Gene expression imputation across multiple brain regions provides insights into schizophrenia risk

iPSYCH-GEMS Schizophrenia Working Group, CommonMind Consortium, The Schizophrenia Working Group of the PsyUniversity of Copenhagenchiatric Genomics Consortium, Laura M. Huckins, Amanda Dobbyn, Douglas M. Ruderfer, Gabriel Hoffman, Weiqing Wang, Antonio F. Pardiñas, Veera M. Rajagopal, Thomas D. Als, Hoang T. Nguyen, Kiran Girdhar, James Boocock, Panos Roussos, Menachem Fromer, Robin Kramer, Enrico Domenici, Eric R. Gamazon, Shaun M. Purcell & 348 others Jessica S. Johnson, Hardik R. Shah, Lambertus L. Klein, Kristen K. Dang, Benjamin A. Logsdon, Milind C. Mahajan, Lara M. Mangravite, Hiroyoshi Toyoshiba, Raquel E. Gur, Chang Gyu Hahn, Eric Schadt, David A. Lewis, Vahram Haroutunian, Mette A. Peters, Barbara K. Lipska, Joseph D. Buxbaum, Keisuke Hirai, Thanneer M. Perumal, Laurent Essioux, Stephan Ripke, Benjamin M. Neale, Aiden Corvin, James T.R. Walters, Kai How Farh, Peter A. Holmans, Phil Lee, Brendan Bulik-Sullivan, David A. Collier, Hailiang Huang, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu A. Bacanu, Martin Begemann, Richard A. Belliveau, Judit Bene, Sarah E. Bergen, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Stanley V. Catts, Kimberly D. Chambert, Raymond C.K. Chan, Ronald Y.L. Chen, Eric Y.H. Chen, Wei Cheng, Eric F.C. Cheung, Siow Ann Chong, C. Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, James J. Crowley, David Curtis, Michael Davidson, Kenneth L. Davis, Franziska Degenhardt, Jurgen Del Favero, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Srdjan Djurovic, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H. Fanous, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B. Freimer, Marion Friedl, Joseph I. Friedman, Menachem Fromer, Giulio Genovese, Lyudmila Georgieva, Ina Giegling, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I. Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Lieuwe de Haan, Christian Hammer, Marian L. Hamshere, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Annette M. Hartmann, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, David M. Hougaard, Masashi Ikeda, Inge Joa, Antonio Julia, Rene S. Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, James L. Kennedy, Andrey Khrunin, Yunjung Kim, Janis Klovins, James A. Knowles, Bettina Konte, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K. Kahler, Claudine Laurent, Jimmy Lee Chee Keong, S. Hong Lee, Sophie E. Legge, Bernard Lerer, Miaoxin Li, Tao Li, Kung Yee Liang, Jeffrey Lieberman, Svetlana Limborska, Carmel M. Loughland, Jan Lubinski, Jouko Lonnqvist, Milan Macek, Patrik K.E. Magnusson, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Colm McDonald, Andrew M. McIntosh, Sandra Meier, Carin J. Meijer, Bela Melegh, Ingrid Melle, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Lili Milani, Vihra Milanova, Younes Mokrab, Derek W. Morris, Ole Mors, Kieran C. Murphy, Robin M. Murray, Inez Myin-Germeys, Bertram Muller-Myhsok, Mari Nelis, Igor Nenadic, Deborah A. Nertney, Gerald Nestadt, Kristin K. Nicodemus, Liene Nikitina-Zake, Laura Nisenbaum, Annelie Nordin, Eadbhard O’Callaghan, Colm O’Dushlaine, F. Anthony O’Neill, Sang Yun Oh, Ann Olincy, Line Olsen, Jim Van Os, Christos Pantelis, George N. Papadimitriou, Sergi Papiol, Elena Parkhomenko, Michele T. Pato, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O. Perkins, Olli Pietiläinen, Jonathan Pimm, Andrew J. Pocklington, John Powell, Alkes Price, Ann E. Pulver, Shaun M. Purcell, Digby Quested, Henrik B. Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander L. Richards, Joshua L. Roffman, Panos Roussos, Douglas M. Ruderfer, Veikko Salomaa, Alan R. Sanders, Ulrich Schall, Christian R. Schubert, Thomas G. Schulze, Kang Sim, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Jianxin Shi, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, Petr Slominsky, Jordan W. Smoller, Hon Cheong So, Chris C.A. Spencer, Eli A. Stahl, Hreinn Stefansson, Stacy Steinberg, Elisabeth Stogmann, Richard E. Straub, Eric Strengman, Jana Strohmaier, T. Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Dragan M. Svrakic, Jin P. Szatkiewicz, Erik Soderman, Srinivas Thirumalai, Draga Toncheva, Sarah Tosato, Juha Veijola, John Waddington, Dermot Walsh, Dai Wang, Qiang Wang, Bradley T. Webb, Mark Weiser, Dieter B. Wildenauer, Nigel M. Williams, Stephanie Williams, Stephanie H. Witt, Aaron R. Wolen, Emily H.M. Wong, Brandon K. Wormley, Hualin Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Naomi R. Wray, Kari Stefansson, Peter M. Visscher, Rolf Adolfsson, Ole A. Andreassen, Douglas H.R. Blackwood, Elvira Bramon, Joseph D. Buxbaum, Anders D. Børglum, Sven Cichon, Ariel Darvasi, Enrico Domenici, Hannelore Ehrenreich, Tonu Esko, Pablo V. Gejman, Michael Gill, Hugh Gurling, Christina M. Hultman, Nakao Iwata, Assen V. Jablensky, Erik G. Jonsson, Kenneth S. Kendler, George Kirov, Jo Knight, Todd Lencz, Douglas F. Levinson, Qingqin S. Li, Jianjun Liu, Anil K. Malhotra, Steven A. McCarroll, Andrew McQuillin, Jennifer L. Moran, Preben Bo Mortensen, Bryan J. Mowry, Markus M. Nothen, Roel A. Ophoff, Michael J. Owen, Aarno Palotie, Carlos N. Pato, Tracey L. Petryshen, Danielle Posthuma, Marcella Rietschel, Brien P. Riley, Dan Rujescu, Pak C. Sham, Pamela Sklar, David St Clair, Daniel R. Weinberger, Jens R. Wendland, Thomas Werge, Mark J. Daly, Patrick F. Sullivan, Michael C. O’Donovan, Anders D. Børglum, Ditte Demontis, Veera Manikandan Rajagopal, Thomas D. Als, Manuel Mattheisen, Jakob Grove, Thomas Werge, Preben Bo Mortensen, Carsten Bøcker Pedersen, Esben Agerbo, Marianne Giørtz Pedersen, Ole Mors, Merete Nordentoft, David M. Hougaard, Jonas Bybjerg-Grauholm, Marie Bækvad-Hansen, Christine Søholm Hansen, Ditte Demontis, Anders D. Børglum, James T.R. Walters, Michael C. O’Donovan, Patrick Sullivan, Michael J. Owen, Bernie Devlin, Solveig K. Sieberts, Nancy J. Cox, Hae Kyung Im, Pamela Sklar, Eli A. Stahl

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression.

LanguageEnglish
Pages659–674
Number of pages15
JournalNature Genetics
Volume51
DOIs
Publication statusPublished - 25 Mar 2019

Fingerprint

Genome-Wide Association Study
Prefrontal Cortex
Schizophrenia
Tay-Sachs Disease
Gene Expression
Brain
Genes
Genotype
Conditioning (Psychology)

Cite this

iPSYCH-GEMS Schizophrenia Working Group, CommonMind Consortium, & The Schizophrenia Working Group of the PsyUniversity of Copenhagenchiatric Genomics Consortium (2019). Gene expression imputation across multiple brain regions provides insights into schizophrenia risk. Nature Genetics, 51, 659–674. https://doi.org/10.1038/s41588-019-0364-4
iPSYCH-GEMS Schizophrenia Working Group ; CommonMind Consortium ; The Schizophrenia Working Group of the PsyUniversity of Copenhagenchiatric Genomics Consortium. / Gene expression imputation across multiple brain regions provides insights into schizophrenia risk. In: Nature Genetics. 2019 ; Vol. 51. pp. 659–674.
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abstract = "Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression.",
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Hong} and Legge, {Sophie E.} and Bernard Lerer and Miaoxin Li and Tao Li and Liang, {Kung Yee} and Jeffrey Lieberman and Svetlana Limborska and Loughland, {Carmel M.} and Jan Lubinski and Jouko Lonnqvist and Milan Macek and Magnusson, {Patrik K.E.} and Maher, {Brion S.} and Wolfgang Maier and Jacques Mallet and Sara Marsal and Manuel Mattheisen and Morten Mattingsdal and McCarley, {Robert W.} and Colm McDonald and McIntosh, {Andrew M.} and Sandra Meier and Meijer, {Carin J.} and Bela Melegh and Ingrid Melle and Mesholam-Gately, {Raquelle I.} and Andres Metspalu and Michie, {Patricia T.} and Lili Milani and Vihra Milanova and Younes Mokrab and Morris, {Derek W.} and Ole Mors and Murphy, {Kieran C.} and Murray, {Robin M.} and Inez Myin-Germeys and Bertram Muller-Myhsok and Mari Nelis and Igor Nenadic and Nertney, {Deborah A.} and Gerald Nestadt and Nicodemus, {Kristin K.} and Liene Nikitina-Zake and Laura Nisenbaum and Annelie Nordin and Eadbhard O’Callaghan and Colm O’Dushlaine and O’Neill, {F. Anthony} and Oh, {Sang Yun} and Ann Olincy and Line Olsen and {Van Os}, Jim and Christos Pantelis and Papadimitriou, {George N.} and Sergi Papiol and Elena Parkhomenko and Pato, {Michele T.} and Tiina Paunio and Milica Pejovic-Milovancevic and Perkins, {Diana O.} and Olli Pietil{\"a}inen and Jonathan Pimm and Pocklington, {Andrew J.} and John Powell and Alkes Price and Pulver, {Ann E.} and Purcell, {Shaun M.} and Digby Quested and Rasmussen, {Henrik B.} and Abraham Reichenberg and Reimers, {Mark A.} and Richards, {Alexander L.} and Roffman, {Joshua L.} and Panos Roussos and Ruderfer, {Douglas M.} and Veikko Salomaa and Sanders, {Alan R.} and Ulrich Schall and Schubert, {Christian R.} and Schulze, {Thomas G.} and Kang Sim and Scolnick, {Edward M.} and Scott, {Rodney J.} and Seidman, {Larry J.} and Jianxin Shi and Engilbert Sigurdsson and Teimuraz Silagadze and Silverman, {Jeremy M.} and Kang Sim and Petr Slominsky and Smoller, {Jordan W.} and So, {Hon Cheong} and Spencer, {Chris C.A.} and Stahl, {Eli A.} and Hreinn Stefansson and Stacy Steinberg and Elisabeth Stogmann and Straub, {Richard E.} and Eric Strengman and Jana Strohmaier and Stroup, {T. 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iPSYCH-GEMS Schizophrenia Working Group, CommonMind Consortium & The Schizophrenia Working Group of the PsyUniversity of Copenhagenchiatric Genomics Consortium 2019, 'Gene expression imputation across multiple brain regions provides insights into schizophrenia risk', Nature Genetics, vol. 51, pp. 659–674. https://doi.org/10.1038/s41588-019-0364-4

Gene expression imputation across multiple brain regions provides insights into schizophrenia risk. / iPSYCH-GEMS Schizophrenia Working Group; CommonMind Consortium; The Schizophrenia Working Group of the PsyUniversity of Copenhagenchiatric Genomics Consortium.

In: Nature Genetics, Vol. 51, 25.03.2019, p. 659–674.

Research output: Contribution to JournalArticleAcademicpeer-review

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AU - Pardiñas, Antonio F.

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AU - Kennedy, James L.

AU - Khrunin, Andrey

AU - Kim, Yunjung

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AU - Nikitina-Zake, Liene

AU - Nisenbaum, Laura

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PY - 2019/3/25

Y1 - 2019/3/25

N2 - Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression.

AB - Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression.

UR - http://www.scopus.com/inward/record.url?scp=85063585118&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85063585118&partnerID=8YFLogxK

U2 - 10.1038/s41588-019-0364-4

DO - 10.1038/s41588-019-0364-4

M3 - Article

VL - 51

SP - 659

EP - 674

JO - Nature Genetics

T2 - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

ER -

iPSYCH-GEMS Schizophrenia Working Group, CommonMind Consortium, The Schizophrenia Working Group of the PsyUniversity of Copenhagenchiatric Genomics Consortium. Gene expression imputation across multiple brain regions provides insights into schizophrenia risk. Nature Genetics. 2019 Mar 25;51:659–674. https://doi.org/10.1038/s41588-019-0364-4