Copy number variations of chromosome 16p13.1 region associated with schizophrenia

Abstract

Deletions and reciprocal duplications of the chromosome 16p13.1 region have recently been reported in several cases of autism and mental retardation (MR). As genomic copy number variants found in these two disorders may also associate with schizophrenia, we examined 4345 schizophrenia patients and 35 079 controls from 8 European populations for duplications and deletions at the 16p13.1 locus, using microarray data. We found a threefold excess of duplications and deletions in schizophrenia cases compared with controls, with duplications present in 0.30% of cases versus 0.09% of controls (P = 0.007) and deletions in 0.12 % of cases and 0.04% of controls (P > 0.05). The region can be divided into three intervals defined by flanking low copy repeats. Duplications spanning intervals I and II showed the most significant (P = 0.00010) association with schizophrenia. The age of onset in duplication and deletion carriers among cases ranged from 12 to 35 years, and the majority were males with a family history of psychiatric disorders. In a single Icelandic family, a duplication spanning intervals I and II was present in two cases of schizophrenia, and individual cases of alcoholism, attention deficit hyperactivity disorder and dyslexia. Candidate genes in the region include NTAN1 and NDE1. We conclude that duplications and perhaps also deletions of chromosome 16p13.1, previously reported to be associated with autism and MR, also confer risk of schizophrenia.

Phenotypic manifestations of copy number variation in chromosome 16p13.11

“…21 Interestingly, the duplications have also been associated with autism, cognitive impairment 17 and schizophrenia. 23,24,30 These data combined with the findings reported in this study suggest that the duplication of the region is indeed pathogenic though the penetrance is clearly incomplete. Although the small sample size and variable expressivity preclude the definitive correlation of the size and extent of the duplication with the neuro-cognitive phenotype, we observed that all patients with duplication extending centromeric to interval II (patients 6, 7, 8 and 10) had language or motor delays along with ADHD and behavioral abnormalities while only two of the five patients (patients 4 and 9) with proximal breakpoints within interval II presented with neurocognitive issues.…”

“…The fact that region of 16p13.11 centromeric to interval II is gene poor and that significant neuropsychiatric manifestations have been previously documented with duplications involving intervals I and II imply that this is the critical region responsible for these features. 14,17,23 Ullman et al 17 had previously hypothesized that duplications that are paternally transmitted are benign while the maternal transmission leads to clinical manifestations. However, there are no known or predicted imprinted genes in the region (http://www.geneimprint.com/site/genes-by-species).…”

“…14,17 Whereas the deletions have been associated with epilepsy [18][19][20] multiple congenital anomalies and cognitive impairment, 14,17 duplications have been implicated in autism spectrum disorders, intellectual disability 10,17,21,22 and schizophrenia. 23,24 The phenotypes associated with CNVs of 16p13.11 are not consistent and both deletions and duplications of the region have been observed in 'phenotypically normal' individuals. 14,17 The inconsistencies in clinical presentations and the presence of the rearrangement in unaffected relatives may be due to factors, such as incomplete penetrance, variable expressivity, failure to recognize subtle manifestations or imprinting.…”

Ohnologs are overrepresented in pathogenic copy number mutations

“…S1). One ohnolog, MYH11, is thought to carry the risk of developing aortic dissection in patients with 16p13.11 duplications (44), whereas NDE1, also an ohnolog, is the strongest candidate for neurodevelopmental phenotypes associated with CNVs at this locus (45,46). Two other ohnologs within the critical region, ABCC1 and ABCC6, encode the multidrug resistance-associated proteins 1 and 6.…”

Genetic studies of schizophrenia: an update

“…As a result, CNVs can change the dosage of one or more genes in the regions covered affects the NRXN1 gene [35][36][37][38][39][40][41][42] , and 7p36.3 dup only affects the VIPR2 gene [38,43,44] . CNVs that alter the expression of multiple genes include 1q21.1 del/dup (34 genes) [36][37][38][39]41,[45][46][47] , 3q29del/dup (21 genes) [38][39][40]44,48,49] , 15q13.3del (12 genes) [38,39,44,46,47,49] , 16p13.1dup (11 genes) [40,41,50,51] , and 22q11.2del/dup (53 genes) [38,39,44,46,47,[51][52][53][54][55][56] , etc. (see Table 2 for more details).…”