philip Awadalla,Alan Hodgkinson,Yun Li,Xinghua Shi,Andrew Quitadamo,Gerton Lunter,Jonathan Marchini,Simon Myers,Claire Churchhouse,Olivier Delaneau,Anjali Gupta-Hinch,Warren W. Kretzschmar,Zamin Iqbal,Iain Mathieson,Androniki Menelaou,Andrew J. Rimmer,Dionysia K. Xifara,Taras K. Oleksyk,Yunxin Fu,Xiaoming Liu,Momiao Xiong,Lynn B. Jorde,David J. Witherspoon,Jinchuan Xing,Brian L. Browning,Sharon R. Browning,Fereydoun Hormozdiari,Peter H. Sudmant,Ekta Khurana,Chris Tyler-Smith,Cornelis A. Albers,Qasim Ayub,Yuan Chen,Vincenza Colonna,Luke Jostins,Klaudia Walter,Yali Xue,Mark Gerstein,Alexej Abyzov,Suganthi Balasubramanian,Jieming Chen,Declan Clarke,Yao Fu,Arif Harmanci,Mike Jin,Dong-Hoon Lee,Jeremy Liu,Xinmeng Jasmine Mu,Jing Zhang,Yan Zhang,Christopher Hartl,Khalid Shakir,Jeremiah D. Degenhardt,Sascha Meiers,Benjamin Raeder,Francesco Paolo Casale,Oliver Stegle,Eric-Wubbo Lameijer,Ira M. Hall,Vineet Bafna,Jacob J. Michaelson,Eugene J. Gardner,Ryan E. Mills,Gargi Dayama,Ken Chen,Xian Fan,Zechen Chong,Tenghui Chen,Mark Chaisson,John Huddleston,Maika Malig,Bradley J. Nelson,Nicholas F. Parrish,Ben Blackburne,Sarah J. Lindsay,Zemin Ning,Yujun Zhang,Hugo Y. K. Lam,Cristina Sisu,Danny Challis,Uday S. Evani,James T. Lu,Uma Nagaswamy,Jin Yu,Wangshen Li,Lukas Habegger,Haiyuan Yu,Fiona Cunningham,Ian Dunham,Kasper Lage,Jakob Berg Jespersen,Heiko Horn,Donghoon Kim,Rob DeSalle,Apurva Narechania,Melissa A. Wilson Sayres,Fernando L. Mendez,G. David Poznik,Peter A. Underhill,Lachlan Coin,David Mittelman,Ruby Banerjee,Maria Cerezo,Thomas W. Fitzgerald,Sandra Louzada,Andrea Massaia,Graham R S Ritchie,Fengtang Yang,Divya Kalra,Walker Hale,Xu Dan,Kathleen C. Barnes,Christine Beiswanger,Hongyu Cai,Hongzhi Cao,Brenna M. Henn,Danielle Jones,Jane Kaye,Alastair Kent,Angeliki Kerasidou,Rasika A. Mathias,Pilar N. Ossorio,Michael Parker,Charles N. Rotimi,Charmaine D.M. Royal,Karla Sandoval,Yeyang Su,Zhongming Tian,Sarah A. Tishkoff,Marc Via,Yuhong Wang,Huanming Yang,Ling Yang,Jiayong Zhu,Walter F. Bodmer,Gabriel Bedoya,Zhiming Cai,Yang Gao,Jiayou Chu,Leena Peltonen,Andrés C. García-Montero,Alberto Orfao,Julie Dutil,Juan Carlos Martínez-Cruzado,R. Mathias,Anselm Hennis,Harold Watson,Colin A. McKenzie,Firdausi Qadri,Regina C. LaRocque,Xiaoyan Deng,Danny Asogun,Onikepe A. Folarin,Christian T. Happi,Omonwunmi Omoniwa,Matt Stremlau,Ridhi Tariyal,Muminatou Jallow,Fatoumatta Sisay Joof,Tumani Corrah,Kirk A. Rockett,Dominic P. Kwiatkowski,Jaspal S. Kooner,Trâ`n Tịnh Hiê`n,Sarah J. Dunstan,Nguyen Thuy Hang,Richard Fonnie,Robert F. Garry,Lansana Kanneh,Lina M. Moses,John S. Schieffelin,Don Grant,Carla Gallo,Giovanni Poletti,Danish Saleheen,Asif Rasheed,Lisa D. Brooks,Adam Felsenfeld,Jean E. McEwen,Yekaterina Vaydylevich,Audrey Duncanson,Michael Dunn,Jeffery A. Schloss +479 more
TL;DR: The 1000 Genomes Project as mentioned in this paper provided a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations, and reported the completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole genome sequencing, deep exome sequencing and dense microarray genotyping.
Journal ArticleDOI
Systematic localization of common disease-associated variation in regulatory DNA.
Matthew T. Maurano,Richard Humbert,Eric Rynes,Robert E. Thurman,Eric Haugen,Hao Wang,Alex Reynolds,Richard Sandstrom,Hongzhu Qu,Hongzhu Qu,Jennifer A. Brody,Anthony Shafer,Fidencio Neri,Kristen Lee,Tanya Kutyavin,Sandra Stehling-Sun,Audra K. Johnson,Theresa K. Canfield,Erika Giste,Morgan Diegel,Daniel Bates,R. Scott Hansen,Shane Neph,Peter J. Sabo,Shelly Heimfeld,Antony Raubitschek,Steven F. Ziegler,Chris Cotsapas,Nona Sotoodehnia,Ian A. Glass,Shamil R. Sunyaev,Rajinder Kaul,John A. Stamatoyannopoulos +32 more
TL;DR: P pervasive involvement of regulatory DNA variation in common human disease and provide pathogenic insights into diverse disorders are suggested.
Journal ArticleDOI
The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019.
Annalisa Buniello,Jacqueline A. L. MacArthur,Maria Cerezo,Laura W. Harris,James D. Hayhurst,Cinzia Malangone,Aoife McMahon,Joannella Morales,Edward Mountjoy,Edward Mountjoy,Elliot Sollis,Daniel Suveges,Olga Vrousgou,Patricia L. Whetzel,M. Ridwan Amode,Jose A. Guillen,Harpreet Singh Riat,Stephen J. Trevanion,Peggy Hall,Heather Junkins,Paul Flicek,Tony Burdett,Lucia A. Hindorff,Fiona Cunningham,Helen Parkinson +24 more
TL;DR: Improved data access is improved with the release of a new RESTful API to support high-throughput programmatic access, an improved web interface and a new summary statistics database.