Microduplications of 16p11.2 are Associated with Schizophrenia

Nature Genetics (Impact Factor: 29.35). 11/2009; 41(11):1223-7. DOI: 10.1038/ng.474
Source: PubMed


Recurrent microdeletions and microduplications of a 600-kb genomic region of chromosome 16p11.2 have been implicated in childhood-onset developmental disorders. We report the association of 16p11.2 microduplications with schizophrenia in two large cohorts. The microduplication was detected in 12/1,906 (0.63%) cases and 1/3,971 (0.03%) controls (P = 1.2 x 10(-5), OR = 25.8) from the initial cohort, and in 9/2,645 (0.34%) cases and 1/2,420 (0.04%) controls (P = 0.022, OR = 8.3) of the replication cohort. The 16p11.2 microduplication was associated with a 14.5-fold increased risk of schizophrenia (95% CI (3.3, 62)) in the combined sample. A meta-analysis of datasets for multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia (P = 4.8 x 10(-7)), bipolar disorder (P = 0.017) and autism (P = 1.9 x 10(-7)). In contrast, the reciprocal microdeletion was associated only with autism and developmental disorders (P = 2.3 x 10(-13)). Head circumference was larger in patients with the microdeletion than in patients with the microduplication (P = 0.0007).

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Available from: Francis J Mcmahon, Oct 07, 2015
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    • "deletion (Golzio et al., 2012). Importantly, these phenotypes in the fish are capturing the mirror phenotypes of humans (McCarthy et al., 2009). Given this strong functional evidence, we focused on investigating the interaction pattern of KCTD13 across four spatiotemporal networks. "
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    ABSTRACT: The psychiatric disorders autism and schizophrenia have a strong genetic component, and copy number variants (CNVs) are firmly implicated. Recurrent deletions and duplications of chromosome 16p11.2 confer a high risk for both diseases, but the pathways disrupted by this CNV are poorly defined. Here we investigate the dynamics of the 16p11.2 network by integrating physical interactions of 16p11.2 proteins with spatiotemporal gene expression from the developing human brain. We observe profound changes in protein interaction networks throughout different stages of brain development and/or in different brain regions. We identify the late mid-fetal period of cortical development as most critical for establishing the connectivity of 16p11.2 proteins with their co-expressed partners. Furthermore, our results suggest that the regulation of the KCTD13-Cul3-RhoA pathway in layer 4 of the inner cortical plate is crucial for controlling brain size and connectivity and that its dysregulation by de novo mutations may be a potential determinant of 16p11.2 CNV deletion and duplication phenotypes. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 02/2015; 85(4):742-54. DOI:10.1016/j.neuron.2015.01.010 · 15.05 Impact Factor
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    • "Newly found CNV's associated with schizophrenia now include duplications within the neuropeptide receptor gene VIPR2 (Vacic et al., 2011) and CNVs of the 16p11.2 region (Guha et al., 2013; McCarthy et al., 2009). Due to the rarity of such CNVs, very large cohorts are required for detecting their association with illness. "
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    ABSTRACT: The 4th Schizophrenia International Research Society Conference was held in Florence, Italy, April 5–9, 2014 and this year had as its emphasis, “Fostering Collaboration in Schizophrenia Research”. Student travel awardees served as rapporteurs for each oral session, summarized the important contributions of each session and then each report was integrated into a final summary of data discussed at the entire conference by topic. It is hoped that by combining data from different presentations, patterns of interest will emerge and thus lead to new progress for the future.In addition, the following report provides an overview of the conference for those who were present, but could not participate in all sessions, and those who did not have the opportunity to attend, but who would be interested in an update on current investigations ongoing in the field of schizophrenia research.
    Schizophrenia Research 10/2014; DOI:10.1016/j.schres.2014.08.032 · 3.92 Impact Factor
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    • "on a kinase located on chromosome 16p11.2, a gene susceptibility locus for autism and schizophrenia (Weiss et al., 2008; McCarthy et al., 2009). Genetic risk for schizophrenia is associated with the JNK pathway (Winchester et al., 2012), and the interleukin- 1 receptor accessory protein like-1 gene, implicated in monogenic forms of mental retardation and autism, signals through JNK (Pavlowsky et al., 2010). "
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    ABSTRACT: Genetic anomalies on the JNK pathway confer susceptibility to autism spectrum disorders, schizophrenia, and intellectual disability. The mechanism whereby a gain or loss of function in JNK signaling predisposes to these prevalent dendrite disorders, with associated motor dysfunction, remains unclear. Here we find that JNK1 regulates the dendritic field of L2/3 and L5 pyramidal neurons of the mouse motor cortex (M1), the main excitatory pathway controlling voluntary movement. In Jnk1-/- mice, basal dendrite branching of L5 pyramidal neurons is increased in M1, as is cell soma size, whereas in L2/3, dendritic arborization is decreased. We show that JNK1 phosphorylates rat HMW-MAP2 on T1619, T1622, and T1625 (Uniprot P15146) corresponding to mouse T1617, T1620, T1623, to create a binding motif, that is critical for MAP2 interaction with and stabilization of microtubules, and dendrite growth control. Targeted expression in M1 of GFP-HMW-MAP2 that is pseudo-phosphorylated on T1619, T1622, and T1625 increases dendrite complexity in L2/3 indicating that JNK1 phosphorylation of HMW-MAP2 regulates the dendritic field. Consistent with the morphological changes observed in L2/3 and L5, Jnk1-/- mice exhibit deficits in limb placement and motor coordination, while stride length is reduced in older animals. In summary, JNK1 phosphorylates HMW-MAP2 to increase its stabilization of microtubules while at the same time controlling dendritic fields in the main excitatory pathway of M1. Moreover, JNK1 contributes to normal functioning of fine motor coordination. We report for the first time, a quantitative Sholl analysis of dendrite architecture, and of motor behavior in Jnk1-/- mice. Our results illustrate the molecular and behavioral consequences of interrupted JNK1 signaling and provide new ground for mechanistic understanding of those prevalent neuropyschiatric disorders where genetic disruption of the JNK pathway is central.
    Frontiers in Cellular Neuroscience 09/2014; 8:272. DOI:10.3389/fncel.2014.00272 · 4.29 Impact Factor
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