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.

PJC has received grant support from Bayer and consultant fees from Verona pharmaceuticals. MHC has received grant support from Bayer. JCW is co-founder of Greenstone Biosciences. EKS has received grant support from GlaxoSmithKline and Bayer. CPH reports grant support from Boehringer-Ingelheim, Novartis, Bayer and Vertex. VEO previously served on independent data and monitoring committees (IDMC) for Regeneron and Sanofi, and receives compensation from the American Medical Association for his role as associate editor for JAMA. FA is an employee of Illumina, Inc. and is an inventor on a patent application related to TensorQTL filed by the Broad Institute. LMR is a consultant for the TOPMed Administrative Coordinating Center (through Westat). SCJP is supported by Pfizer. GRA is an employee of Regeneron Pharmaceuticals, he owns stock and stock options for Regeneron Pharmaceuticals.

Molecular data for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). RNASeq for "NHLBI TOPMed: Whole Genome Sequencing and Related Phenotypes in the Framingham Heart Study" (phs000974)" was performed at the Northwest Genomics Center (HHSN268201600032I). Genome Sequencing for "NHLBI TOPMed: Whole Genome Sequencing and Related Phenotypes in the Framingham Heart Study" (phs000974)" was performed at Broad Genomics (HHSN268201600034I, 3U54HG003067-12S2, 3R01HL092577-06S1). RNASeq for "NHLBI TOPMed: Genetic Epidemiology of COPD (COPDGene) (phs000951)" was performed at the Northwest Genomics Center (HHSN268201600032I). Genome Sequencing for "NHLBI TOPMed: Genetic Epidemiology of COPD (COPDGene) (phs000951)" was performed at Broad Genomics (HHSN268201500014C) and the Northwest Genomics Center (3R01HL089856-08S1). RNASeq for "NHLBI TOPMed - NHGRI CCDG: Genes-Environments and Admixture in Latino Asthmatics (GALA II) (phs000920)" was performed at Broad Genomics (HHSN268201600034I). Genome Sequencing for ""NHLBI TOPMed - NHGRI CCDG: Genes-Environments and Admixture in Latino Asthmatics (GALA II) (phs000920)" was performed at NYGC Genomics (3R01HL117004-02S3). RNASeq for "NHLBI TOPMed: Study of African Americans, Asthma, Genes and Environment (SAGE) (phs000921)" was performed at Broad Genomics (HHSN268201600034I). Genome Sequencing for "NHLBI TOPMed: Study of African Americans, Asthma, Genes and Environment (SAGE) (phs000921)" was performed at NYGC Genomics (3R01HL117004-02S3) and the Northwest Genomics Center (HHSN268201600032I). RNASeq for "NHLBI TOPMed: SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) (phs001927)" was performed at Northwest Genomics Center (HHSN268201600032I). Genome Sequencing for "NHLBI TOPMed: SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) (phs001927)" was performed at Broad Genomics (HHSN268201600034I). RNASeq for "NHLBI TOPMed: MESA and MESA Family AA-CAC (phs001416)" was performed at Northwest Genomics Center (HHSN268201600032I) and Broad Genomics (HHSN268201600034I). Genome Sequencing for "NHLBI TOPMed: MESA and MESA Family AA-CAC (phs001416)" was performed at Broad Genomics (3U54HG003067-13S1, HHSN268201600034I, HHSN268201500014C). RNASeq for "NHLBI TOPMed: Women's Health Initiative (WHI) (phs001237)" was performed at Broad Genomics (HHSN268201600034I). Genome Sequencing for "NHLBI TOPMed: Women's Health Initiative (WHI) (phs001237)" was performed at Broad Genomics (HHSN268201500014C). RNASeq for "NHLBI TOPMed: Lung Tissue Research Consortium (LTRC) (phs001662)" was performed at Northwest Genomics Center (HHSN268201600032I). Genome Sequencing for "NHLBI TOPMed: Lung Tissue Research Consortium (LTRC) (phs001662)" was performed at Broad Genomics (HHSN268201600034I). Core support including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Core support including phenotype harmonization, data management, sample-identity QC, and general program coordination were provided by the TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract HHSN268201800001I). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. The Framingham Heart Study (FHS) acknowledges the support of contracts NO1-HC-25195, HHSN268201500001I and 75N92019D00031 from the National Heart, Lung and Blood Institute and grant supplement R01 HL092577-06S1 for this research. We also acknowledge the dedication of the FHS study participants without whom this research would not be possible. Dr. Vasan is supported in part by the Evans Medical Foundation and the Jay and Louis Coffman Endowment from the Department of Medicine, Boston University School of Medicine. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, 75N92021D00005. The COPDGene project described was supported by grants from the National Heart, Lung, and Blood Institute (U01 HL089897 and U01 HL089856), and by NIH contract 75N92023D00011. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health. The COPDGene project is also supported by the COPD Foundation through contributions made to an Industry Advisory Committee that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Sunovion. A full listing of COPDGene investigators can be found at: http://www.copdgene.org/directory. This study utilized biological specimens and data provided by the Lung Tissue Research Consortium (LTRC) supported by the National Heart, Lung, and Blood Institute (NHLBI). The LTRC TOPMed project was also supported by P01 HL114501 and R01 HL133135. Whole genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). WGS for "NHLBI TOPMed: Multi-Ethnic Study of Atherosclerosis (MESA)" (phs001416.v3.p1) was performed at the Broad Institute of MIT and Harvard (3U54HG003067-13S1). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1). Phenotype harmonization, data management, sample-identity QC, and general study coordination, were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1), and TOPMed MESA Multi-Omics (HHSN2682015000031/HSN26800004). The MESA projects are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for the Multi-Ethnic Study of Atherosclerosis (MESA) projects are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1TR001881, DK063491, HL148610, and R01HL105756. The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutes can be found at http://www.mesa-nhlbi.org. The Genes-environments and Admixture in Latino Asthmatics (GALA II) Study was supported by the National Heart, Lung, and Blood Institute of the National Institute of Health (NIH) grants R01HL117004 and X01HL134589; study enrollment supported by the Sandler Family Foundation, the American Asthma Foundation, the RWJF Amos Medical Faculty Development Program, Harry Wm. and Diana V. Hind Distinguished Professor in Pharmaceutical Sciences II and the National Institute of Environmental Health Sciences grant R01ES015794 . The GALA II study collaborators include Shannon Thyne, UCSF; Harold J. Farber, Texas Children's Hospital; Denise Serebrisky, Jacobi Medical Center; Rajesh Kumar, Lurie Children's Hospital of Chicago; Emerita Brigino-Buenaventura, Kaiser Permanente; Michael A. LeNoir, Bay Area Pediatrics; Kelley Meade, UCSF Benioff Children's Hospital, Oakland; William Rodriguez-Cintron, VA Hospital, Puerto Rico; Pedro C. Avila, Northwestern University; Jose R. Rodriguez-Santana, Centro de Neumologia Pediatrica; Luisa N. Borrell, City University of New York; Adam Davis, UCSF Benioff Children's Hospital, Oakland; Saunak Sen, University of Tennessee and Fred Lurmann, Sonoma Technologies, Inc. The authors acknowledge the families and patients for their participation and thank the numerous health care providers and community clinics for their support and participation in GALA II. In particular, the authors thank study coordinator Sandra Salazar; the recruiters who obtained the data: Duanny Alva, MD, Gaby Ayala-Rodriguez, Lisa Caine, Elizabeth Castellanos, Jaime Colon, Denise DeJesus, Blanca Lopez, Brenda Lopez, MD, Louis Martos, Vivian Medina, Juana Olivo, Mario Peralta, Esther Pomares, MD, Jihan Quraishi, Johanna Rodriguez, Shahdad Saeedi, Dean Soto, Ana Taveras; and the lab researcher Celeste Eng who processed the biospecimens. The Study of African Americans, Asthma, Genes and Environments (SAGE) was supported by by the National Heart, Lung, and Blood Institute of the National Institute of Health (NIH) grants R01HL117004 and X01HL134589; study enrollment supported by the Sandler Family Foundation, the American Asthma Foundation, the RWJF Amos Medical Faculty Development Program, Harry Wm. and Diana V. Hind Distinguished Professor in Pharmaceutical Sciences II. The SAGE study collaborators include Harold J. Farber, Texas Children's Hospital; Emerita Brigino-Buenaventura, Kaiser Permanente; Michael A. LeNoir, Bay Area Pediatrics; Kelley Meade, UCSF Benioff Children's Hospital, Oakland; Luisa N. Borrell, City University of New York; Adam Davis, UCSF Benioff Children's Hospital, Oakland and Fred Lurmann, Sonoma Technologies, Inc. The authors acknowledge the families and patients for their participation and thank the numerous health care providers and community clinics for their support and participation in SAGE. In particular, the authors thank study coordinator Sandra Salazar; the recruiters who obtained the data: Lisa Caine, Elizabeth Castellanos, Brenda Lopez, MD, Shahdad Saeedi; and the lab researcher Celeste Eng who processed the biospecimens. The authors thank the SPIROMICS participants and participating physicians, investigators, study coordinators, and staff for making this research possible. More information about the study and how to access SPIROMICS data is available at www.spiromics.org. The authors would like to acknowledge the University of North Carolina at Chapel Hill BioSpecimen Processing Facility (http://bsp.web.unc.edu/) and Alexis Lab (https://www.med.unc.edu/cemalb/facultyresearch/alexislab/) for sample processing, storage, and sample disbursements. The University of North Carolina BioSpecimen Processing Facility (RRID: SCR_021290 ; https://bsp.web.unc.edu) was supported in part by NCI Cancer Center Support Grant 5P30CA016086-46 and the NIEHS UNC Center for Environmental Health and Susceptibility Center grant 5P30ES010126. We would like to acknowledge the following current and former investigators of the SPIROMICS sites and reading centers: Neil E Alexis, MD; Wayne H Anderson, PhD; Mehrdad Arjomandi, MD; Igor Barjaktarevic, MD, PhD; R Graham Barr, MD, DrPH; Patricia Basta, PhD; Lori A Bateman, MS; Christina Bellinger, MD; Surya P Bhatt, MD; Eugene R Bleecker, MD; Richard C Boucher, MD; Russell P Bowler, MD, PhD; Russell G Buhr, MD, PhD; Stephanie A Christenson, MD; Alejandro P Comellas, MD; Christopher B Cooper, MD, PhD; David J Couper, PhD; Gerard J Criner, MD; Ronald G Crystal, MD; Jeffrey L Curtis, MD; Claire M Doerschuk, MD; Mark T Dransfield, MD; M Bradley Drummond, MD; Christine M Freeman, PhD; Craig Galban, PhD; Katherine Gershner, DO; MeiLan K Han, MD, MS; Nadia N Hansel, MD, MPH; Annette T Hastie, PhD; Eric A Hoffman, PhD; Yvonne J Huang, MD; Robert J Kaner, MD; Richard E Kanner, MD; Mehmet Kesimer, PhD; Eric C Kleerup, MD; Jerry A Krishnan, MD, PhD; Wassim W Labaki, MD; Lisa M LaVange, PhD; Stephen C Lazarus, MD; Fernando J Martinez, MD, MS; Merry-Lynn McDonald, PhD; Deborah A Meyers, PhD; Wendy C Moore, MD; John D Newell Jr, MD; Elizabeth C Oelsner, MD, MPH; Jill Ohar, MD; Wanda K O'Neal, PhD; Victor E Ortega, MD, PhD; Robert Paine, III, MD; Laura Paulin, MD, MHS; Stephen P Peters, MD, PhD; Cheryl Pirozzi, MD; Nirupama Putcha, MD, MHS; Sanjeev Raman, MBBS, MD; Stephen I Rennard, MD; Donald P Tashkin, MD; J Michael Wells, MD; Robert A Wise, MD; and Prescott G Woodruff, MD, MPH. The project officers from the Lung Division of the National Heart, Lung, and Blood Institute were Lisa Postow, PhD, and Lisa Viviano, BSN; SPIROMICS was supported by contracts from the NIH/NHLBI (HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, HHSN268200900020C), grants from the NIH/NHLBI (U01 HL137880, U24 HL141762, R01 HL182622, and R01 HL144718), and supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from Amgen; AstraZeneca/MedImmune; Bayer; Bellerophon Therapeutics; Boehringer-Ingelheim Pharmaceuticals, Inc.; Chiesi Farmaceutici S.p.A.; Forest Research Institute, Inc.; Genentech; GlaxoSmithKline; Grifols Therapeutics, Inc.; Ikaria, Inc.; MGC Diagnostics; Novartis Pharmaceuticals Corporation; Nycomed GmbH; Polarean; ProterixBio; Regeneron Pharmaceuticals, Inc.; Sanofi; Sunovion; Takeda Pharmaceutical Company; and Theravance Biopharma and Mylan/Viatris. LK was supported by funding from National Cancer Institute (R00CA246076). LMR is funded by R01AG075884.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

For the WHI study: the Institutional Review Board from the Fred Hutchinson Cancer Center approved the studies. For the SPIROMICS study: the Institutional Review Boards for the participating sites (University of North Carolina at Chapel Hill, Columbia University, Temple University, Johns Hopkins University, Wake Forest University, University of Michigan, University of Illinois at Chicago, University of Iowa, University of Utah, National Jewish Health, University of California at San Francisco, and University of California at Los Angeles) approved the studies. For the FHS study: all protocols for participant examinations and collection of genetic materials for this study were approved by the Boston Medical Center Institutional Review Board For GALAII and SAGE studies: The local institutional review board from the University of California San Francisco Human Research Protection Program approved the studies (IRB# 10-02877 for SAGE and 10-00889 for GALA II) For MESA study: The study was approved by the Institutional Review Boards at The Lundquist Institute (formerly Los Angeles BioMedical Research Institute) at Harbor-UCLA Medical Center, University of Washington, Wake Forest School of Medicine, Northwestern University, University of Minnesota, Columbia University, and Johns Hopkins University. For LTRC and COPDGene studies: The MassGeneral Brigham IRB gave ethical approval for this work.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Individual level data is available through the database of Genotypes and Phenotypes (dbGaP). All accessions are listed in acknowledgments. Cis- and trans-e/sQTL summary statistics and fine-mapping results will be available in the TOPMed Genomic Summary Results repository (dbGaP phs001974).