De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia

By G. Kirov, A. Pocklington, P. Holmans, D. Ivanov, M. Ikeda, D. Ruderfer, J. Moran, K. Chambert, D. Toncheva, L. Georgieva and 20 more. Molecular Psychiatry, 2011

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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 × 10−6). This was largely explained by enrichment for members of the N-methyl-D-aspartate receptor (NMDAR) (P=4.24 × 10−6) and neuronal activity-regulated cytoskeleton-associated protein (ARC) (P=3.78 × 10−8) 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.

Subfields: Developmental Neuroscience, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/43cb35f347b9594804c95313ef1c6809807895c4

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Citations in the corpus

Mapping genomic loci implicates genes and synaptic biology in schizophrenia (2022, background): “This is further supported by studies showing substantial effects on schizophrenia risk of CNVs 39 and rare damaging coding variants in genes with similar functions, including some of the same genes (SCHEMA; companion paper).”
Biological Psychology : Stress (2016, neutral): “Analyses of de novo copy number variations also implicate NMDA receptors, with enrichment of nonsynonymous polymorphisms and loss of function mutations in the GRIN2A gene in individuals with schizophrenia (Fromer et al., 2014; Kirov et al., 2012).”
Discovery and statistical genotyping of copy-number variation from whole-exome sequencing depth. (2012, methodology): “In fact, copynumber changes are the variants that have the largest known effect on the risk of schizophrenia possibly as a result of the constant introduction of de novo germline mutations.(7) However, knowledge regarding the scope of CNV effects on disease is still incomplete.”
Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders (2014, background): “01).(31) The average size of de novo CNVs was also larger than the size of all rare CNVs in our affected (188 kb) and control (159 kb) subjects.”
Genomic dissection of bipolar disorder and schizophrenia including 28 subphenotypes (2018, background): “…of rare, moderate to highly penetrant copy-number variants (CNVs) and de novo CNVs are seen in SCZ patients (Gulsuner and McClellan, 2015; Kirov et al., 2012; Marshall et al., 2017; Stone et al., 2008; Szatkiewicz et al., 2014), while the involvement of CNVs in BD is less clear (Green et…”