Cross-cohort analysis of expression and splicing quantitative trait loci in TOPMed
Abstract
Most genetic variants associated with complex traits are hypothesized to regulate gene expression. To understand the genetics underlying gene expression variability, we characterized 14,324 RNA-sequencing samples from the Trans-Omics for Precision Medicine program and performed expression and splicing quantitative trait locus (e/sQTL) analyses in six tissues and cell types, including whole blood ( n = 6454) and lung ( n = 1291). We detected tens of thousands of secondary cis-e/sQTLs, showing that secondary cis-e/sQTL discovery remains unsaturated. We fine-mapped UK Biobank–derived genome-wide association study (GWAS) signals from 164 traits and identified e/sQTL colocalizations for 10,611 GWAS signals, including 7096 that colocalize with secondary e/sQTLs. Our results suggest that even larger e/sQTL analyses will uncover additional secondary e/sQTLs, further benefiting GWAS interpretation.
Article Details
Journal Info
Science
American Association for the Advancement of Science
Authors (285)
Peter Orchard
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
Thomas W. Blackwell
Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
Linda Kachuri
Department of Epidemiology and Population Health, School of Medicine, Stanford University, Stanford, CA, USA.
Peter J. Castaldi
Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.
Michael H. Cho
Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.
Stephanie A. Christenson
Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, School of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Peter Durda
Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
Stacey Gabriel
Craig P. Hersh
Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.
Scott Huntsman
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Seungyong Hwang
Department of Genetics, Stanford University, Stanford, CA, USA.
Roby Joehanes
Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Mari Johnson
Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Xingnan Li
Division of Data Driven and Digital Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Honghuang Lin
Framingham Heart Study, National Heart, Lung, and Blood Institute, National Institutes of Health and Boston University, Framingham, MA, USA.
Ching-Ti Liu
Department of Biostatistics, School of Public Health, Boston University, Boston, MA, USA.
Yongmei Liu
Division of Cardiology, Department of Medicine, School of Medicine, Duke University, Durham, NC, USA.
Angel C. Y. Mak
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Ani W. Manichaikul
Department of Genome Sciences, School of Medicine, University of Virginia, Charlottesville, VA, USA.
David T. Paik
Aabida Saferali
Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.
Joshua D. Smith
Kent D. Taylor
The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Russell P. Tracy
Laboratory for Clinical Biochemistry Research, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
Jiongming Wang
Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
Mingqiang Wang
Joshua S. Weinstock
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
Jeffrey Weiss
Heather E. Wheeler
Program in Bioinformatics, Loyola University Chicago, Chicago, IL, USA.
Ying Zhou
Sebastian Zöllner
Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
Joseph C. Wu
Luisa Mestroni
Department of Medicine, Adult Medical Genetics Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Sharon Graw
Department of Medicine, Adult Medical Genetics Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Matthew R. G. Taylor
Department of Medicine, Adult Medical Genetics Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Victor E. Ortega
Department of Medicine, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Phoenix, AZ, USA.
W. Craig Johnson
Collaborative Health Studies Coordinating Center, University of Washington, Seattle, WA, USA.
Weiniu Gan
National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Gonçalo Abecasis
Deborah A. Nickerson
Northwest Genomics Center, University of Washington, Seattle, WA, USA.
Namrata Gupta
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Kristin Ardlie
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Prescott G. Woodruff
Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, School of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Russell P. Bowler
Department of Genomic Sciences and Systems Biology, Cleveland Clinic, Cleveland, OH, USA.
Deborah A. Meyers
Department of Medicine, Mayo Clinic, Scottsdale, AZ, USA.
Alex Reiner
Department of Epidemiology, University of Washington, Seattle, WA, USA.
Charles Kooperberg
Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Elad Ziv
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Ramachandran S. Vasan
Framingham Heart Study, National Heart, Lung, and Blood Institute, National Institutes of Health and Boston University, Framingham, MA, USA.
Martin G. Larson
Framingham Heart Study, National Heart, Lung, and Blood Institute, National Institutes of Health and Boston University, Framingham, MA, USA.
L. Adrienne Cupples
Framingham Heart Study, National Heart, Lung, and Blood Institute, National Institutes of Health and Boston University, Framingham, MA, USA.
Edwin K. Silverman
Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.
Stephen S. Rich
Department of Genome Sciences, School of Medicine, University of Virginia, Charlottesville, VA, USA.
Nancy Heard-Costa
Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, USA.
Hua Tang
Department of Genetics, Stanford University, Stanford, CA, USA.
Jerome I. Rotter
Albert V. Smith
Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
Daniel Levy
Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
François Aguet
Laura J. Scott
Laura M. Raffield
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Stephen C. J. Parker
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
Namiko Abe
New York Genome Center, New York, NY, USA.
Laura Almasy
Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA.
Seth Ament
University of Maryland, Baltimore, MD, USA.
Pramod Anugu
University of Mississippi, Jackson, MS, USA.
Paul Auer
Medical College of Wisconsin, Milwaukee, WI, USA.
Dimitrios Avramopoulos
Johns Hopkins University, Baltimore, MD, USA.
Adithya Balasubramanian
Baylor College of Medicine Human Genome Sequencing Center, Houston, TX, USA.
R. Graham Barr
Columbia University, New York, NY, USA.
Lucas Barwick
The Emmes Corporation, Rockville, MD, USA.
Terri Beaty
Johns Hopkins University, Baltimore, MD, USA.
Diane Becker
Johns Hopkins University, Baltimore, MD, USA.
Lewis Becker
Johns Hopkins University, Baltimore, MD, USA.
Amber Beitelshees
University of Maryland, Baltimore, MD, USA.
Takis Benos
University of Pittsburgh, Pittsburgh, PA, USA.
Marcos Bezerra
Fundação de Hematologia e Hemoterapia de Pernambuco - Hemope, Recife, Brazil.
Joshua Bis
University of Washington, Seattle, WA, USA.
Jennifer Brody
University of Washington, Seattle, WA, USA.
Ulrich Broeckel
Medical College of Wisconsin, Milwaukee, WI, USA.
Jai Broome
University of Washington, Seattle, WA, USA.
Karen Bunting
New York Genome Center, New York, NY, USA.
Erin Buth
University of Washington, Seattle, WA, USA.
Vincent Carey
Brigham andWomen’s Hospital, Boston, MA, USA.
Cara Carty
Washington State University, Pullman, WA, USA.
Richard Casaburi
University of California, Los Angeles, Los Angeles, CA, USA.
Mark Chaffin
Broad Institute, Cambridge, MA, USA.
Christy Chang
University of Maryland, Baltimore, MD, USA.
Yi-Cheng Chang
National Taiwan University, Taipei, Taiwan (Province of China).
Sameer Chavan
University of Colorado at Denver, Denver, CO, USA.
Bo-Juen Chen
New York Genome Center, New York, NY, USA.
Wei-Min Chen
University of Virginia, Charlottesville, VA, USA.
Seung Hoan Choi
Broad Institute, Cambridge, MA, USA.
Lee-Ming Chuang
National Taiwan University, Taipei, Taiwan (Province of China).
Ren-Hua Chung
National Health Research Institute Taiwan, Miaoli County, Taiwan (Province of China).
Matthew Conomos
University of Washington, Seattle, WA, USA.
Elaine Cornell
University of Vermont, Burlington, VT, USA.
Carolyn Crandall
University of California, Los Angeles, Los Angeles, CA, USA.
James Crapo
National Jewish Health, Denver, CO, USA.
Jeffrey Curtis
University of Michigan, Ann Arbor, MI, USA.
Coleen Damcott
University of Maryland, Baltimore, MD, USA.
Sean David
University of Chicago, Chicago, IL, USA.
Lisa de las Fuentes
Washington University in St. Louis, St. Louis, MO, USA.
Paul de Vries
University of Texas Health at Houston, Houston, TX, USA.
Ranjan Deka
University of Cincinnati, Cincinnati, OH, USA.
Dawn DeMeo
Brigham andWomen’s Hospital, Boston, MA, USA.
Scott Devine
University of Maryland, Baltimore, MD, USA.
Huyen Dinh
Baylor College of Medicine Human Genome Sequencing Center, Houston, TX, USA.
Harsha Doddapaneni
Qing Duan
University of North Carolina, Chapel Hill, NC, USA.
Ravi Duggirala
University of Texas Rio Grande Valley School of Medicine, Edinburg, TX, USA.
Charles Eaton
Harvard University, Cambridge, MA, USA.
Lynette Ekunwe
University of Mississippi, Jackson, MS, USA.
Adel El Boueiz
Washington University in St. Louis, St. Louis, MO, USA.
Leslie Emery
University of Washington, Seattle, WA, USA.
Charles Farber
University of Virginia, Charlottesville, VA, USA.
Jesse Farek
Baylor College of Medicine Human Genome Sequencing Center, Houston, TX, USA.
Nora Franceschini
University of North Carolina, Chapel Hill, NC, USA.
Chris Frazar
University of Washington, Seattle, WA, USA.
Mao Fu
University of Maryland, Baltimore, MD, USA.
Stephanie M. Fullerton
University of Washington, Seattle, WA, USA.
Lucinda Fulton
Washington University in St. Louis, St. Louis, MO, USA.
Shanshan Gao
University of Colorado at Denver, Denver, CO, USA.
Yan Gao
Margery Gass
Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Heather Geiger
Auyon Ghosh
Brigham andWomen’s Hospital, Boston, MA, USA.
Chris Gignoux
Stanford University, Stanford, CA, USA.
David Glahn
Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA.
Stephanie Gogarten
University of Washington, Seattle, WA, USA.
Da-Wei Gong
University of Maryland, Baltimore, MD, USA.
Harald Goring
University of Texas Rio Grande Valley School of Medicine, San Antonio, TX, USA.
Daniel Grine
University of Colorado at Denver, Denver, CO, USA.
C. Charles Gu
Washington University in St. Louis, St. Louis, MO, USA.
Yue Guan
University of Maryland, Baltimore, MD, USA.
Michael Hall
University of Mississippi, Jackson, MS, USA.
Yi Han
Daniel Harris
University of Maryland, Philadelphia, PA, USA.
Ben Heavner
David Herrington
Wake Forest Baptist Health, Winston-Salem, NC, USA.
Brian Hobbs
Elliott Hong
University of Maryland, Baltimore, MD, USA.
Karin Hoth
University of Iowa, Iowa City, IA.
Chao (Agnes) Hsiung
National Health Research Institute Taiwan, Miaoli County, Taiwan (Province of China).
Jianhong Hu
Yi-Jen Hung
Tri-Service General Hospital National Defense Medical Center, Taiwan (Province of China).
Haley Huston
Blood Works Northwest, Seattle, WA, USA.
Chii Min Hwu
Taichung Veterans General Hospital Taiwan, Taichung City, Taiwan (Province of China).
Rebecca Jackson
Deepti Jain
University of Washington, Seattle, WA, USA.
Jill Johnsen
University of Washington, Seattle, WA, USA.
Rich Johnston
Emory University, Atlanta, GA, USA.
Kimberly Jones
Johns Hopkins University, Baltimore, MD, USA.
Michael Kessler
Alyna Khan
University of Washington, Seattle, WA, USA.
Ziad Khan
Wonji Kim
Harvard University, Cambridge, MA, USA.
John Kimoff
McGill University, Montréal, QC, Canada.
Greg Kinney
University of Colorado at Denver, Aurora, CO, USA.
Holly Kramer
Loyola University, Maywood, IL, USA.
Christoph Lange
Harvard School of Public Health, Boston, MA, USA.
Ethan Lange
University of Colorado at Denver, Denver, CO, USA.
Cathy Laurie
University of Washington, Seattle, WA, USA.
Cecelia Laurie
University of Washington, Seattle, WA, USA.
Meryl LeBoff
Brigham andWomen’s Hospital, Boston, MA, USA.
Sandra Lee
Baylor College of Medicine Human Genome Sequencing Center, Houston, TX, USA.
Wen-Jane Lee
Taichung Veterans General Hospital Taiwan, Taichung City, Taiwan (Province of China).
David Levine
University of Washington, Seattle, WA, USA.
Joshua Lewis
University of Maryland, Baltimore, MD, USA.
Yun Li
Xihong Lin
Simin Liu
Brown University, Providence, RI, USA.
Yu Liu
Barry Make
Johns Hopkins University, Baltimore, MD, USA.
Alisa Manning
Broad Institute, Harvard University, Massachusetts General Hospital, Boston, MA, USA.
JoAnn Manson
Brigham andWomen’s Hospital, Boston, MA, USA.
Lisa Martin
Melissa Marton
New York Genome Center, New York City, NY, USA.
Susan Mathai
University of Colorado at Denver, Denver, CO, USA.
Susanne May
Patrick McArdle
University of Maryland, Baltimore, MD, USA.
Merry-Lynn McDonald
Sean McFarland
Harvard University, Cambridge, MA, USA.
Daniel McGoldrick
University of Washington, Seattle, WA, USA.
Caitlin McHugh
University of Washington, Seattle, WA, USA.
Hao Mei
University of Mississippi, Jackson, MS, USA.
James Meigs
Massachusetts General Hospital, Boston, MA, USA.
Vipin Menon
Baylor College of Medicine Human Genome Sequencing Center, Houston, TX, USA.
Nancy Min
University of Mississippi, Jackson, MS, USA.
Matt Moll
Brigham andWomen’s Hospital, Boston, MA, USA.
Zeineen Momin
Baylor College of Medicine Human Genome Sequencing Center, Houston, TX, USA.
May Montasser
National Heart, Lung, and Blood Institute, Bethesda, MD, USA.
Josyf C Mychaleckyj
University of Virginia, Charlottesville, VA, USA.
Rakhi Naik
Johns Hopkins University, Baltimore, MD, USA.
Take Naseri
Pradeep Natarajan
Sarah C. Nelson
Bonnie Neltner
University of Colorado at Denver, Denver, CO, USA.
Caitlin Nessner
Baylor College of Medicine Human Genome Sequencing Center, Houston, TX, USA.
Osuji Nkechinyere
Baylor College of Medicine Human Genome Sequencing Center, Houston, TX, USA.
Jeff O'Connell
University of Maryland, Baltimore, MD, USA.
Tim O’Connor
University of Maryland, Baltimore, MD, USA.
Heather Ochs-Balcom
University at Buffalo, Buffalo, NY, USA.
Geoffrey Okwuonu
Baylor College of Medicine Human Genome Sequencing Center, Houston, TX, USA.
James Pankow
University of Minnesota, Minneapolis, MN, USA.
Cora Parker
RTI International, Research Triangle Park, NC, USA.
Gina Peloso
Boston University, Boston, MA, USA.
Juan Manuel Peralta
University of Texas Rio Grande Valley School of Medicine, Edinburg, TX, USA.
Marco Perez
Stanford University, Stanford, CA, USA.
James Perry
University of Maryland, Baltimore, MD, USA.
Ulrike Peters
Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Lawrence S Phillips
Emory University, Atlanta, GA, USA.
Toni Pollin
University of Maryland, Baltimore, MD, USA.
Julia Powers Becker
University of Colorado at Denver, Denver, CO, USA.
Meher Preethi Boorgula
University of Colorado at Denver, Denver, CO, USA.
Bruce Psaty
University of Washington, Seattle, WA, USA.
Dandi Qiao
Brigham andWomen’s Hospital, Boston, MA, USA.
Nicholas Rafaels
University of Colorado at Denver, Denver, CO, USA.
Mahitha Rajendran
Baylor College of Medicine Human Genome Sequencing Center, Houston, TX, USA.
Laura Rasmussen-Torvik
Northwestern University, Chicago, IL, USA.
Aakrosh Ratan
University of Virginia, Charlottesville, VA, USA.
Robert Reed
University of Maryland, Baltimore, MD, USA.
Elizabeth Regan
National Jewish Health, Denver, CO, USA.
Muagututi‘a Sefuiva Reupena
Lutia I Puava Ae Mapu I Fagalele, Apia, Samoa.
Rebecca Robillard
University of Ottawa, Ottawa, ON, Canada.
Carolina Roselli
Broad Institute, Cambridge, MA, USA.
Ingo Ruczinski
Johns Hopkins University, Baltimore, MD, USA.
Alexi Runnels
Pamela Russell
University of Colorado at Denver, Denver, CO, USA.
Kathleen Ryan
University of Maryland, Baltimore, MD, USA.
Ester Cerdeira Sabino
Universidade de Sao Paulo, Sao Paulo, Brazil.
Shabnam Salimi
University of Maryland, Seattle, WA, USA.
Sejal Salvi
Baylor College of Medicine Human Genome Sequencing Center, Houston, TX, USA.
Steven Salzberg
Johns Hopkins University, Baltimore, MD, USA.
Kevin Sandow
Lundquist Institute, Torrance, CA, USA.
Jireh Santibanez
Baylor College of Medicine Human Genome Sequencing Center, Houston, TX, USA.
Karen Schwander
Washington University in St. Louis, St. Louis, MO, USA.
Frank Sciurba
University of Pittsburgh, Pittsburgh, PA, USA.
Frédéric Sériès
Université Laval, Quebec City, Canada.
Amol Shetty
University of Maryland, Baltimore, MD, USA.
Aniket Shetty
University of Colorado at Denver, Denver, CO, USA.
Brian Silver
UMass Memorial Medical Center, Worcester, MA, USA.
Robert Skomro
University of Saskatchewan, Saskatoon, Canada.
Tanja Smith
New York Genome Center, New York, NY, USA.
Sylvia Smoller
Albert Einstein College of Medicine, New York, NY, USA.
Beverly Snively
Wake Forest Baptist Health, Winston-Salem, NC, USA.
Adrienne M. Stilp
Garrett Storm
University of Colorado at Denver, Aurora, CO, USA.
Elizabeth Streeten
University of Maryland, Baltimore, MD, USA.
Jessica Lasky Su
Brigham andWomen’s Hospital, Boston, MA, USA.
Yun Ju Sung
Washington University in St. Louis, St. Louis, MO, USA.
Jody Sylvia
Brigham andWomen’s Hospital, Boston, MA, USA.
Adam Szpiro
University of Washington, Seattle, WA, USA.
Margaret Taub
Johns Hopkins University, Baltimore, MD, USA.
Simeon Taylor
University of Maryland, Baltimore, MD, USA.
Timothy A. Thornton
University of Washington, Seattle, WA, USA.
Machiko Threlkeld
University of Washington, Seattle, WA, USA.
Lesley Tinker
Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
David Tirschwell
University of Washington, Seattle, WA, USA.
Hemant Tiwari
University of Alabama, Birmingham, AL, USA.
Catherine Tong
University of Washington, Seattle, WA, USA.
Michael Tsai
University of Minnesota, Minneapolis, MN, USA.
Dhananjay Vaidya
Johns Hopkins University, Baltimore, MD, USA.
Tarik Walker
University of Colorado at Denver, Denver, CO, USA.
Robert Wallace
University of Iowa, Iowa City, IA.
Avram Walts
University of Colorado at Denver, Denver, CO, USA.
Fei Fei Wang
University of Washington, Seattle, WA, USA.
Heming Wang
Karol Watson
University of California, Los Angeles, Los Angeles, CA, USA.
Jennifer Watt
Baylor College of Medicine Human Genome Sequencing Center, Houston, TX, USA.
Lu-Chen Weng
Massachusetts General Hospital, Boston, MA, USA.
Jennifer Wessel
Indiana University, Indianapolis, IN, USA.
Kayleen Williams
University of Washington, Seattle, WA, USA.
Carla Wilson
Brigham andWomen’s Hospital, Boston, MA, USA.
James Wilson
Lara Winterkorn
New York Genome Center, New York City, NY, USA.
Quenna Wong
Baojun Wu
Henry Ford Health System, Detroit, MI, USA.
Huichun Xu
University of Maryland, Baltimore, MD, USA.
Lisa Yanek
Johns Hopkins University, Baltimore, MD, USA.
Ivana Yang
University of Colorado at Denver, Denver, CO, USA.
Seyedeh Maryam Zekavat
Broad Institute, Cambridge, MA, USA.
Snow Xueyan Zhao
National Jewish Health, Denver, CO, USA.
Wei Zhao
Xiaofeng Zhu