Cross-cohort analysis of expression and splicing quantitative trait loci in TOPMed
Orchard, P.; Blackwell, T. W.; Kachuri, L.; Castaldi, P. J.; Cho, M. H.; Christenson, S. A.; Durda, P.; Gabriel, S.; Hersh, C. P.; Huntsman, S.; Hwang, S.; Joehanes, R.; Johnson, M.; Li, X.; Lin, H.; Liu, C.-T.; Liu, Y.; Mak, A. C. Y.; Manichaikul, A. W.; Paik, D.; Saferali, A.; Smith, J. D.; Taylor, K. D.; Tracy, R. P.; Wang, J.; Wang, M.; Weinstock, J. S.; Weiss, J.; Wheeler, H. E.; Zhou, Y.; Zoellner, S.; Wu, J. C.; Mestroni, L.; Graw, S.; Taylor, M. R. G.; Ortega, V. E.; Johnson, C. W.; Gan, W.; Abecasis, G.; Nickerson, D. A.; Gupta, N.; Ardlie, K.; Woodruff, P. G.; Zheng, Y.; Bowler, R. P
Show 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.
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