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

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.

Original languageEnglish
Pages (from-to)659–674
Number of pages15
JournalNature Genetics
Volume51
DOIs
Publication statusPublished - 25 Mar 2019

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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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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 - Huckins, Laura M.

AU - Dobbyn, Amanda

AU - Ruderfer, Douglas M.

AU - Hoffman, Gabriel

AU - Wang, Weiqing

AU - Pardiñas, Antonio F.

AU - Rajagopal, Veera M.

AU - Als, Thomas D.

AU - T. Nguyen, Hoang

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 - 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 - Ripke, Stephan

AU - Neale, Benjamin M.

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AU - Walters, James T.R.

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AU - Bulik-Sullivan, Brendan

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AU - Wray, Naomi R.

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AU - Blackwood, Douglas H.R.

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AU - Børglum, Anders D.

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AU - Darvasi, Ariel

AU - Domenici, Enrico

AU - Ehrenreich, Hannelore

AU - Esko, Tonu

AU - Gejman, Pablo V.

AU - Gill, Michael

AU - Gurling, Hugh

AU - Hultman, Christina M.

AU - Iwata, Nakao

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AU - Jonsson, Erik G.

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AU - Malhotra, Anil K.

AU - McCarroll, Steven A.

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AU - Moran, Jennifer L.

AU - Mortensen, Preben Bo

AU - Mowry, Bryan J.

AU - Nothen, Markus M.

AU - Ophoff, Roel A.

AU - Owen, Michael J.

AU - Palotie, Aarno

AU - Pato, Carlos N.

AU - Petryshen, Tracey L.

AU - Posthuma, Danielle

AU - Rietschel, Marcella

AU - Riley, Brien P.

AU - Rujescu, Dan

AU - Sham, Pak C.

AU - Sklar, Pamela

AU - Clair, David St

AU - Weinberger, Daniel R.

AU - Wendland, Jens R.

AU - Werge, Thomas

AU - Daly, Mark J.

AU - Sullivan, Patrick F.

AU - O’Donovan, Michael C.

AU - Børglum, Anders D.

AU - Demontis, Ditte

AU - Rajagopal, Veera Manikandan

AU - Als, Thomas D.

AU - Mattheisen, Manuel

AU - Grove, Jakob

AU - Werge, Thomas

AU - Mortensen, Preben Bo

AU - Pedersen, Carsten Bøcker

AU - Agerbo, Esben

AU - Pedersen, Marianne Giørtz

AU - Mors, Ole

AU - Nordentoft, Merete

AU - Hougaard, David M.

AU - Bybjerg-Grauholm, Jonas

AU - Bækvad-Hansen, Marie

AU - Hansen, Christine Søholm

AU - Demontis, Ditte

AU - Børglum, 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 - iPSYCH-GEMS Schizophrenia Working Group

AU - CommonMind Consortium

AU - The Schizophrenia Working Group of the PsyUniversity of Copenhagenchiatric Genomics Consortium

PY - 2019/3/25

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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.

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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

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