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

CommonMind Consortium, Psychiat Genomics Consortium, iPSYCH-GEMS Schizophrenia Working

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)659-+
Number of pages18
JournalNature Genetics
Volume51
Issue number4
DOIs
Publication statusPublished - Apr 2019

Cite this

CommonMind Consortium, Psychiat Genomics Consortium, & iPSYCH-GEMS Schizophrenia Working (2019). Gene expression imputation across multiple brain regions provides insights into schizophrenia risk. Nature Genetics, 51(4), 659-+. https://doi.org/10.1038/s41588-019-0364-4
CommonMind Consortium ; Psychiat Genomics Consortium ; iPSYCH-GEMS Schizophrenia Working. / Gene expression imputation across multiple brain regions provides insights into schizophrenia risk. In: Nature Genetics. 2019 ; Vol. 51, No. 4. pp. 659-+.
@article{d6e6c2e4507b483d8cf3b71f5df5ed84,
title = "Gene expression imputation across multiple brain regions provides insights into schizophrenia risk",
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.",
keywords = "ACUTE INTERMITTENT PORPHYRIA, COGNITIVE DEFICITS, ASSOCIATION, MOUSE, TRANSCRIPTOME, CHILDHOOD, TRAITS, PSYCHOSIS, DISORDER, VARIANTS",
author = "{CommonMind Consortium} and {Psychiat Genomics Consortium} and {iPSYCH-GEMS Schizophrenia Working} and Huckins, {Laura M.} and Amanda Dobbyn and Ruderfer, {Douglas M.} and Gabriel Hoffman and Weiqing Wang and Pardinas, {Antonio F.} and Rajagopal, {Veera M.} and Als, {Thomas D.} and Nguyen, {Hoang T.} and Kiran Girdhar and James Boocock and Panos Roussos and Menachem Fromer and Robin Kramer and Enrico Domenici and Gamazon, {Eric R.} and Purcell, {Shaun M.} and Ditte Demontis and Borglum, {Anders D.} and Walters, {James T. R.} and O'Donovan, {Michael C.} and Patrick Sullivan and Owen, {Michael J.} and Bernie Devlin and Sieberts, {Solveig K.} and Cox, {Nancy J.} and Im, {Hae Kyung} and Pamela Sklar and Stahl, {Eli A.} and Johnson, {Jessica S.} and Shah, {Hardik R.} and Klein, {Lambertus L.} and Dang, {Kristen K.} and Logsdon, {Benjamin A.} and Mahajan, {Milind C.} and Mangravite, {Lara M.} and Hiroyoshi Toyoshiba and Gur, {Raquel E.} and Chang-Gyu Hahn and Eric Schadt and Lewis, {David A.} and Vahram Haroutunian and Peters, {Mette A.} and Lipska, {Barbara K.} and Buxbaum, {Joseph D.} and Keisuke Hirai and Perumal, {Thanneer M.} and Laurent Essioux and Rajagopal, {Veera Manikandan} and Manuel Mattheisen and Jakob Grove and Thomas Werge and Mortensen, {Preben Bo} and Pedersen, {Carsten Bocker} and Esben Agerbo and Pedersen, {Marianne Giortz} and Ole Mors and Merete Nordentoft and Hougaard, {David M.} and Jonas Bybjerg-Grauholm and Marie Baekvad-Hansen and Hansen, {Christine Soholm} and Stephan Ripke and Neale, {Benjamin M.} and Aiden Corvin and Kai-How Farh and Holmans, {Peter A.} and Phil Lee and Brendan Bulik-Sullivan and Collier, {David A.} and Hailiang Huang and Pers, {Tune H.} and Ingrid Agartz and Margot Albus and Madeline Alexander and Farooq Amin and Bacanu, {Silviu A.} and Martin Begemann and Belliveau, {Richard A.} and Judit Bene and Bergen, {Sarah E.} and Elizabeth Bevilacqua and Bigdeli, {Tim B.} and Black, {Donald W.} and Richard Bruggeman and Buccola, {Nancy G.} and Buckner, {Randy L.} and William Byerley and Wiepke Cahn and Guiqing Cai and Dominique Campion and Cantor, {Rita M.} and Carr, {Vaughan J.} and Noa Carrera and Stanley Catts and Chambert, {Kimberly D.} and Chan, {Raymond C. K.} and Chen, {Ronald Y. L.} and Chen, {Eric Y. H.} and Wei Cheng and Cheung, {Eric F. C.} and Chong, {Siow Ann} and Cloninger, {C. Robert} and David Cohen and Nadine Cohen and Paul Cormican and Nick Craddock and Crowley, {James J.} and David Curtis and Michael Davidson and Davis, {Kenneth L.} and Franziska Degenhardt and {Del Favero}, Jurgen and Dimitris Dikeos and Timothy Dinan and Srdjan Djurovic and Gary Donohoe and Elodie Drapeau and Jubao Duan and Frank Dudbridge and Naser Durmishi and Peter Eichhammer and Johan Eriksson and Valentina Escott-Price and Laurent Essioux and Fanous, {Ayman H.} and Farrell, {Martilias S.} and Josef Frank and Lude Franke and Robert Freedman and Freimer, {Nelson B.} and Marion Friedl and Joseph Friedman and Menachem Fromer and Giulio Genovese and Lyudmila Georgieva and Ina Giegling and Paola Giusti-Rodriguez and Stephanie Godard and Jacqueline Goldstein and Vera Golimbet and Srihari Gopal and Jacob Gratten and {de Haan}, Lieuwe and Christian Hammer and Hamshere, {Marian L.} and Mark Hansen and Thomas Hansen and Vahram Haroutunian and Hartmann, {Annette M.} and Henskens, {Frans A.} and Stefan Herms and Hirschhorn, {Joel N.} and Per Hoffmann and Andrea Hofman and Mads Hollegaard and Masashi Ikeda and Inge Joa and Antonio Julia and Kahn, {Rene S.} and Luba Kalaydjieva and Sena Karachanak-Yankova and Juha Karjalainen and David Kavanagh and Keller, {Matthew C.} and Kennedy, {James L.} and Andrey Khrunin and Yunjung Kim and Janis Klovins and Knowles, {James A.} and Bettina Konte and Vaidutis Kucinskas and Kucinskiene, {Zita Ausrele} and Hana Kuzelova-Ptackova and Kahler, {Anna K.} and Claudine Laurent and Keong, {Jimmy Lee Chee} and Lee, {S. Hong} and Legge, {Sophie E.} and Bernard Lerer and Miaoxin Li and Tao Li and Kung-Yee Liang 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 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 Raquelle Mesholam-Gately 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 Sang-Yun Oh 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 Pietilainen and Jonathan Pimm and Pocklington, {Andrew J.} and John Powell and Schwab, {Sibylle G.} and Scott, {Rodney J.} and Spencer, {Chris C. A.} and Qiang Wang and Wildenauer, {Dieter B.} and Williams, {Nigel M.} and Wong, {Emily H. M.} and Assen Jablensky and Mowry, {Bryan J.}",
year = "2019",
month = "4",
doi = "10.1038/s41588-019-0364-4",
language = "English",
volume = "51",
pages = "659--+",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group - Macmillan Publishers",
number = "4",

}

CommonMind Consortium, Psychiat Genomics Consortium & iPSYCH-GEMS Schizophrenia Working 2019, 'Gene expression imputation across multiple brain regions provides insights into schizophrenia risk' Nature Genetics, vol. 51, no. 4, pp. 659-+. https://doi.org/10.1038/s41588-019-0364-4

Gene expression imputation across multiple brain regions provides insights into schizophrenia risk. / CommonMind Consortium; Psychiat Genomics Consortium; iPSYCH-GEMS Schizophrenia Working.

In: Nature Genetics, Vol. 51, No. 4, 04.2019, p. 659-+.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Gene expression imputation across multiple brain regions provides insights into schizophrenia risk

AU - CommonMind Consortium

AU - Psychiat Genomics Consortium

AU - iPSYCH-GEMS Schizophrenia Working

AU - Huckins, Laura M.

AU - Dobbyn, Amanda

AU - Ruderfer, Douglas M.

AU - Hoffman, Gabriel

AU - Wang, Weiqing

AU - Pardinas, Antonio F.

AU - Rajagopal, Veera M.

AU - Als, Thomas D.

AU - Nguyen, Hoang T.

AU - Girdhar, Kiran

AU - Boocock, James

AU - Roussos, Panos

AU - Fromer, Menachem

AU - Kramer, Robin

AU - Domenici, Enrico

AU - Gamazon, Eric R.

AU - Purcell, Shaun M.

AU - Demontis, Ditte

AU - Borglum, Anders D.

AU - Walters, James T. R.

AU - O'Donovan, Michael C.

AU - Sullivan, Patrick

AU - Owen, Michael J.

AU - Devlin, Bernie

AU - Sieberts, Solveig K.

AU - Cox, Nancy J.

AU - Im, Hae Kyung

AU - Sklar, Pamela

AU - Stahl, Eli A.

AU - Johnson, Jessica S.

AU - Shah, Hardik R.

AU - Klein, Lambertus L.

AU - Dang, Kristen K.

AU - Logsdon, Benjamin A.

AU - Mahajan, Milind C.

AU - Mangravite, Lara M.

AU - Toyoshiba, Hiroyoshi

AU - Gur, Raquel E.

AU - Hahn, Chang-Gyu

AU - Schadt, Eric

AU - Lewis, David A.

AU - Haroutunian, Vahram

AU - Peters, Mette A.

AU - Lipska, Barbara K.

AU - Buxbaum, Joseph D.

AU - Hirai, Keisuke

AU - Perumal, Thanneer M.

AU - Essioux, Laurent

AU - Rajagopal, Veera Manikandan

AU - Mattheisen, Manuel

AU - Grove, Jakob

AU - Werge, Thomas

AU - Mortensen, Preben Bo

AU - Pedersen, Carsten Bocker

AU - Agerbo, Esben

AU - Pedersen, Marianne Giortz

AU - Mors, Ole

AU - Nordentoft, Merete

AU - Hougaard, David M.

AU - Bybjerg-Grauholm, Jonas

AU - Baekvad-Hansen, Marie

AU - Hansen, Christine Soholm

AU - Ripke, Stephan

AU - Neale, Benjamin M.

AU - Corvin, Aiden

AU - Farh, Kai-How

AU - Holmans, Peter A.

AU - Lee, Phil

AU - Bulik-Sullivan, Brendan

AU - Collier, David A.

AU - Huang, Hailiang

AU - Pers, Tune H.

AU - Agartz, Ingrid

AU - Albus, Margot

AU - Alexander, Madeline

AU - Amin, Farooq

AU - Bacanu, Silviu A.

AU - Begemann, Martin

AU - Belliveau, Richard A.

AU - Bene, Judit

AU - Bergen, Sarah E.

AU - Bevilacqua, Elizabeth

AU - Bigdeli, Tim B.

AU - Black, Donald W.

AU - Bruggeman, Richard

AU - Buccola, Nancy G.

AU - Buckner, Randy L.

AU - Byerley, William

AU - Cahn, Wiepke

AU - Cai, Guiqing

AU - Campion, Dominique

AU - Cantor, Rita M.

AU - Carr, Vaughan J.

AU - Carrera, Noa

AU - Catts, Stanley

AU - Chambert, Kimberly D.

AU - Chan, Raymond C. K.

AU - Chen, Ronald Y. L.

AU - Chen, Eric Y. H.

AU - Cheng, Wei

AU - Cheung, Eric F. C.

AU - Chong, Siow Ann

AU - Cloninger, C. Robert

AU - Cohen, David

AU - Cohen, Nadine

AU - Cormican, Paul

AU - Craddock, Nick

AU - Crowley, James J.

AU - Curtis, David

AU - Davidson, Michael

AU - Davis, Kenneth L.

AU - Degenhardt, Franziska

AU - Del Favero, Jurgen

AU - Dikeos, Dimitris

AU - Dinan, Timothy

AU - Djurovic, Srdjan

AU - Donohoe, Gary

AU - Drapeau, Elodie

AU - Duan, Jubao

AU - Dudbridge, Frank

AU - Durmishi, Naser

AU - Eichhammer, Peter

AU - Eriksson, Johan

AU - Escott-Price, Valentina

AU - Essioux, Laurent

AU - Fanous, Ayman H.

AU - Farrell, Martilias S.

AU - Frank, Josef

AU - Franke, Lude

AU - Freedman, Robert

AU - Freimer, Nelson B.

AU - Friedl, Marion

AU - Friedman, Joseph

AU - Fromer, Menachem

AU - Genovese, Giulio

AU - Georgieva, Lyudmila

AU - Giegling, Ina

AU - Giusti-Rodriguez, Paola

AU - Godard, Stephanie

AU - Goldstein, Jacqueline

AU - Golimbet, Vera

AU - Gopal, Srihari

AU - Gratten, Jacob

AU - de Haan, Lieuwe

AU - Hammer, Christian

AU - Hamshere, Marian L.

AU - Hansen, Mark

AU - Hansen, Thomas

AU - Haroutunian, Vahram

AU - Hartmann, Annette M.

AU - Henskens, Frans A.

AU - Herms, Stefan

AU - Hirschhorn, Joel N.

AU - Hoffmann, Per

AU - Hofman, Andrea

AU - Hollegaard, Mads

AU - Ikeda, Masashi

AU - Joa, Inge

AU - Julia, Antonio

AU - Kahn, Rene S.

AU - Kalaydjieva, Luba

AU - Karachanak-Yankova, Sena

AU - Karjalainen, Juha

AU - Kavanagh, David

AU - Keller, Matthew C.

AU - Kennedy, James L.

AU - Khrunin, Andrey

AU - Kim, Yunjung

AU - Klovins, Janis

AU - Knowles, James A.

AU - Konte, Bettina

AU - Kucinskas, Vaidutis

AU - Kucinskiene, Zita Ausrele

AU - Kuzelova-Ptackova, Hana

AU - Kahler, Anna K.

AU - Laurent, Claudine

AU - Keong, Jimmy Lee Chee

AU - Lee, S. Hong

AU - Legge, Sophie E.

AU - Lerer, Bernard

AU - Li, Miaoxin

AU - Li, Tao

AU - Liang, Kung-Yee

AU - Lieberman, Jeffrey

AU - Limborska, Svetlana

AU - Loughland, Carmel M.

AU - Lubinski, Jan

AU - Lonnqvist, Jouko

AU - Macek, Milan

AU - Magnusson, Patrik K. E.

AU - Maher, Brion S.

AU - Maier, Wolfgang

AU - Mallet, Jacques

AU - Marsal, Sara

AU - Mattingsdal, Morten

AU - McCarley, Robert W.

AU - McDonald, Colm

AU - McIntosh, Andrew M.

AU - Meier, Sandra

AU - Meijer, Carin J.

AU - Melegh, Bela

AU - Melle, Ingrid

AU - Mesholam-Gately, Raquelle

AU - Metspalu, Andres

AU - Michie, Patricia T.

AU - Milani, Lili

AU - Milanova, Vihra

AU - Mokrab, Younes

AU - Morris, Derek W.

AU - Mors, Ole

AU - Murphy, Kieran C.

AU - Murray, Robin M.

AU - Myin-Germeys, Inez

AU - Muller-Myhsok, Bertram

AU - Nelis, Mari

AU - Nenadic, Igor

AU - Nertney, Deborah A.

AU - Nestadt, Gerald

AU - Nicodemus, Kristin K.

AU - Nikitina-Zake, Liene

AU - Nisenbaum, Laura

AU - Nordin, Annelie

AU - O'Callaghan, Eadbhard

AU - O'Dushlaine, Colm

AU - O'Neill, F. Anthony

AU - Oh, Sang-Yun

AU - Olincy, Ann

AU - Olsen, Line

AU - Van Os, Jim

AU - Pantelis, Christos

AU - Papadimitriou, George N.

AU - Papiol, Sergi

AU - Parkhomenko, Elena

AU - Pato, Michele T.

AU - Paunio, Tiina

AU - Pejovic-Milovancevic, Milica

AU - Perkins, Diana O.

AU - Pietilainen, Olli

AU - Pimm, Jonathan

AU - Pocklington, Andrew J.

AU - Powell, John

AU - Schwab, Sibylle G.

AU - Scott, Rodney J.

AU - Spencer, Chris C. A.

AU - Wang, Qiang

AU - Wildenauer, Dieter B.

AU - Williams, Nigel M.

AU - Wong, Emily H. M.

AU - Jablensky, Assen

AU - Mowry, Bryan J.

PY - 2019/4

Y1 - 2019/4

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.

KW - ACUTE INTERMITTENT PORPHYRIA

KW - COGNITIVE DEFICITS

KW - ASSOCIATION

KW - MOUSE

KW - TRANSCRIPTOME

KW - CHILDHOOD

KW - TRAITS

KW - PSYCHOSIS

KW - DISORDER

KW - VARIANTS

U2 - 10.1038/s41588-019-0364-4

DO - 10.1038/s41588-019-0364-4

M3 - Article

VL - 51

SP - 659-+

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 4

ER -

CommonMind Consortium, Psychiat Genomics Consortium, iPSYCH-GEMS Schizophrenia Working. Gene expression imputation across multiple brain regions provides insights into schizophrenia risk. Nature Genetics. 2019 Apr;51(4):659-+. https://doi.org/10.1038/s41588-019-0364-4