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

Qile Dai, Geyu Zhou, Hongyu Zhao, Tõnu Esko, Dorret I. Boomsma, Michel G. Nivard, Jenny van Dongen, Michael P. Epstein*, Jingjing Yang*, eQTLGen Consortium

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Article number1271
JournalNature Communications
Volume14
Issue number1
DOIs
Publication statusPublished - 7 Mar 2023

Bibliographical note

Funding Information:
The authors thank Dr Greg Gibson from Georgia Tech for his insightful comments and discussion that help the development and improve the quality of this manuscript. This work was supported by National Institutes of Health grant awards R35GM138313 (Q.D., J.Y.), RF1AG071170 (Q.D., M.P.E.), and Estonian Research Council Grant PUT (PRG1291) for T.E. NIH/NIA grants P30AG10161, R01AG15819, R01AG17917, R01AG30146, R01AG36836, R01AG56352, U01AG32984, U01AG46152, U01AG61356, the Illinois Department of Public Health, the Translational Genomics Research Institute support the generation of the ROS/MAP data led by A.S.B., P.L.D.J. and D.A.B. The Young Finns Study has been financially supported by the Academy of Finland: grants 322098, 286284, 134309 (Eye), 126925, 121584, 124282, 255381, 256474, 283115, 319060, 320297, 314389, 338395, 330809, and 104821, 129378 (Salve), 117797 (Gendi), and 141071 (Skidi), the Social Insurance Institution of Finland, Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (grant X51001), Juho Vainio Foundation, Paavo Nurmi Foundation, Finnish Foundation for Cardiovascular Research, Finnish Cultural Foundation, The Sigrid Juselius Foundation, Tampere Tuberculosis Foundation, Emil Aaltonen Foundation, Yrjö Jahnsson Foundation, Signe and Ane Gyllenberg Foundation, Diabetes Research Foundation of Finnish Diabetes Association, EU Horizon 2020 (grant 755320 for TAXINOMISIS and grant 848146 for To Aition), European Research Council (grant 742927 for MULTIEPIGEN project), Tampere University Hospital Supporting Foundation, and Finnish Society of Clinical Chemistry and the Cancer Foundation Finland. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2023, The Author(s).

Funding

The authors thank Dr Greg Gibson from Georgia Tech for his insightful comments and discussion that help the development and improve the quality of this manuscript. This work was supported by National Institutes of Health grant awards R35GM138313 (Q.D., J.Y.), RF1AG071170 (Q.D., M.P.E.), and Estonian Research Council Grant PUT (PRG1291) for T.E. NIH/NIA grants P30AG10161, R01AG15819, R01AG17917, R01AG30146, R01AG36836, R01AG56352, U01AG32984, U01AG46152, U01AG61356, the Illinois Department of Public Health, the Translational Genomics Research Institute support the generation of the ROS/MAP data led by A.S.B., P.L.D.J. and D.A.B. The Young Finns Study has been financially supported by the Academy of Finland: grants 322098, 286284, 134309 (Eye), 126925, 121584, 124282, 255381, 256474, 283115, 319060, 320297, 314389, 338395, 330809, and 104821, 129378 (Salve), 117797 (Gendi), and 141071 (Skidi), the Social Insurance Institution of Finland, Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (grant X51001), Juho Vainio Foundation, Paavo Nurmi Foundation, Finnish Foundation for Cardiovascular Research, Finnish Cultural Foundation, The Sigrid Juselius Foundation, Tampere Tuberculosis Foundation, Emil Aaltonen Foundation, Yrjö Jahnsson Foundation, Signe and Ane Gyllenberg Foundation, Diabetes Research Foundation of Finnish Diabetes Association, EU Horizon 2020 (grant 755320 for TAXINOMISIS and grant 848146 for To Aition), European Research Council (grant 742927 for MULTIEPIGEN project), Tampere University Hospital Supporting Foundation, and Finnish Society of Clinical Chemistry and the Cancer Foundation Finland. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

FundersFunder number
National Institutes of HealthR35GM138313, RF1AG071170
National Institutes of Health
National Institute on AgingR01AG56352, U01AG61356, U01AG46152, R01AG36836, R01AG30146, P30AG10161, R01AG15819, R01AG17917, U01AG32984
National Institute on Aging
Illinois Department of Public Health
Yrjö Jahnssonin Säätiö
European Research Council742927
European Research Council
Eesti TeadusagentuurPRG1291
Eesti Teadusagentuur
Academy of Finland320297, 322098, 129378, 338395, 256474, 255381, 314389, 141071, 134309, 124282, 126925, 121584, 117797, 283115, 104821, 319060, 330809, 286284
Academy of Finland
Suomen Kulttuurirahasto
Juho Vainion Säätiö
Signe ja Ane Gyllenbergin Säätiö
Emil Aaltosen Säätiö
Sydäntutkimussäätiö
Sigrid Juséliuksen Säätiö
Tampereen Tuberkuloosisäätiö
Horizon 2020848146, 755320
Horizon 2020
Diabetesliitto
Paavo Nurmen Säätiö
Tays
Syöpäsäätiö
Turun Yliopistollinen KeskussairaalaX51001
Turun Yliopistollinen Keskussairaala
Suomen kliinisen kemian yhdistys

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