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Nat Genet. 2019 Apr;51(4):659-674. doi: 10.1038/s41588-019-0364-4. Epub 2019 Mar 25.

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

Collaborators (336)

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 Jr, 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, Escott-Price V, Essioux L, Fanous AH, Farrell MS, Frank J, Franke L, Freedman R, Freimer NB, Friedl M, Friedman JI, Fromer M, Genovese G, Georgieva L, Giegling I, Giusti-Rodríguez P, Godard S, Goldstein JI, Golimbet V, Gopal S, Gratten J, de Haan L, Hammer C, Hamshere ML, Hansen M, Hansen T, Haroutunian V, Hartmann AM, Henskens FA, Herms S, Hirschhorn JN, Hoffmann P, Hofman A, Hollegaard MV, Hougaard DM, Ikeda M, Joa I, Julia A, Kahn RS, Kalaydjieva L, Karachanak-Yankova S, Karjalainen J, Kavanagh D, Keller MC, Kennedy JL, Khrunin A, Kim Y, Klovins J, Knowles JA, Konte B, Kucinskas V, Kucinskiene ZA, Kuzelova-Ptackova H, Kahler AK, Laurent C, Keong JLC, Lee SH, Legge SE, Lerer B, Li M, Li T, Liang KY, Lieberman J, Limborska S, Loughland CM, Lubinski J, Lonnqvist J, Macek M Jr, Magnusson PKE, Maher BS, Maier W, Mallet J, Marsal S, Mattheisen M, Mattingsdal M, McCarley RW, McDonald C, McIntosh AM, Meier S, Meijer CJ, Melegh B, Melle I, Mesholam-Gately RI, Metspalu A, Michie PT, Milani L, Milanova V, Mokrab Y, Morris DW, Mors O, Murphy KC, Murray RM, Myin-Germeys I, Muller-Myhsok B, Nelis M, Nenadic I, Nertney DA, Nestadt G, Nicodemus KK, Nikitina-Zake L, Nisenbaum L, Nordin A, O'Callaghan E, O'Dushlaine C, O'Neill FA, Oh SY, Olincy A, Olsen L, Van Os J, Pantelis C, Papadimitriou GN, Papiol S, Parkhomenko E, Pato MT, Paunio T, Pejovic-Milovancevic M, Perkins DO, Pietiläinen O, Pimm J, Pocklington AJ, Powell J, Price A, Pulver AE, Purcell SM, Quested D, Rasmussen HB, Reichenberg A, Reimers MA, Richards AL, Roffman JL, Roussos P, Ruderfer DM, Salomaa V, Sanders AR, Schall U, Schubert CR, Schulze TG, Schwab SG, Scolnick EM, Scott RJ, Seidman LJ, Shi J, Sigurdsson E, Silagadze T, Silverman JM, Sim K, Slominsky P, Smoller JW, So HC, Spencer CCA, Stahl EA, Stefansson H, Steinberg S, Stogmann E, Straub RE, Strengman E, Strohmaier J, Stroup TS, Subramaniam M, Suvisaari J, Svrakic DM, Szatkiewicz JP, Soderman E, Thirumalai S, Toncheva D, Tosato S, Veijola J, Waddington J, Walsh D, Wang D, Wang Q, Webb BT, Weiser M, Wildenauer DB, Williams NM, Williams S, Witt SH, Wolen AR, Wong EHM, Wormley BK, Xi HS, Zai CC, Zheng X, Zimprich F, Wray NR, Stefansson K, Visscher PM, Adolfsson R, Andreassen OA, Blackwood DHR, Bramon E, Buxbaum JD, Børglum AD, Cichon S, Darvasi A, Domenici E, Ehrenreich H, Esko T, Gejman PV, Gill M, Gurling H, Hultman CM, Iwata N, Jablensky AV, Jonsson EG, Kendler KS, Kirov G, Knight J, Lencz T, Levinson DF, Li QS, Liu J, Malhotra AK, McCarroll SA, McQuillin A, Moran JL, Mortensen PB, Mowry BJ, Nothen MM, Ophoff RA, Owen MJ, Palotie A, Pato CN, Petryshen TL, Posthuma D, Rietschel M, Riley BP, Rujescu D, Sham PC, Sklar P, Clair DS, Weinberger DR, Wendland JR, Werge T, Daly MJ, Sullivan PF, O'Donovan MC, Børglum AD, Demontis D, Rajagopal VM, Als TD, Mattheisen M, Grove J, Werge T, Mortensen PB, Pedersen CB, Agerbo E, Pedersen MG, Mors O, Nordentoft M, Hougaard DM, Bybjerg-Grauholm J, Bækvad-Hansen M, Hansen CS.

Author information

1
Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA. laura.huckins@mssm.edu.
2
Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA. laura.huckins@mssm.edu.
3
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA. laura.huckins@mssm.edu.
4
Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. laura.huckins@mssm.edu.
5
Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
6
Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
7
Vanderbilt University Medical Center, Nashville, TN, USA.
8
Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
9
MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
10
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
11
The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.
12
Center for Integrative Sequencing, Aarhus University, Aarhus, Denmark.
13
Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
14
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
15
Human Brain Collection Core, National Institute of Mental Health, Bethesda, MD, USA.
16
Laboratory of Neurogenomic Biomarkers, Centre for Integrative Biology (CIBIO), University of Trento, Trento, Italy.
17
Clare Hall, University of Cambridge, Cambridge, UK.
18
University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
19
Karolinska Institutet, Stockholm, Sweden.
20
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
21
Systems Biology, Sage Bionetworks, Seattle, WA, USA.
22
Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA.

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.

PMID:
30911161
DOI:
10.1038/s41588-019-0364-4
[Indexed for MEDLINE]

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