OTTERS: A powerful TWAS framework leveraging summary-level reference data

Dai, Qile; Zhou, Geyu; Zhao, Hongyu; Võsa, Urmo; Franke, Lude; Battle, Alexis; Teumer, Alexander; Lehtimäki, Terho; Raitakari, Olli T.; Esko, Tõnu; Consortium, eQTLGen; Epstein, Michael P.; Yang, Jingjing; Ahsan, Habibul; Pierce, Brandon L.; Tong, Lin

doi:10.6082/vnm1c-qw521

Published March 7, 2023 | Version v1

Journal article Open

OTTERS: A powerful TWAS framework leveraging summary-level reference data

1. Emory University
2. Yale University
3. University of Tartu
4. University of Groningen
5. Johns Hopkins University
6. University Medicine Greifswald
7. Tampere University
8. University of Turku
9. University of Chicago

Most existing TWAS tools require individual-level eQTL reference data and thus are not applicable to summary-level reference eQTL datasets. The development of TWAS methods that can harness summary-level reference data is valuable to enable TWAS in broader settings and enhance power due to increased reference sample size. Thus, we develop a TWAS framework called OTTERS (Omnibus Transcriptome Test using Expression Reference Summary data) that adapts multiple polygenic risk score (PRS) methods to estimate eQTL weights from summary-level eQTL reference data and conducts an omnibus TWAS. We show that OTTERS is a practical and powerful TWAS tool by both simulations and application studies.

Notes

The University of Chicago authors are members of the eQTLGen Consortium.

Data availability

ROS/MAP/MSBB WGS data used in our simulation studies are available through Synapse with data access application (https://www.synapse.org/#!Synapse:syn10901595). The eQTLGen consortium data are available from the consortium portal website (https://www.eqtlgen.org). UK Biobank summary-level GWAS data are available through the Alkes Group (https://alkesgroup.broadinstitute.org/UKBB). Individual-level GTEx reference data are available through dbGap (Accession phs000424.v8.p2). Summary eQTL data of blood tissue in GTEx cohort are available from GTEx Portal (https://console.cloud.google.com/storage/browser/gtex-resources/GTEx_Analysis_v8_QTLs/GTEx_Analysis_v8_eQTL_all_associations). Significant genes from TWAS-hub are available from http://twas-hub.org. The summary eQTL weights of blood tissue generated by OTTERS (from eQTLGen data) and summary TWAS results generated by OTTERS for cardiovascular disease (from UK Biobank data) are available from Synapse (https://doi.org/10.7303/syn51009573).

Source code for OTTERS is available from https://github.com/daiqile96/OTTERS. All scripts used to generate intermediate or final data and figures are available from GitHub page https://github.com/daiqile96/OTTERS_paper and available in Zenodo with the identifier https://doi.org/10.5281/zenodo.7566827. Source code for ACAT is available from https://github.com/yaowuliu/ACAT. Source code for FUSION is available from http://gusevlab.org/projects/fusion. Source code for lassosum is available from https://github.com/tshmak/lassosum. Source code for PRS-CS is available from https://github.com/getian107/PRScs. Source code for SDPR is available from https://github.com/eldronzhou/SDPR. Plink version 1.9 is used and available at https://www.cog-genomics.org/plink/.

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