| Title: | Transcriptomic signatures across human tissues identify functional rare genetic variation |
| Journal: | Science |
| Published: | 10 Sep 2020 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/32913073/ |
| DOI: | https://doi.org/10.1126/science.aaz5900 |
| URL: | http://repositori.upf.edu/bitstream/10230/58044/1/Ferraro_sci_tran.pdf |
| Citations: | 115 (45 in last 2 years) as of 8 Aug 2024 |
Publication 5917
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Abstract
Rare genetic variants are abundant across the human genome, and identifying their function and phenotypic impact is a major challenge. Measuring aberrant gene expression has aided in identifying functional, large-effect rare variants (RVs). Here, we expanded detection of genetically driven transcriptome abnormalities by analyzing gene expression, allele-specific expression, and alternative splicing from multitissue RNA-sequencing data, and demonstrate that each signal informs unique classes of RVs. We developed Watershed, a probabilistic model that integrates multiple genomic and transcriptomic signals to predict variant function, validated these predictions in additional cohorts and through experimental assays, and used them to assess RVs in the UK Biobank, the Million Veterans Program, and the Jackson Heart Study. Our results link thousands of RVs to diverse molecular effects and provide evidence to associate RVs affecting the transcriptome with human traits.</p>
6 Keywords
- Genetic Variation
- Genome, Human
- Humans
- Multifactorial Inheritance
- Organ Specificity
- Transcriptome
209 Authors
- Nicole M. Ferraro
- Benjamin J. Strober
- Jonah Einson
- Nathan S. Abell
- Francois Aguet
- Alvaro N. Barbeira
- Margot Brandt
- Maja Bucan
- Stephane E. Castel
- Joe R. Davis
- Emily Greenwald
- Gaelen T. Hess
- Austin T. Hilliard
- Rachel L. Kember
- Bence Kotis
- YoSon Park
- Gina Peloso
- Shweta Ramdas
- Alexandra J. Scott
- Craig Smail
- Emily K. Tsang
- Seyedeh M. Zekavat
- Marcello Ziosi
- Aradhana
- Kristin G. Ardlie
- Themistocles L. Assimes
- Michael C. Bassik
- Christopher D. Brown
- Adolfo Correa
- Ira Hall
- Hae Kyung Im
- Xin Li
- Pradeep Natarajan
- Tuuli Lappalainen
- Pejman Mohammadi
- Stephen B. Montgomery
- Alexis Battle
- François Aguet
- Shankara Anand
- Kristin G. Ardlie
- Stacey Gabriel
- Gad A. Getz
- Aaron Graubert
- Kane Hadley
- Robert E. Handsaker
- Katherine H. Huang
- Seva Kashin
- Xiao Li
- Daniel G. MacArthur
- Samuel R. Meier
- Jared L. Nedzel
- Duyen T. Nguyen
- Ayellet V. Segrè
- Ellen Todres
- Brunilda Balliu
- Alvaro N. Barbeira
- Alexis Battle
- Rodrigo Bonazzola
- Andrew Brown
- Christopher D. Brown
- Stephane E. Castel
- Donald F. Conrad
- Daniel J. Cotter
- Nancy Cox
- Sayantan Das
- Olivia M. de Goede
- Emmanouil T. Dermitzakis
- Jonah Einson
- Barbara E. Engelhardt
- Eleazar Eskin
- Tiffany Y. Eulalio
- Nicole M. Ferraro
- Elise D. Flynn
- Laure Fresard
- Eric R. Gamazon
- Diego Garrido-Martín
- Nicole R. Gay
- Michael J. Gloudemans
- Roderic Guigó
- Andrew R. Hame
- Yuan He
- Paul J. Hoffman
- Farhad Hormozdiari
- Lei Hou
- Hae Kyung Im
- Brian Jo
- Silva Kasela
- Manolis Kellis
- Sarah Kim-Hellmuth
- Alan Kwong
- Tuuli Lappalainen
- Xin Li
- Yanyu Liang
- Serghei Mangul
- Pejman Mohammadi
- Stephen B. Montgomery
- Manuel Muñoz-Aguirre
- Daniel C. Nachun
- Andrew B. Nobel
- Meritxell Oliva
- YoSon Park
- Yongjin Park
- Princy Parsana
- Abhiram S. Rao
- Ferran Reverter
- John M. Rouhana
- Chiara Sabatti
- Ashis Saha
- Matthew Stephens
- Barbara E. Stranger
- Benjamin J. Strober
- Nicole A. Teran
- Ana Viñuela
- Gao Wang
- Xiaoquan Wen
- Fred Wright
- Valentin Wucher
- Yuxin Zou
- Pedro G. Ferreira
- Gen Li
- Marta Melé
- Esti Yeger-Lotem
- Mary E. Barcus
- Debra Bradbury
- Tanya Krubit
- Jeffrey A. McLean
- Liqun Qi
- Karna Robinson
- Nancy V. Roche
- Anna M. Smith
- Leslie Sobin
- David E. Tabor
- Anita Undale
- Jason Bridge
- Lori E. Brigham
- Barbara A. Foster
- Bryan M. Gillard
- Richard Hasz
- Marcus Hunter
- Christopher Johns
- Mark Johnson
- Ellen Karasik
- Gene Kopen
- William F. Leinweber
- Alisa McDonald
- Michael T. Moser
- Kevin Myer
- Kimberley D. Ramsey
- Brian Roe
- Saboor Shad
- Jeffrey A. Thomas
- Gary Walters
- Michael Washington
- Joseph Wheeler
- Scott D. Jewell
- Daniel C. Rohrer
- Dana R. Valley
- David A. Davis
- Deborah C. Mash
- Philip A. Branton
- Laura K. Barker
- Heather M. Gardiner
- Maghboeba Mosavel
- Laura A. Siminoff
- Paul Flicek
- Maximilian Haeussler
- Thomas Juettemann
- W. James Kent
- Christopher M. Lee
- Conner C. Powell
- Kate R. Rosenbloom
- Magali Ruffier
- Dan Sheppard
- Kieron Taylor
- Stephen J. Trevanion
- Daniel R. Zerbino
- Nathan S. Abell
- Joshua Akey
- Lin Chen
- Kathryn Demanelis
- Jennifer A. Doherty
- Andrew P. Feinberg
- Kasper D. Hansen
- Peter F. Hickey
- Farzana Jasmine
- Lihua Jiang
- Rajinder Kaul
- Muhammad G. Kibriya
- Jin Billy Li
- Qin Li
- Shin Lin
- Sandra E. Linder
- Brandon L. Pierce
- Lindsay F. Rizzardi
- Andrew D. Skol
- Kevin S. Smith
- Michael Snyder
- John Stamatoyannopoulos
- Hua Tang
- Meng Wang
- Latarsha J. Carithers
- Ping Guan
- Susan E. Koester
- A. Roger Little
- Helen M. Moore
- Concepcion R. Nierras
- Abhi K. Rao
- Jimmie B. Vaught
- Simona Volpi
Enabling scientific discoveries that improve human health