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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.

SUBMITTER: Ingason A

PROVIDER: S-EPMC3330746 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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

Ingason A A Rujescu D D Cichon S S Sigurdsson E E Sigmundsson T T Pietiläinen O P H OP Buizer-Voskamp J E JE Strengman E E Francks C C Muglia P P Gylfason A A Gustafsson O O Olason P I PI Steinberg S S Hansen T T Jakobsen K D KD Rasmussen H B HB Giegling I I Möller H-J HJ Hartmann A A Crombie C C Fraser G G Walker N N Lonnqvist J J Suvisaari J J Tuulio-Henriksson A A Bramon E E Kiemeney L A LA Franke B B Murray R R Vassos E E Toulopoulou T T Mühleisen T W TW Tosato S S Ruggeri M M Djurovic S S Andreassen O A OA Zhang Z Z Werge T T Ophoff R A RA Rietschel M M Nöthen M M MM Petursson H H Stefansson H H Peltonen L L Collier D D Stefansson K K St Clair D M DM

Molecular psychiatry 20090929 1

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 ...[more]

PMID: 19786961

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Project description:Schizophrenia is a common mental disorder with high heritability and strong genetic heterogeneity. Common disease-common variants hypothesis predicts that schizophrenia is attributable in part to common genetic variants. However, recent studies have clearly demonstrated that copy number variations (CNVs) also play pivotal roles in schizophrenia susceptibility and explain a proportion of missing heritability. Though numerous CNVs have been identified, many of the regions affected by CNVs show poor overlapping among different studies, and it is not known whether the genes disrupted by CNVs contribute to the risk of schizophrenia. By using cumulative scoring, we systematically prioritized the genes affected by CNVs in schizophrenia. We identified 8 top genes that are frequently disrupted by CNVs, including NRXN1, CHRNA7, BCL9, CYFIP1, GJA8, NDE1, SNAP29, and GJA5. Integration of genes affected by CNVs with known schizophrenia susceptibility genes (from previous genetic linkage and association studies) reveals that many genes disrupted by CNVs are also associated with schizophrenia. Further protein-protein interaction (PPI) analysis indicates that protein products of genes affected by CNVs frequently interact with known schizophrenia-associated proteins. Finally, systematic integration of CNVs prioritization data with genetic association and PPI data identifies key schizophrenia candidate genes. Our results provide a global overview of genes impacted by CNVs in schizophrenia and reveal a densely interconnected molecular network of de novo CNVs in schizophrenia. Though the prioritized top genes represent promising schizophrenia risk genes, further work with different prioritization methods and independent samples is needed to confirm these findings. Nevertheless, the identified key candidate genes may have important roles in the pathogenesis of schizophrenia, and further functional characterization of these genes may provide pivotal targets for future therapeutics and diagnostics.

Dataset Information

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

Publications

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

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