An Efficient Multiple-Testing Adjustment for eQTL Studies that Accounts for Linkage Disequilibrium between Variants
Joe R. Davis,Laure Fresard,David A. Knowles,Mauro Pala,Carlos Bustamante,Alexis Battle,Stephen B. Montgomery +6 more
TLDR
This work presents an alternative correction method called eigenMT, which runs over 500 times faster than permutation-based methods and has adjusted p values that closely approximate empirical ones.Abstract:
Methods for multiple-testing correction in local expression quantitative trait locus (cis-eQTL) studies are a trade-off between statistical power and computational efficiency. Bonferroni correction, though computationally trivial, is overly conservative and fails to account for linkage disequilibrium between variants. Permutation-based methods are more powerful, though computationally far more intensive. We present an alternative correction method called eigenMT, which runs over 500 times faster than permutations and has adjusted p values that closely approximate empirical ones. To achieve this speed while also maintaining the accuracy of permutation-based methods, we estimate the effective number of independent variants tested for association with a particular gene, termed Meff, by using the eigenvalue decomposition of the genotype correlation matrix. We employ a regularized estimator of the correlation matrix to ensure Meff is robust and yields adjusted p values that closely approximate p values from permutations. Finally, using a common genotype matrix, we show that eigenMT can be applied with even greater efficiency to studies across tissues or conditions. Our method provides a simpler, more efficient approach to multiple-testing correction than existing methods and fits within existing pipelines for eQTL discovery.read more
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The GTEx Consortium atlas of genetic regulatory effects across human tissues
François Aguet,Alvaro N. Barbeira,Rodrigo Bonazzola,Andrew A. Brown,SE Castel,Brian Jo,Silva Kasela,Sarah Kim-Hellmuth,Yanyu Liang,Meritxell Oliva,Elise D. Flynn,Princy Parsana,Laure Fresard,Eric R. Gamazon,Andrew R. Hamel,Yuan He,Farhad Hormozdiari,Pejman Mohammadi,Manuel Muñoz-Aguirre,YoSon Park,Ashis Saha,Ayellet V. Segrè,Benjamin J. Strober,Xiaoquan Wen,Wucher,Kristin G. Ardlie,Alexis Battle,Christopher D. Brown,Nancy J. Cox,Souvik Das,Emmanouil T. Dermitzakis,Barbara E. Engelhardt,D Garrido-Martin,Gad Getz,Roderic Guigó,Robert E. Handsaker,Paul J. Hoffman,Hae Kyung Im,Seva Kashin,Alan Kwong,Lappalainen T,Xiao Li,Daniel G. MacArthur,Stephen B. Montgomery,John M. Rouhana,Matthew Stephens,Barbara E. Stranger,Ellen Todres,Ana Viñuela,Gao Wang,Yuxin Zou,Shankara Anand,S. Gabriel,Aaron Graubert,Kane Hadley,Katherine H. Huang,Meier,Jared L. Nedzel,Duyen T. Nguyen,Brunilda Balliu,Donald F. Conrad,Daniel J. Cotter,OM deGoede,Jonah Einson,Eskin E,Tiffany Eulalio,Nicole M. Ferraro,Michael J. Gloudemans,Lei Hou,Serghei Mangul,Daniel Nachun,Andrew B. Nobel,Abhiram Rao,Ferran Reverter,Chiara Sabatti,Andrew D Skol,Nicole A. Teran,Fred A. Wright,Pedro G. Ferreira,Gen Li,Marta Melé,Esti Yeger-Lotem,Mary Barcus,Debra Bradbury,T Krubit,Jeffrey McLean,Liqun Qi,Karna Robinson,Nancy Roche,Anna M. Smith,David E. Tabor,Anita H. Undale,Jason Bridge,Lori E. Brigham,Barbara A. Foster,Bryan Gillard,Rick Hasz,Marcus Hunter,Christopher Johns,Mark H. Johnson,Ellen Karasik,Gene Kopen,William F. Leinweber,Alisa McDonald,Mike Moser,Kevin Myer,Kimberly Ramsey,Bruce A. Roe,Saboor Shad,Jeffrey A. Thomas,Gary Walters,Michael Washington,Jessica Wheeler,Scott D. Jewell,Daniel C. Rohrer,David A. Davis,Deborah C. Mash,Leslie H. Sobin,Laura Barker,HM Gardiner,Maghboeba Mosavel,Laura A. Siminoff,Paul Flicek,Maximilian Haeussler,Thomas Juettemann,W. J. Kent,Christopher Lee,CC Powell,Kate R. Rosenbloom,Magali Ruffier,Dan Sheppard,Kieron Taylor,Stephen J. Trevanion,Zerbino,Nathan S. Abell,Joshua M. Akey,Lin Chen,Kathryn Demanelis,Jennifer A. Doherty,Andrew P. Feinberg,Kasper D. Hansen,Peter Hickey,Farzana Jasmine,Lihua Jiang,Rajinder Kaul,Manolis Kellis,Muhammad G. Kibriya,Jin Billy Li,Qin Li,Shin Lin,Sandra Linder,Brandon L. Pierce,Lindsay F. Rizzardi,Kevin S. Smith,Michael Snyder,John A. Stamatoyannopoulos,Hua Tang,Meng Wang,Phillip Branton,Latarsha J. Carithers,Ping Guan,Susan E. Koester,AR Little,Helen M. Moore,Concepcion R. Nierras,Abhi Rao,Jimmie B. Vaught,Simona Volpi +167 more
Posted ContentDOI
The GTEx Consortium atlas of genetic regulatory effects across human tissues
François Aguet,Alvaro N. Barbeira,Rodrigo Bonazzola,Andrew A. Brown,SE Castel,Brian Jo,Silva Kasela,Sarah Kim-Hellmuth,Yanyu Liang,Meritxell Oliva,Princy E Parsana,Elise Flynn,Laure Fresard,Eric R Gaamzon,Andrew R Hamel,Yuan He,Farhad Hormozdiari,Pejman Mohammadi,Manuel Muñoz-Aguirre,YoSon Park,Ashis Saha,Ayellet V Segrć,Benjamin J Strober,Xiaoquan Wen,Valentin Wucher,Sayantan Das,D Garrido-Martin,Robert E Handsaker,Paul J Hoffman,Seva Kashin,Alan Kwong,Xiao Li,Daniel G. MacArthur,John M. Rouhana,Matthew Stephens,Ellen Todres,Ana Viñuela,Gao Wang,Yuxin Zou,Christopher D. Brown,Nancy Cox,Emmanouil T. Dermitzakis,Barbara E. Engelhardt,Gad Getz,Roderic Guigo,Stephen B. Montgomery,Barbara E Stranger,Hae Kyung Im,Alexis Battle,Kristin G. Ardlie,Lappalainen T +50 more
TL;DR: Analysis of the v8 data provides insights into the tissue-specificity of genetic effects, and shows that cell type composition is a key factor in understanding gene regulatory mechanisms in human tissues.
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
Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology
Manuel A. R. Ferreira,Judith M. Vonk,Hansjörg Baurecht,Ingo Marenholz,Ingo Marenholz,Chao Tian,Joshua D. Hoffman,Quinta Helmer,Annika Tillander,Vilhelmina Ullemar,Jenny van Dongen,Yi Lu,Franz Rüschendorf,Jorge Esparza-Gordillo,Jorge Esparza-Gordillo,Jorge Esparza-Gordillo,Chris W. Medway,Edward Mountjoy,Kimberley Burrows,Oliver Hummel,Sarah Grosche,Sarah Grosche,Ben Michael Brumpton,Ben Michael Brumpton,John S. Witte,Jouke-Jan Hottenga,Gonneke Willemsen,Jie Zheng,Elke Rodriguez,Melanie Hotze,Andre Franke,Joana A. Revez,Jonathan Beesley,Melanie C. Matheson,Shyamali C. Dharmage,L. Bain,Lars G. Fritsche,Maiken Elvestad Gabrielsen,Brunilda Balliu,Jonas B. Nielsen,Wei Zhou,Kristian Hveem,Arnulf Langhammer,Oddgeir L. Holmen,Mari Løset,Gonçalo R. Abecasis,Gonçalo R. Abecasis,Cristen J. Willer,Andreas Arnold,Georg Homuth,Carsten Oliver Schmidt,Philip J. Thompson,Nicholas G. Martin,David L. Duffy,Natalija Novak,Holger Schulz,Stefan Karrasch,Christian Gieger,Konstantin Strauch,Ronald B. Melles,David A. Hinds,Norbert Hubner,Stephan Weidinger,Patrik K. E. Magnusson,Rick Jansen,Eric Jorgenson,Young-Ae Lee,Young-Ae Lee,Dorret I. Boomsma,Catarina Almqvist,Catarina Almqvist,Robert Karlsson,Gerard H. Koppelman,Lavinia Paternoster +73 more
TL;DR: A genome-wide association study of a broad allergic disease phenotype that considers the presence of any one of these three diseases identified 136 independent risk variants, including 73 not previously reported, which implicate 132 nearby genes in allergic disease pathophysiology.
Journal ArticleDOI
Genomic basis for RNA alterations in cancer
Claudia Calabrese,Natalie R. Davidson,Deniz Demircioğlu,Deniz Demircioğlu,Nuno A. Fonseca,Yao He,André Kahles,Kjong-Van Lehmann,Fenglin Liu,Yuichi Shiraishi,Cameron M. Soulette,Lara Urban,Liliana Greger,Siliang Li,Dongbing Liu,Marc D. Perry,Marc D. Perry,Qian Xiang,Fan Zhang,Junjun Zhang,Peter Bailey,Serap Erkek,Katherine A. Hoadley,Yong Hou,Matthew R. Huska,Helena Kilpinen,Jan O. Korbel,Maximillian G. Marin,Julia Markowski,Tannistha Nandi,Qiang Pan-Hammarström,Chandra Sekhar Pedamallu,Chandra Sekhar Pedamallu,Reiner Siebert,Stefan G. Stark,Hong Su,Patrick Tan,Patrick Tan,Sebastian M. Waszak,Christina K. Yung,Shida Zhu,Philip Awadalla,Philip Awadalla,Chad J. Creighton,Matthew Meyerson,Matthew Meyerson,B. F. Francis Ouellette,Kui Wu,Huanming Yang,Alvis Brazma,Angela N. Brooks,Angela N. Brooks,Angela N. Brooks,Jonathan Göke,Gunnar Rätsch,Roland F. Schwarz,Oliver Stegle,Oliver Stegle,Zemin Zhang +58 more
TL;DR: The most comprehensive catalogue of cancer-associated gene alterations to date, obtained by characterizing tumour transcriptomes from 1,188 donors of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Gome Atlas (TCGA) was presented in this article.
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