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.

Here, the authors present a TWAS framework OTTERS that adapts multiple polygenic risk score methods to estimate eQTL weights from summary-level eQTL data. Both simulation and real studies show OTTERS is powerful across a wide range of genetic architectures.

Details

Title
OTTERS: a powerful TWAS framework leveraging summary-level reference data
Author
Dai, Qile 1 ; Zhou, Geyu 2 ; Zhao, Hongyu 3   VIAFID ORCID Logo  ; Võsa, Urmo 4   VIAFID ORCID Logo  ; Franke, Lude 5   VIAFID ORCID Logo  ; Battle, Alexis 6   VIAFID ORCID Logo  ; Teumer, Alexander 7   VIAFID ORCID Logo  ; Lehtimäki, Terho 8   VIAFID ORCID Logo  ; Raitakari, Olli T. 9 ; Esko, Tõnu 4 ; Agbessi, Mawussé 10 ; Ahsan, Habibul 11 ; Alves, Isabel 10 ; Andiappan, Anand Kumar 12 ; Arindrarto, Wibowo 13 ; Awadalla, Philip 10 ; Beutner, Frank 14 ; Jan Bonder, Marc 15 ; Boomsma, Dorret I. 16 ; Christiansen, Mark W. 17 ; Claringbould, Annique 5 ; Deelen, Patrick 18 ; Favé, Marie-Julie 10 ; Frayling, Timothy 19 ; Gharib, Sina A. 20 ; Gibson, Greg 21 ; Heijmans, Bastiaan T. 13 ; Hemani, Gibran 22 ; Jansen, Rick 23 ; Kähönen, Mika 24 ; Kalnapenkis, Anette 4 ; Kasela, Silva 4 ; Kettunen, Johannes 25 ; Kim, Yungil 26 ; Kirsten, Holger 27 ; Kovacs, Peter 28 ; Krohn, Knut 29 ; Kronberg, Jaanika 4 ; Kukushkina, Viktorija 4 ; Kutalik, Zoltan 30 ; Lee, Bernett 12 ; Loeffler, Markus 27 ; Marigorta, Urko M. 31 ; Mei, Hailang 32 ; Milani, Lili 4 ; Montgomery, Grant W. 33 ; Müller-Nurasyid, Martina 34 ; Nauck, Matthias 35 ; Nivard, Michel G. 36 ; Penninx, Brenda 23 ; Perola, Markus 37 ; Pervjakova, Natalia 4 ; Pierce, Brandon L. 11 ; Powell, Joseph 38 ; Prokisch, Holger 39 ; Psaty, Bruce M. 40 ; Ripatti, Samuli 41 ; Rotzschke, Olaf 12 ; Rüeger, Sina 30 ; Saha, Ashis 6 ; Scholz, Markus 27 ; Schramm, Katharina 42 ; Seppälä, Ilkka 8 ; Slagboom, Eline P. 13 ; Stehouwer, Coen D. A. 43 ; Stumvoll, Michael 44 ; Sullivan, Patrick 45 ; ‘t Hoen, Peter A. C. 46 ; Thiery, Joachim 47 ; Tong, Lin 11 ; Tönjes, Anke 48 ; van Dongen, Jenny 16 ; van Iterson, Maarten 13 ; van Meurs, Joyce 49 ; Veldink, Jan H. 50 ; Verlouw, Joost 49 ; Visscher, Peter M. 33 ; Völker, Uwe 51 ; Westra, Harm-Jan 5 ; Wijmenga, Cisca 52 ; Yaghootka, Hanieh 53 ; Yang, Jian 54 ; Zeng, Biao 21 ; Zhang, Futao 33 ; Epstein, Michael P. 55   VIAFID ORCID Logo  ; Yang, Jingjing 55   VIAFID ORCID Logo 

1  Emory University School of Public Health, Department of Biostatistics and Bioinformatics, Atlanta, USA (GRID:grid.189967.8) (ISNI:0000 0001 0941 6502); Emory University School of Medicine, Center for Computational and Quantitative Genetics, Department of Human Genetics, Atlanta, USA (GRID:grid.189967.8) (ISNI:0000 0001 0941 6502) 
2  Yale University, Program of Computational Biology and Bioinformatics, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710) 
3  Yale University, Program of Computational Biology and Bioinformatics, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710); Yale School of Public Health, Department of Biostatistics, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710) 
4  University of Tartu, Estonian Genome Centre, Institute of Genomics, Tartu, Estonia (GRID:grid.10939.32) (ISNI:0000 0001 0943 7661) 
5  University Medical Center Groningen, Department of Genetics, University of Groningen, Groningen, The Netherlands (GRID:grid.4494.d) (ISNI:0000 0000 9558 4598); Oncode Institute, Utrecht, The Netherlands (GRID:grid.499559.d) 
6  Johns Hopkins University, Department of Computer Science, and Departments of Biomedical Engineering, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
7  University Medicine Greifswald, Institute for Community Medicine, Greifswald, Germany (GRID:grid.5603.0) 
8  Tampere University, Department of Clinical Chemistry, Fimlab Laboratories and Finnish Centre for Cardiovascular Disease Tampere, Faculty of Medicine and Health Technology, Tampere, Finland (GRID:grid.502801.e) (ISNI:0000 0001 2314 6254) 
9  University of Turku and Turku University Hospital, Centre for Population Health Research, Turku, Finland (GRID:grid.1374.1) (ISNI:0000 0001 2097 1371); University of Turku, Research Centre of Applied and Preventive Cardiovascular Medicine, Turku, Finland (GRID:grid.1374.1) (ISNI:0000 0001 2097 1371); Turku University Hospital, Department of Clinical Physiology and Nuclear Medicine, Turku, Finland (GRID:grid.410552.7) (ISNI:0000 0004 0628 215X) 
10  Ontario Institute for Cancer Research, Computational Biology, Toronto, Canada (GRID:grid.419890.d) (ISNI:0000 0004 0626 690X) 
11  University of Chicago, Department of Public Health Sciences, Chicago, USA (GRID:grid.170205.1) (ISNI:0000 0004 1936 7822) 
12  Singapore Immunology Network, Agency for Science Technology and Research, Singapore, Singapore (GRID:grid.430276.4) (ISNI:0000 0004 0387 2429) 
13  Leiden University Medical Center, Leiden, The Netherlands (GRID:grid.10419.3d) (ISNI:0000000089452978) 
14  Universität Leipzig, Heart Center Leipzig, Leipzig, Germany (GRID:grid.9647.c) (ISNI:0000 0004 7669 9786) 
15  University Medical Center Groningen, Department of Genetics, University of Groningen, Groningen, The Netherlands (GRID:grid.4494.d) (ISNI:0000 0000 9558 4598); European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany (GRID:grid.4709.a) (ISNI:0000 0004 0495 846X) 
16  Vrije Universiteit Amsterdam, Department of Biological Psychology, Amsterdam, The Netherlands (GRID:grid.12380.38) (ISNI:0000 0004 1754 9227) 
17  University of Washington, Cardiovascular Health Research Unit, Seattle, USA (GRID:grid.34477.33) (ISNI:0000000122986657) 
18  University Medical Center Groningen, Department of Genetics, University of Groningen, Groningen, The Netherlands (GRID:grid.4494.d) (ISNI:0000 0000 9558 4598); Oncode Institute, Utrecht, The Netherlands (GRID:grid.499559.d); University Medical Centre Groningen, Genomics Coordination Center, Groningen, The Netherlands (GRID:grid.4494.d) (ISNI:0000 0000 9558 4598); University Medical Centre Utrecht, Department of Genetics, Utrecht, The Netherlands (GRID:grid.7692.a) (ISNI:0000000090126352) 
19  University of Exeter Medical School, Royal Devon & Exeter Hospital, Genetics of Complex Traits, Exeter, UK (GRID:grid.8391.3) (ISNI:0000 0004 1936 8024) 
20  University of Washington, Cardiovascular Health Research Unit, Seattle, USA (GRID:grid.34477.33) (ISNI:0000000122986657); University of Washington, Department of Medicine, Seattle, USA (GRID:grid.34477.33) (ISNI:0000000122986657) 
21  Georgia Tech, School of Biological Sciences, Atlanta, USA (GRID:grid.213917.f) (ISNI:0000 0001 2097 4943) 
22  University of Bristol, MRC Integrative Epidemiology Unit, Bristol, UK (GRID:grid.5337.2) (ISNI:0000 0004 1936 7603) 
23  Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands (GRID:grid.12380.38) (ISNI:0000 0004 1754 9227) 
24  Tampere University, Department of Clinical Physiology, Tampere University Hospital and Faculty of Medicine and Health Technology, Tampere, Finland (GRID:grid.502801.e) (ISNI:0000 0001 2314 6254) 
25  University of Helsinki, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071) 
26  Johns Hopkins University, Department of Computer Science, and Departments of Biomedical Engineering, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311); Icahn School of Medicine at Mount Sinai, Genetics and Genomic Science Department, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
27  Universität Leipzig, Institut für Medizinische InformatiK, Statistik und Epidemiologie, LIFE – Leipzig Research Center for Civilization Diseases, Leipzig, Germany (GRID:grid.9647.c) (ISNI:0000 0004 7669 9786) 
28  Universität Leipzig, IFB Adiposity Diseases, Leipzig, Germany (GRID:grid.9647.c) (ISNI:0000 0004 7669 9786) 
29  Universität Leipzig, Interdisciplinary Center for Clinical Research, Faculty of Medicine, Leipzig, Germany (GRID:grid.9647.c) (ISNI:0000 0004 7669 9786) 
30  Lausanne University Hospital, Lausanne, Switzerland (GRID:grid.8515.9) (ISNI:0000 0001 0423 4662) 
31  Georgia Tech, School of Biological Sciences, Atlanta, USA (GRID:grid.213917.f) (ISNI:0000 0001 2097 4943); Bizkaia Science and Technology Park, Integrative Genomics Lab, CIC bioGUNE, Derio, Spain (GRID:grid.420161.0); Basque Foundation for Science, IKERBASQUE, Bilbao, Spain (GRID:grid.424810.b) (ISNI:0000 0004 0467 2314) 
32  Leiden University Medical Center, Department of Medical Statistics and Bioinformatics, Leiden, The Netherlands (GRID:grid.10419.3d) (ISNI:0000000089452978) 
33  University of Queensland, Institute for Molecular Bioscience, Brisbane, Australia (GRID:grid.1003.2) (ISNI:0000 0000 9320 7537) 
34  Helmholtz Zentrum München – German Research Center for Environmental Health, Institute of Genetic Epidemiology, Neuherberg, Germany (GRID:grid.4567.0) (ISNI:0000 0004 0483 2525); University Hospital Munich, Ludwig Maximilian’s University, Department of Medicine I, München, Germany (GRID:grid.5252.0) (ISNI:0000 0004 1936 973X); DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (GRID:grid.452396.f) (ISNI:0000 0004 5937 5237) 
35  Institute of Clinical Chemistry and Laboratory Medicine, Greifswald University Hospital, Greifswald, Germany (GRID:grid.412469.c) (ISNI:0000 0000 9116 8976); German Center for Cardiovascular Research (partner site Greifswald), Greifswald, Germany (GRID:grid.452396.f) (ISNI:0000 0004 5937 5237) 
36  VU, Department of Biological Psychology, Faculty of Behaviour and Movement Sciences, Amsterdam, The Netherlands (GRID:grid.12380.38) (ISNI:0000 0004 1754 9227) 
37  National Institute for Health and Welfare, University of Helsinki, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071) 
38  Garvan Institute of Medical Research, Garvan-Weizmann Centre for Cellular Genomics, Sydney, Australia (GRID:grid.415306.5) (ISNI:0000 0000 9983 6924) 
39  Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany (GRID:grid.4567.0) (ISNI:0000 0004 0483 2525); Technical University Munich, Institute of Human Genetics, Munich, Germany (GRID:grid.6936.a) (ISNI:0000000123222966) 
40  University of Washington, Cardiovascular Health Research Unit, Seattle, USA (GRID:grid.34477.33) (ISNI:0000000122986657); Kaiser Permanente Washington Health Research Institute, Seattle, USA (GRID:grid.488833.c) (ISNI:0000 0004 0615 7519) 
41  University of Helsinki, Statistical and Translational Genetics, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071) 
42  Helmholtz Zentrum München – German Research Center for Environmental Health, Institute of Genetic Epidemiology, Neuherberg, Germany (GRID:grid.4567.0) (ISNI:0000 0004 0483 2525); University Hospital Munich, Ludwig Maximilian’s University, Department of Medicine I, München, Germany (GRID:grid.5252.0) (ISNI:0000 0004 1936 973X) 
43  Maastricht University Medical Center, Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht, The Netherlands (GRID:grid.412966.e) (ISNI:0000 0004 0480 1382) 
44  Universität Leipzig, Department of Medicine, Leipzig, Germany (GRID:grid.9647.c) (ISNI:0000 0004 7669 9786) 
45  Karolinska Institutet, Department of Medical Epidemiology and Biostatistics, Stockholm, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626) 
46  Radboud University Medical Center Nijmegen, Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382) 
47  Universität Leipzig, Institute for Laboratory Medicine, LIFE – Leipzig Research Center for Civilization Diseases, Leipzig, Germany (GRID:grid.9647.c) (ISNI:0000 0004 7669 9786) 
48  German Center for Cardiovascular Research (partner site Greifswald), Greifswald, Germany (GRID:grid.452396.f) (ISNI:0000 0004 5937 5237) 
49  Erasmus Medical Centre, Department of Internal Medicine, Rotterdam, The Netherlands (GRID:grid.5645.2) (ISNI:000000040459992X) 
50  Utrecht University, UMC Utrecht Brain Center, University Medical Center Utrecht, Department of Neurology, Utrecht, The Netherlands (GRID:grid.5477.1) (ISNI:0000000120346234) 
51  University Medicine Greifswald, Interfaculty Institute for Genetics and Functional Genomics, Greifswald, Germany (GRID:grid.5603.0) 
52  University Medical Center Groningen, Department of Genetics, University of Groningen, Groningen, The Netherlands (GRID:grid.4494.d) (ISNI:0000 0000 9558 4598) 
53  University of Exeter Medical School, Royal Devon & Exeter Hospital, Genetics of Complex Traits, Exeter, UK (GRID:grid.8391.3) (ISNI:0000 0004 1936 8024); University of Westminster, School of Life Sciences, College of Liberal Arts and Science, London, UK (GRID:grid.12896.34) (ISNI:0000 0000 9046 8598); Luleå University of Technology, Division of Medical Sciences, Department of Health Sciences, Luleå, Sweden (GRID:grid.6926.b) (ISNI:0000 0001 1014 8699) 
54  University of Queensland, Institute for Molecular Bioscience, Brisbane, Australia (GRID:grid.1003.2) (ISNI:0000 0000 9320 7537); Westlake University, School of Life Sciences, Hangzhou, China (GRID:grid.494629.4) (ISNI:0000 0004 8008 9315) 
55  Emory University School of Medicine, Center for Computational and Quantitative Genetics, Department of Human Genetics, Atlanta, USA (GRID:grid.189967.8) (ISNI:0000 0001 0941 6502) 
Pages
1271
Publication year
2023
Publication date
2023
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-023-36862-w
ProQuest document ID
2784121748
Copyright
© The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.