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

Abstract

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.

A genetic model for neurodevelopmental disease

“…CNV and early genome sequencing experiments both implicate hundreds to thousands of different genes underlying various neurological phenotypes [22,39]. Analyses of candidate genes, however, are beginning to converge on a subset of protein-protein interaction networks or biological processes, many of which are strongly tied to neurodevelopment [18,52,[62][63][64]. Genes involved in synaptic function have been repeatedly shown to play a role in neurological disorders [62,63,65,66].…”

“…Analyses of candidate genes, however, are beginning to converge on a subset of protein-protein interaction networks or biological processes, many of which are strongly tied to neurodevelopment [18,52,[62][63][64]. Genes involved in synaptic function have been repeatedly shown to play a role in neurological disorders [62,63,65,66]. Recent studies of ASD have identified overrepresentation of CNS development genes in addition to several other pathways [21,65,67].…”

The one and the many: effects of the cell adhesion molecule pathway on neuropsychological function in psychosis

“…cognition; McIntosh et al 2013). This analysis approach indicates that the composite effect of many small genetic variants contribute substantially to SZ variance (about 25%; International Schizophrenia Consortium et al 2009;Kirov et al 2012). Polygenic analysis has also provided further evidence of genetic overlap between related phenotypes; for example, McIntosh et al (2013) recently reported that polygenic SZ risk scores could be used to explain variance in longitudinal measures of age-related changes in cognitive function.…”

“…neurexin; Dean et al 2003). Disruption of several CAM genes has been reported in patients with psychosis, including de novo copy number variants in neurexin-1 (NRXN1) (Rujescu et al 2009;Kirov et al 2012), neuroligin-2 (Sun et al 2011) and several others [including members of the DLG (Discs large) gene family; Kirov et al 2012], each of which has been associated with increased illness risk.…”

Genetic studies of schizophrenia: an update

“…As a result, CNVs can change the dosage of one or more genes in the regions covered affects the NRXN1 gene [35][36][37][38][39][40][41][42] , and 7p36.3 dup only affects the VIPR2 gene [38,43,44] . CNVs that alter the expression of multiple genes include 1q21.1 del/dup (34 genes) [36][37][38][39]41,[45][46][47] , 3q29del/dup (21 genes) [38][39][40]44,48,49] , 15q13.3del (12 genes) [38,39,44,46,47,49] , 16p13.1dup (11 genes) [40,41,50,51] , and 22q11.2del/dup (53 genes) [38,39,44,46,47,[51][52][53][54][55][56] , etc. (see Table 2 for more details).…”