Recurrent CNVs Disrupt Three Candidate Genes in Schizophrenia Patients

Abstract

Schizophrenia is a severe psychiatric disease with complex etiology, affecting approximately 1% of the general population. Most genetics studies so far have focused on disease association with common genetic variation, such as single-nucleotide polymorphisms (SNPs), but it has recently become apparent that large-scale genomic copy-number variants (CNVs) are involved in disease development as well. To assess the role of rare CNVs in schizophrenia, we screened 54 patients with deficit schizophrenia using Affymetrix's GeneChip 250K SNP arrays. We identified 90 CNVs in total, 77 of which have been reported previously in unaffected control cohorts. Among the genes disrupted by the remaining rare CNVs are MYT1L, CTNND2, NRXN1, and ASTN2, genes that play an important role in neuronal functioning but--except for NRXN1--have not been associated with schizophrenia before. We studied the occurrence of CNVs at these four loci in an additional cohort of 752 patients and 706 normal controls from The Netherlands. We identified eight additional CNVs, of which the four that affect coding sequences were found only in the patient cohort. Our study supports a role for rare CNVs in schizophrenia susceptibility and identifies at least three candidate genes for this complex disorder.

Rare copy number variation in cerebral palsy

“…38 CTNND2 has been associated with intellectual disability in cri-du-chat syndrome 36 (OMIM 604275), autism when deleted, 38,39 and schizophrenia when duplicated. 37 Previous studies have reported both dosage variation and disruptive effects resulting from CNVs involving CTNND2. 37,40 This gene has a predicted HI of 26.1%.…”

“…37 Previous studies have reported both dosage variation and disruptive effects resulting from CNVs involving CTNND2. 37,40 This gene has a predicted HI of 26.1%. (v) A 219-bp duplication in case P025 involving exon 1 of MCPH1.…”

“…CTNND2 is highly expressed in foetal brain and has an important role in neuronal functioning, adhesion, and migration. 36,37 It is involved in early embryogenesis and encodes an adhesive junction-associated protein of the armadillo/b-catenin superfamily. 38 CTNND2 has been associated with intellectual disability in cri-du-chat syndrome 36 (OMIM 604275), autism when deleted, 38,39 and schizophrenia when duplicated.…”

Early-onset obesity and paternal 2pter deletion encompassing the ACP1, TMEM18, and MYT1L genes

“…The MYT1L gene encodes for a C2HC-type zinc finger transcription factor highly expressed in developing neuronal cells. 17 When duplicated this gene has been associated with schizophrenia 18,19 and major depressive disorder. 20 Heterozygous loss of function of the MYT1L gene deleted in all our patients could be responsible for the behavioural difficulties and psychomotor retardation described in patients with 2pter deletion as proposed by Stevens et al 7 All patients (P1-5) have mild to severe ID.…”

Implications of gene copy-number variation in health and diseases

“…36 Another group of researchers identified 90 CNVs in 54 patients, of which 13 were rare CNVs disrupting genes associated with SZ such as MYT1L, CTNND2 and ASTN2. 37 To confirm the association of these rare CNVs a large cohort of samples is needed.…”