A transcriptome-wide association study implicates specific pre-and post-synaptic abnormalities in schizophrenia

Lynsey S. Hall; Christopher W. Medway; Oliver Pain; Antonio F. Pardiñas; Elliott G. Rees; Valentina Escott-Price; Andrew Pocklington; Nicholas J. Bray; Peter A. Holmans; James T.R. Walters; Michael J. Owen; Michael C. O'Donovan

doi:10.1093/hmg/ddz253

A transcriptome-wide association study implicates specific pre-and post-synaptic abnormalities in schizophrenia

Lynsey S. Hall, Christopher W. Medway, Oliver Pain, Antonio F. Pardiñas, Elliott G. Rees, Valentina Escott-Price, Andrew Pocklington, Nicholas J. Bray, Peter A. Holmans, James T.R. Walters, Michael J. Owen^*, Michael C. O'Donovan

^*Corresponding author for this work

Cardiff Law School
Department of Psychology, Division of Psychology and Language Sciences, University College London, London, England2MRC Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, King???s College London, London, England
King's College London

Research output: Contribution to journal › Article › peer-review

47 Citations (Scopus)

Abstract

Schizophrenia is a complex highly heritable disorder. Genome-wide association studies (GWAS) have identified multiple loci that influence the risk of developing schizophrenia, although the causal variants driving these associations and their impacts on specific genes are largely unknown. We identify a significant correlation between schizophrenia risk and expression at 89 genes in the dorsolateral prefrontal cortex (P ≤ 9.43 × 10^-6), including 20 novel genes. Genes whose expression correlate with schizophrenia were enriched for those involved in abnormal CNS synaptic transmission (P_FDR = 0.02) and antigen processing and presentation of peptide antigen via MHC class I (P_FDR = 0.02). Within the CNS synaptic transmission set, we identify individual significant candidate genes to which we assign direction of expression changes in schizophrenia. The findings provide strong candidates for experimentally probing the molecular basis of synaptic pathology in schizophrenia.

Original language	English
Article number	ddz253
Pages (from-to)	159-167
Number of pages	9
Journal	Human Molecular Genetics
Volume	29
Issue number	1
DOIs	https://doi.org/10.1093/hmg/ddz253
Publication status	Published - 1 Jan 2020

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Hall, L. S., Medway, C. W., Pain, O., Pardiñas, A. F., Rees, E. G., Escott-Price, V., Pocklington, A., Bray, N. J., Holmans, P. A., Walters, J. T. R., Owen, M. J., & O'Donovan, M. C. (2020). A transcriptome-wide association study implicates specific pre-and post-synaptic abnormalities in schizophrenia. Human Molecular Genetics, 29(1), 159-167. Article ddz253. https://doi.org/10.1093/hmg/ddz253

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abstract = "Schizophrenia is a complex highly heritable disorder. Genome-wide association studies (GWAS) have identified multiple loci that influence the risk of developing schizophrenia, although the causal variants driving these associations and their impacts on specific genes are largely unknown. We identify a significant correlation between schizophrenia risk and expression at 89 genes in the dorsolateral prefrontal cortex (P ≤ 9.43 × 10-6), including 20 novel genes. Genes whose expression correlate with schizophrenia were enriched for those involved in abnormal CNS synaptic transmission (PFDR = 0.02) and antigen processing and presentation of peptide antigen via MHC class I (PFDR = 0.02). Within the CNS synaptic transmission set, we identify individual significant candidate genes to which we assign direction of expression changes in schizophrenia. The findings provide strong candidates for experimentally probing the molecular basis of synaptic pathology in schizophrenia.",

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AU - Rees, Elliott G.

AU - Escott-Price, Valentina

AU - Pocklington, Andrew

AU - Bray, Nicholas J.

AU - Holmans, Peter A.

AU - Walters, James T.R.

AU - Owen, Michael J.

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N2 - Schizophrenia is a complex highly heritable disorder. Genome-wide association studies (GWAS) have identified multiple loci that influence the risk of developing schizophrenia, although the causal variants driving these associations and their impacts on specific genes are largely unknown. We identify a significant correlation between schizophrenia risk and expression at 89 genes in the dorsolateral prefrontal cortex (P ≤ 9.43 × 10-6), including 20 novel genes. Genes whose expression correlate with schizophrenia were enriched for those involved in abnormal CNS synaptic transmission (PFDR = 0.02) and antigen processing and presentation of peptide antigen via MHC class I (PFDR = 0.02). Within the CNS synaptic transmission set, we identify individual significant candidate genes to which we assign direction of expression changes in schizophrenia. The findings provide strong candidates for experimentally probing the molecular basis of synaptic pathology in schizophrenia.

AB - Schizophrenia is a complex highly heritable disorder. Genome-wide association studies (GWAS) have identified multiple loci that influence the risk of developing schizophrenia, although the causal variants driving these associations and their impacts on specific genes are largely unknown. We identify a significant correlation between schizophrenia risk and expression at 89 genes in the dorsolateral prefrontal cortex (P ≤ 9.43 × 10-6), including 20 novel genes. Genes whose expression correlate with schizophrenia were enriched for those involved in abnormal CNS synaptic transmission (PFDR = 0.02) and antigen processing and presentation of peptide antigen via MHC class I (PFDR = 0.02). Within the CNS synaptic transmission set, we identify individual significant candidate genes to which we assign direction of expression changes in schizophrenia. The findings provide strong candidates for experimentally probing the molecular basis of synaptic pathology in schizophrenia.

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A transcriptome-wide association study implicates specific pre-and post-synaptic abnormalities in schizophrenia

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