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

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Huckins, LM
Dobbyn, A
Ruderfer, DM
Hoffman, G
Wang, W
PardiƱas, AF
Rajagopal, VM
Als, TD
T. Nguyen, H
Girdhar, K
Boocock, J
Roussos, P
Fromer, M
Kramer, R
Domenici, E
Gamazon, ER
Purcell, S
Johnson, JS
Shah, HR
Klein, LL
Dang, KK
Logsdon, BA
Mahajan, MC
Mangravite, LM
Toyoshiba, H
Gur, RE
Hahn, CG
Schadt, E
Lewis, DA
Haroutunian, V
Peters, MA
Lipska, BK
Buxbaum, JD
Hirai, K
Perumal, TM
Essioux, L
Ripke, S
Neale, BM
Corvin, A
Walters, JTR
Farh, KH
Holmans, PA
Lee, P
Bulik-Sullivan, B
Collier, DA
Huang, H
Pers, TH
Agartz, I
Agerbo, E
Albus, M
Alexander, M
Amin, F
Bacanu, SA
Begemann, M
Belliveau, RA
Bene, J
Bergen, SE
Bevilacqua, E
Bigdeli, TB
Black, DW
Bruggeman, R
Buccola, NG
Buckner, RL
Byerley, W
Cahn, W
Cai, G
Campion, D
Cantor, RM
Carr, VJ
Carrera, N
Catts, SV
Chambert, KD
Chan, RCK
Chen, RYL
Chen, EYH
Cheng, W
Cheung, EFC
Chong, SA
Cloninger, CR
Cohen, D
Cohen, N
Cormican, P
Craddock, N
Crowley, JJ
Curtis, D
Davidson, M
Davis, KL
Degenhardt, F
Del Favero, J
Demontis, D
Dikeos, D
Dinan, T
Djurovic, S
Donohoe, G
Drapeau, E
Duan, J
Dudbridge, F
Durmishi, N
Eichhammer, P
Eriksson, J
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2019
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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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Nature Genetics

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51

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4

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Biological sciences

Biomedical and clinical sciences

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