Large recurrent microdeletions associated with schizophrenia

Abstract

Reduced fecundity, associated with severe mental disorders1, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism2 schizophrenia3 and mental retardation4. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation4,5 and autism2. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia.

Association between the 2-bp deletion polymorphism in the duplicated version of the alpha7 nicotinic receptor gene and P50 sensory gating

“…The rare 15q13.3 microdeletion is strongly associated with many neuropsychiatric conditions, including schizophrenia. [25][26][27] This deletion is recurrent and probably arises from non-allelic homologous recombination when two direct repeats misalign during meiosis. Two large direct repeats likely to be responsible include CHRNA7 and CHRFAM7A 71 (see Supplementary Figure 1a).…”

“…These deletions are very rare in the general population (B0.02%), but more common in schizophrenia, autism/developmental disorders and some forms of intellectual impairment (B0.2-0.3%) and even more common in idiopathic generalized epilepsy (B1.0%). [25][26][27][28] These B2-Mb microdeletions lead to the loss of CHRNA7 and five other genes (Supplementary Figure 1a), but smaller variants that show a similar range of phenotypes remove only CHRNA7 and one other gene. 29 These observations strongly implicate the CHRNA7 region in schizophrenia and other neuropsychiatric disorders.…”

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…Cyfip1 and Cyfip2 are members of a highly conserved gene family 52 , and dysregulation of Cyfip1 expression levels leads to pathological changes in neuronal maturation and connectivity, both of which may contribute to the development of the neurological symptoms observed in ASD and schizophrenia 63 . A CNV in the 15q11.2 region of the human genome has been implicated in several neurological and neuropsychiatric conditions [64][65][66][67][68][69][70] and a CYFIP1 CNV within 15q11.2 has been linked to ASD 71 , with an upregulation of CYFIP1 mRNA being demonstrated in genomewide expression profiling of ASD patients with 15q11-q13 duplication 72 . A rare CYFIP1 deletion has also been reported in a patient with a mild intellectual disability and a pervasive developmental disorder not otherwise specified 71 .…”

The translationally relevant mouse model of the 15q13.3 microdeletion syndrome reveals deficits in neuronal spike firing matching clinical neurophysiological biomarkers seen in schizophrenia

“…Certain copy number variants (CNVs) in the human population have recently been shown to be associated with a high risk for developing schizophrenia (Stefansson et al . 2008, Levinson et al . 2011) and provide the basis for genetic schizophrenia models with high construct validity.…”