Faculty Collaboration Database

Cross-cohort analysis of expression and splicing quantitative trait loci in TOPMed. Science 2026 Jul 16;393(6808):eadx2989

Date

07/16/2026

Pubmed ID

42462027

DOI

10.1126/science.adx2989

Scopus ID

2-s2.0-105045591152 (requires institutional sign-in at Scopus site)

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.

Author List

Orchard P, Blackwell TW, Kachuri L, Castaldi PJ, Cho MH, Christenson SA, Durda P, Gabriel S, Hersh CP, Huntsman S, Hwang S, Joehanes R, Johnson M, Li X, Lin H, Liu CT, Liu Y, Mak ACY, Manichaikul AW, Paik DT, Saferali A, Smith JD, Taylor KD, Tracy RP, Wang J, Wang M, Weinstock JS, Weiss J, Wheeler HE, Zhou Y, Zöllner S, Wu JC, Mestroni L, Graw S, Taylor MRG, Ortega VE, Johnson WC, Gan W, Abecasis G, Nickerson DA, Gupta N, Ardlie K, Woodruff PG, Bowler RP, Meyers DA, Reiner A, Kooperberg C, Ziv E, Vasan RS, Larson MG, Cupples LA, Silverman EK, Rich SS, Heard-Costa N, Tang H, Rotter JI, Smith AV, Levy D, NHLBI TOPMed Consortium Multi-Omics Working Group32, NHLBI TOPMed Consortium32§, Aguet F, Scott LJ, Raffield LM, Parker SCJ, Abe N, Almasy L, Ament S, Anugu P, Auer P, Avramopoulos D, Balasubramanian A, Barr RG, Barwick L, Beaty T, Becker D, Becker L, Beitelshees A, Benos T, Bezerra M, Bis J, Brody J, Broeckel U, Broome J, Bunting K, Buth E, Carey V, Carty C, Casaburi R, Chaffin M, Chang C, Chang YC, Chavan S, Chen BJ, Chen WM, Choi SH, Chuang LM, Chung RH, Conomos M, Cornell E, Crandall C, Crapo J, Curtis J, Damcott C, David S, de Las Fuentes L, de Vries P, Deka R, DeMeo D, Devine S, Dinh H, Doddapaneni H, Duan Q, Duggirala R, Eaton C, Ekunwe L, El Boueiz A, Emery L, Farber C, Farek J, Franceschini N, Frazar C, Fu M, Fullerton SM, Fulton L, Gao S, Gao Y, Gass M, Geiger H, Ghosh A, Gignoux C, Glahn D, Gogarten S, Gong DW, Goring H, Grine D, Gu CC, Guan Y, Hall M, Han Y, Harris D, Heavner B, Herrington D, Hobbs B, Hong E, Hoth K, Hsiung CA, Hu J, Hung YJ, Huston H, Hwu CM, Jackson R, Jain D, Johnsen J, Johnston R, Jones K, Kessler M, Khan A, Khan Z, Kim W, Kimoff J, Kinney G, Kramer H, Lange C, Lange E, Laurie C, Laurie C, LeBoff M, Lee S, Lee WJ, Levine D, Lewis J, Li Y, Lin X, Liu S, Liu Y, Make B, Manning A, Manson J, Martin L, Marton M, Mathai S, May S, McArdle P, McDonald ML, McFarland S, McGoldrick D, McHugh C, Mei H, Meigs J, Menon V, Min N, Moll M, Momin Z, Montasser M, Mychaleckyj JC, Naik R, Naseri T, Natarajan P, Nelson SC, Neltner B, Nessner C, Nkechinyere O, O'Connell J, O'Connor T, Ochs-Balcom H, Okwuonu G, Pankow J, Parker C, Peloso G, Peralta JM, Perez M, Perry J, Peters U, Phillips LS, Pollin T, Becker JP, Boorgula MP, Psaty B, Qiao D, Rafaels N, Rajendran M, Rasmussen-Torvik L, Ratan A, Reed R, Regan E, Reupena MS, Robillard R, Roselli C, Ruczinski I, Runnels A, Russell P, Ryan K, Sabino EC, Salimi S, Salvi S, Salzberg S, Sandow K, Santibanez J, Schwander K, Sciurba F, Sériès F, Shetty A, Shetty A, Silver B, Skomro R, Smith T, Smoller S, Snively B, Stilp AM, Storm G, Streeten E, Su JL, Sung YJ, Sylvia J, Szpiro A, Taub M, Taylor S, Thornton TA, Threlkeld M, Tinker L, Tirschwell D, Tiwari H, Tong C, Tsai M, Vaidya D, Walker T, Wallace R, Walts A, Wang FF, Wang H, Watson K, Watt J, Weng LC, Wessel J, Williams K, Wilson C, Wilson J, Winterkorn L, Wong Q, Wu B, Xu H, Yanek L, Yang I, Zekavat SM, Zhao SX, Zhao W, Zhu X

Author

Paul L. Auer PhD Professor in the Data Science Institute department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Cohort Studies
Gene Expression Profiling
Gene Expression Regulation
Genome-Wide Association Study
Humans
Organ Specificity
Polymorphism, Single Nucleotide
Precision Medicine
Quantitative Trait Loci
RNA Splicing
Sequence Analysis, RNA