OTTERS: a powerful TWAS framework leveraging summary-level reference data
Qile Dai, Geyu Zhou, Hongyu Zhao, Urmo Võsa, Lude Franke, Alexis Battle, Alexander Teumer, Terho Lehtimäki, Olli T. Raitakari, Tõnu Esko, Mawussé Agbessi, Habibul Ahsan, Isabel Alves, Anand Kumar Andiappan, Wibowo Arindrarto, Philip Awadalla, Alexis Battle, Frank Beutner, Marc Jan Bonder, Dorret I. Boomsma, Mark Christiansen, Annique Claringbould, Patrick Deelen, Marie-Julie Favé, Timothy M. Frayling, Sina A. Gharib, Greg Gibson, Bastiaan T. Heijmans, Gibran Hemani, Rick Jansen, Mika Kähönen, Anette Kalnapenkis, Silva Kasela, Johannes Kettunen, Yungil Kim, Holger Kirsten, Péter Kovács, Knut Krohn, Jaanika Kronberg, Viktorija Kukushkina, Zoltán Kutalik, Bernett Lee, Markus Loeffler, Urko M. Marigorta, Hailang Mei, Lili Milani, Grant W. Montgomery, Martina Müller‐Nurasyid, Matthias Nauck, Michel G. Nivard, Brenda W.J.H. Penninx, Markus Perola, Natalia Pervjakova, Brandon L. Pierce, Joseph E. Powell, Holger Prokisch, Bruce M. Psaty, Samuli Ripatti, Olaf Rötzschke, Sina Rüeger, Ashis Saha, Markus Scholz, Katharina Schramm, Ilkka Seppälä, P. Eline Slagboom, Coen D.A. Stehouwer, Michael Stümvoll, Patrick Sullivan, Peter A.C. ’t Hoen, Joachim Thiery, Tong Lin, Anke Tönjes, Jenny van Dongen, Maarten van Iterson, Joyce B. J. van Meurs, Jan H. Veldink, Joost Verlouw, Peter M. Visscher, Uwe Völker, Harm-Jan Westra, Cisca Wijmenga, Hanieh Yaghootka, Jian Yang, Biao Zeng, Futao Zhang, Michael P. Epstein, Jingjing Yang, Jingjing Yang, Jingjing Yang
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.