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

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.

SUBMITTER: Hall LS

PROVIDER: S-EPMC7416679 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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

Hall Lynsey S LS Medway Christopher W CW Pain Oliver O Pardiñas Antonio F AF Rees Elliott G EG Escott-Price Valentina V Pocklington Andrew A Bray Nicholas J NJ Holmans Peter A PA Walters James T R JTR Owen Michael J MJ O'Donovan Michael C MC

Human molecular genetics 20200101 1

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 wit ...[more]

PMID: 31691811

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Project description:A small number of rare, recurrent genomic copy number variants (CNVs) are known to substantially increase susceptibility to schizophrenia. As a consequence of the low fecundity in people with schizophrenia and other neurodevelopmental phenotypes to which these CNVs contribute, CNVs with large effects on risk are likely to be rapidly removed from the population by natural selection. Accordingly, such CNVs must frequently occur as recurrent de novo mutations. In a sample of 662 schizophrenia proband-parent trios, we found that rare de novo CNV mutations were significantly more frequent in cases (5.1% all cases, 5.5% family history negative) compared with 2.2% among 2623 controls, confirming the involvement of de novo CNVs in the pathogenesis of schizophrenia. Eight de novo CNVs occurred at four known schizophrenia loci (3q29, 15q11.2, 15q13.3 and 16p11.2). De novo CNVs of known pathogenic significance in other genomic disorders were also observed, including deletion at the TAR (thrombocytopenia absent radius) region on 1q21.1 and duplication at the WBS (Williams-Beuren syndrome) region at 7q11.23. Multiple de novos spanned genes encoding members of the DLG (discs large) family of membrane-associated guanylate kinases (MAGUKs) that are components of the postsynaptic density (PSD). Two de novos also affected EHMT1, a histone methyl transferase known to directly regulate DLG family members. Using a systems biology approach and merging novel CNV and proteomics data sets, systematic analysis of synaptic protein complexes showed that, compared with control CNVs, case de novos were significantly enriched for the PSD proteome (P=1.72 × 10??. This was largely explained by enrichment for members of the N-methyl-D-aspartate receptor (NMDAR) (P=4.24 × 10??) and neuronal activity-regulated cytoskeleton-associated protein (ARC) (P=3.78 × 10??) postsynaptic signalling complexes. In an analysis of 18?492 subjects (7907 cases and 10?585 controls), case CNVs were enriched for members of the NMDAR complex (P=0.0015) but not ARC (P=0.14). Our data indicate that defects in NMDAR postsynaptic signalling and, possibly, ARC complexes, which are known to be important in synaptic plasticity and cognition, play a significant role in the pathogenesis of schizophrenia.

Dataset Information

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

Publications

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

Similar Datasets

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