Peter Orchard, Thomas W. Blackwell, Linda Kachuri, Peter J. Castaldi, Michael H. Cho, Stephanie A. Christenson, Peter Durda, Stacey Gabriel, Craig P. Hersh, Scott Huntsman, S.-J. Hwang, Roby Joehanes, Mari Johnson, Xingnan Li, Honghuang Lin, Ching‐Ti Liu, Yongmei Liu, Angel C. Y. Mak, Ani Manichaikul, David T. Paik, Aabida Saferali, Joshua D. Smith, Kent D. Taylor, Russell P. Tracy, Jiongming Wang, Ming‐Qiang Wang, Joshua S. Weinstock, Jeffrey Weiss, Heather E. Wheeler, Ying Zhou, Sebastian Zoellner, Joseph C. Wu, Luisa Mestroni, Sharon Graw, Matthew R.G. Taylor, Victor E. Ortega, Craig Johnson, Weiniu Gan, Gonçalo Abecasis, Deborah A. Nickerson, Namrata Gupta, Kristin G. Ardlie, Prescott G. Woodruff, Russell P. Bowler, Deborah A. Meyers, Alex Reiner, Charles Kooperberg, Elad Ziv, Ramachandran S. Vasan, Martin G. Larson, L. Adrienne Cupples, Edwin K. Silverman, Stephen S. Rich, Nancy L. Heard‐Costa, Hua Tang, Jerome I. Rotter, Albert V. Smith, Daniel L. Levy, François Aguet, Laura J. Scott, Laura M. Raffield, Stephen C.J. Parker, Namiko Abe, Laura Almasy, Seth Ament, Pramod Anugu, Paul Auer, Dimitrios Avramopoulos, Adithya Balasubramanian, R. Graham Barr, Lucas Barwick, Terri Beaty, Diane Becker, Lewis Becker, Amber Beitelshees, Takis Benos, Marcos Bezerra, Joshua Bis, Jennifer Brody, Ulrich Broeckel, Jai Broome, Karen Bunting, Erin Buth, Vincent Carey, Cara Carty, Richard Casaburi, Mark Chaffin, Christy Chang, Yi-Cheng Chang, Sameer Chavan, Bo-Juen Chen, Wei-Min Chen, Seung Hoan Choi, Lee-Ming Chuang, Ren-Hua Chung, Matthew Conomos, Elaine Cornell, Carolyn Crandall, James Crapo, Jeffrey Curtis
Abstract Most genetic variants associated with complex traits and diseases occur in non-coding genomic regions and are hypothesized to regulate gene expression. To understand the genetics underlying gene expression variability, we characterize 14,324 ancestrally diverse RNA-sequencing samples from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and integrate whole genome sequencing data to perform cis and trans expression and splicing quantitative trait locus ( cis -/trans-e/sQTL) analyses in six tissues and cell types, most notably whole blood (N=6,454) and lung (N=1,291). We show this dataset enables greater detection of secondary cis-e/sQTL signals than was achieved in previous studies, and that secondary cis-eQTL and primary trans-eQTL signal discovery is not saturated even though eGene discovery is. Most TOPMed trans-eQTL signals colocalize with cis-e/sQTL signals, suggesting many trans signals are mediated by cis signals. We fine-map European UK BioBank GWAS signals from 164 traits and colocalize the resulting 34,107 fine-mapped GWAS signals with TOPMed e/sQTL signals, finding that of 10,611 GWAS signals with a colocalization, 7,096 GWAS signals colocalize with at least one secondary e/sQTL signal. These results demonstrate that larger e/sQTL analyses will continue to uncover secondary e/sQTL signals, and that these new signals will benefit GWAS interpretation.