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 language | English |
|---|---|
| Pages (from-to) | 659-+ |
| Number of pages | 18 |
| Journal | Nature Genetics |
| Volume | 51 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Apr 2019 |
Cite this
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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 journal › Article
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 -