Duplications in RB1CC1 are associated with schizophrenia; identification in large European sample sets

Abstract

Schizophrenia (SCZ) is a severe and debilitating neuropsychiatric disorder with an estimated heritability of ~80%. Recently, de novo mutations, identified by next-generation sequencing (NGS) technology, have been suggested to contribute to the risk of developing SCZ. Although these studies show an overall excess of de novo mutations among patients compared with controls, it is not easy to pinpoint specific genes hit by de novo mutations as actually involved in the disease process. Importantly, support for a specific gene can be provided by the identification of additional alterations in several independent patients. We took advantage of existing genome-wide single-nucleotide polymorphism data sets to screen for deletions or duplications (copy number variations, CNVs) in genes previously implicated by NGS studies. Our approach was based on the observation that CNVs constitute part of the mutational spectrum in many human disease-associated genes. In a discovery step, we investigated whether CNVs in 55 candidate genes, suggested from NGS studies, were more frequent among 1637 patients compared with 1627 controls. Duplications in RB1CC1 were overrepresented among patients. This finding was followed-up in large, independent European sample sets. In the combined analysis, totaling 8461 patients and 112 871 controls, duplications in RB1CC1 were found to be associated with SCZ (P=1.29 × 10−5; odds ratio=8.58). Our study provides evidence for rare duplications in RB1CC1 as a risk factor for SCZ.

Integrated Bayesian analysis of rare exonic variants to identify risk genes for schizophrenia and neurodevelopmental disorders

“…First, SETD1A Takata et al, 2016) is the most significant gene across analyses (FDR ∼ 1.5×10 −3 ), TAF13 is also significant across analyses. Of two genes with FDR < 0.1, RB1CC1 was reported in a study of copy-number variation in SCZ (Degenhardt et al, 2013). Second, we found substantial overlap of top genes in this study and gene sets known from previous reports on these same SCZ data Genovese et al (2016).…”

“…SETD1A has been confirmed as the highest statistically significant gene of SCZ in previous studies Takata et al, 2016), while TAF13 was only reported as a potential risk gene in the study of . Interestingly for the RB1CC1 gene, rare duplications were reported to be associated with SCZ with very high odds ratio (8.58) in the study of Degenhardt et al (2013), but has not been reported in other studies since. In addition, as discussed by the authors, duplications at this gene were also observed by Cooper et al (2011) with an odds ratio = 5.29 in a study of 15,767 children with ID and/or DD.…”

“…We found that SETD1A [8,25] is the most significant gene across analyses (FDR ∼ 1.5 × 10 −3 ), and that TAF13 [6] is FDR significant. Of two genes with 0.05 < FDR < 0.1, rare duplications covering RB1CC1 have been reported in SCZ [75] and in ID and/or DD [76]. Two novel conserved non-coding motif gene sets showing brain specific expression [72] were enriched (Table S18), including targets of the transcription factor MAZ and of microRNAs MIR10A/B.…”

Integrated Bayesian analysis of rare exonic variants to identify risk genes for schizophrenia and neurodevelopmental disorders

“…We found that SETD1A [ 8 , 25 ] is the most significant gene across analyses (FDR ∼1.5×10 −3 ), and that TAF13 [ 6 ] is FDR significant. Of two genes with 0.05< FDR <0.1, rare duplications covering RB1CC1 have been reported in SCZ [ 78 ] and in ID and/or DD [ 79 ]. Two novel conserved non-coding motif gene sets showing brain-specific expression [ 73 ] were enriched (Additional file 1 : Table S20), including targets of the transcription factor MAZ and of microRNAs MIR10A/B.…”

RB1CC1 duplication and aberrant overexpression in a patient with schizophrenia: further phenotype delineation and proposal of a pathogenetic mechanism

“…The effect of such duplications on RB1CC1 gene expression has never been evaluated in CNV carriers and, since partial gene duplications of RB1CC1 have also been documented in schizophrenic subjects, it is unproved whether the pathomechanism is mediated by haploinsufficiency due to gene disruption rather than genuine overexpression of the gene. Notably, Degenhardt et al (2013) reported full RB1CC1 duplication in three SCZ patients, partial gene duplication in five patients, and a duplication immediately upstream of the RB1CC1 gene in an additional patient. Importantly, all partial gene duplications were detected by chromosomal microarray only without breakpoint‐level analysis, which is essential to interpret their effects on gene structure in terms of orientation, location, and possible alteration of the reading frame causing loss‐of‐function.…”