2 as the first schizophrenia-associated CNV [21 and 22], analyses of rare CNVs involving >20,000 cases have revealed associations at more than 15 loci [20, 23 and 24] (Figure 2). The majority of these CNVs substantially increase the risk of developing schizophrenia, with odds ratios (OR) between two and 60 [24]. As their frequency among patients is often less than one in 500,
their individual contribution to the total population variation in schizophrenia genetic liability is small [25], although collectively they are found in around 2.5% of patients [24]. Most schizophrenia-associated CNVs are large and recurrent, meaning multiple mutation events have occurred at the exact same, or near identical, genomic location. The breakpoints this website of recurrent CNVs are usually flanked by repetitive genomic elements such as low copy repeats (LCRs), which mediate mutation through non-allelic CHIR-99021 homologous recombination [26]. 10 recurrent CNVs have been associated with schizophrenia at a level of statistical support that survives correction for the multiple testing of 120 potential recurrent CNV loci in the human genome (Figure 2). Drawing biological insights from recurrent CNVs remains a challenge, largely because multiple genes and regulatory elements are often disrupted. However, single-gene disrupting non-recurrent CNVs have also been associated with schizophrenia at NRXN1, VIPR2 and PAK7. These mutations have the potential
to offer clearer insights into disease pathogenesis, although only the NRXN1 G protein-coupled receptor kinase association survives correction for the multiple testing of all human genes (∼20,000). NRXN1 encodes a synaptic cell adhesion molecule neurexin 1 that links presynaptic and postsynaptic neurons [ 27]. Gene-set analyses have
shown rare CNVs in schizophrenia to be enriched among biological pathways previously implicated in schizophrenia, such as the NMDAR and metabotropic glutamate receptor 5 (mGluR5) components of the post synaptic density (PSD), calcium channel signalling (see single nucleotide polymorphisms below) and FMRP targets [20]. Additional gene-sets recently implicated in rare CNV studies include signalling components within the immune system, chromatin remodelling complexes and targets of microRNA miR-10a [20]. Schizophrenia-associated CNVs have been shown to increase risk for additional neuropsychiatric disorders [28• and 29]. For example, schizophrenia-associated duplications of the Williams-Beuren and Prader-Willi/Angelman syndrome regions are also implicated in ASD [9 and 30], deletions of 15q11.2 and 15q13.3 in epilepsy [31 and 32] and duplications of 16p13.11 in attention-deficit hyperactivity disorder (ADHD) [33]. Up to 72 pathogenic CNVs, which include the majority of those presented in Figure 2, are enriched in large cohorts of patients with early onset neurodevelopmental phenotypes, such as ID, ASD and congenital malformations (CM) [34 and 35].
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