Copy Number Variable MicroRNAs in Schizophrenia and Their Neurodevelopmental Gene Targets

Abstract

BACKGROUND-MicroRNAs (miRNAs) are key regulators of gene expression in the human genome and may contribute to risk for neuropsychiatric disorders. miRNAs play an acknowledged role in the strongest of genetic risk factors for schizophrenia, 22q11.2 deletions. We hypothesized that in schizophrenia there would be an enrichment of other rare copy number variants (CNVs) that overlap miRNAs.

Animal models of gene–environment interaction in schizophrenia: A dimensional perspective

“…Some of these mutations are rare and have a moderate-to-large effect. Most are related to copy number variations (CNVs) as well as other types of structural genomic variation including deletions, duplications, and chromosomal rearrangements with potentially different pathogenic mechanisms and phenotypic outcomes (Levinson et al, 2011; Merikangas et al, 2014; Ruderfer et al, 2013; Timms et al, 2013; Warnica et al, 2014). The rate of CNVs in schizophrenia patients is increased, with deletions being observed more frequently than duplications (Buizer-Voskamp et al, 2011; Szatkiewicz et al, 2014).…”

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

“…In this way, while a single gene within a CNV may be informative with regard to mechanisms, it is most likely that these genes implicated by multigenic CNVs act interactively. Recently, there has also been increased focus on the possibility that microRNAs found within CNVs (which also regulate a gene expression program in trans) may be another important part of the polygenic mechanisms resulting from changes in gene copy number [110]. Another interesting feature of CNV disorders is that in some cases, deletions and duplications at the same locus can cause overlapping, reciprocal or quite distinct phenotypes [102,104,[111][112].…”

“…Cxcr4 potentially regulates cortical interneuron migration and placement [149]. There are also a number of microRNA-related loci in this region, including miR-185 and DiGeorge syndrome chromosomal (or critical) region 8, a component of the microprocessor complex that is involved in the initial step of miRNA biogenesis [110]. 22q13 22q13 deletion syndrome, also known as Phelan-McDermid syndrome, is characterized by global developmental delay, absent or severely delayed speech, ASD, neonatal hypotonia, normal or accelerated growth, and dysmorphic features [150,151].…”

Using hiPSCs to model neuropsychiatric copy number variations (CNVs) has potential to reveal underlying disease mechanisms

“…The 22q11.2 deletion was the first CNV to be convincingly implicated in schizophrenia (reviewed Karayiorgou et al, 2010; Schneider et al, 2014). Deletion at this locus is the strongest risk factor for developing schizophrenia with 25% of carriers presenting with psychosis (Warnica et al, 2014). In addition to schizophrenia, it is known that disruption of the 22q11.2 locus is the cause of most cases of DiGeorge and Velocardiofacial syndromes and it contributes to increased risk of psychiatric problems in childhood including autism, anxiety and depression (Elliott Rees et al, 2014).…”

“…The DGCR8 gene disrupted by this deletion is a component of the microRNA processor complex and involved in microRNA biogenesis (Han, 2004; Wang et al, 2007). Another disrupted gene is miR-185, whose target genes have been previously associated with schizophrenia (Warnica et al, 2014). The function of these affected genes has contributed to the hypothesis that the heterogeneous symptoms underlying schizophrenia could be due to many genes becoming dysregulated because of microRNA dysfunction (reviewed Forstner et al, 2013; Geaghan and Cairns, 2014).…”